text:
What was the Treaty of Frankfurt?
The Treaty of Frankfurt ended the Franco-Prussian war and marked the entry of a newly unified Germany which was dominated by the empires of England and France for a long time.… This treaty made France pay them an indemnity of 5 billion Francs and kept an army in France until it had been paid. Because of this, France surrendered Strasburg, Alsace and part of Lorraine to Bismark. (MORE)


text:
Click Here For FREE Info On Getting Started With Clickbank
Clickbank is a website that allows vendors to process payments online. It has an embedded affiliate program. This allows vendors to combine online payment processing with affiliate sales. The vendors on Clickbank sell products such as software and e-books through affiliates.
Why Choose Clickbank?
There are many reasons why vendors opt for Clickbank. One of the main reasons for the popularity of this online payment processing company is that it allows vendors an access to a huge marketplace. Not only that, vendors can get listed for free in the marketplace of their choice. The financial transactions and processing of payment online are automated, reducing human error and making transaction easier. Transactions can be made through credit cards as well as Paypal. Affiliates can be created almost instantaneously, and this is one of the major reasons for the popularity of Clickbank. Not only this, vendors can keep track of all transactions and campaigns through detailed reports. Payment checks are mailed to affiliates twice in thirty days. In fact affiliates earn a lot through commissions and selling of many kinds of products online.
Getting Started
If you wish to be a Clickbank affiliate, you need to sign up for their affiliate program. Register yourself at the site, and you will be sent a confirmation email. Once you are confirmed, you can start promoting Clickbank products.
Promoting Products
There are many ways by which you can promote the products of Clickbank. Seasoned affiliates create websites that promote Clickbank products. While you can earn more through this, you need to know the basics of Search Engine Optimization for this to work. Building profits this way can take some time.....read more
Tuesday, March 25, 2008
How To Get Started With Clickbank
Click Here For FREE Info On Getting Started With Clickbank

subset: commoncrawl


text:
Chamber Concerned at Fair Pay Agreements Proposal
5 June 2018
Fair Pay Agreements are a cause of concern for the business community, says Canterbury Employers' Chamber of Commerce CEO Leeann Watson.
"We are heartened that Business NZ are part of the working group announced today to flesh out the policy, but we are not supportive of a national award type employment regime in New Zealand," said Ms Watson.
"We are therefore disappointed the working group terms of reference do not include whether such a system is necessary. The concept of nationwide employment agreements setting minimum pay and conditions for entire industries or occupations is particularly concerning for small employers who may not be able to absorb costs their larger competitors can."
"It also removes the flexibility in the New Zealand employment relations environment. Under the proposal employers and workers can't negotiate their own conditions – unless they are above the Fair Pay Agreement rates. That's where industrial tension could become an issue – while you can't strike for an FPA, you could strike to get your own rates above the FPA rate, as we saw in the 1970s and 80s in New Zealand."
"This is an employment model we have not seen in New Zealand for a generation – and we are unconvinced of the benefits of re-introducing it," said Ms Watson.
The Chamber will be actively engaged with the working group process and will continue to work with the Government to ensure the outcomes are positive for all New Zealanders.
"We hope the working group will be open to all feedback and consider the modern New Zealand working environment and the future of work. However, we remain opposed to the concept of national awards," says Leeann Watson.


text:
Winsock 10055 Error Fix
Yes No Additional feedback? 1500 characters remaining Submit Skip this Thank you! WSAECONNRESET 10054 Connection reset by peer. The application has tried to determine the status of an overlapped operation which is not yet completed. Do the base stations drop the socket after each update? http://isusaa.org/socket-error/winsock-10055-error.php
This error is returned if an incorrect protocol is explicitly requested in the socket call, or if an address of the wrong family is used for a socket, for example, in Thanks gplana and satsumo, great info and advice. VBA Visual Basic Classic MS Office Programming Introduction to C++: Functions - Using Default Arguments Video by: Ian The viewer will learn how to user default arguments when defining functions. An invalid FILTERSPEC was found in the QoS provider-specific buffer. https://support.microsoft.com/en-us/kb/905628
Socket Error 10054
A completion indication will be given later when the operation has been completed. WSA_QOS_EPROVSPECBUF 11018 Invalid QoS provider buffer. WSA_NOT_ENOUGH_MEMORY 8 Insufficient memory available. Well i have looked around for some good info for the API, but struggling to find much relatively recent documentation.
- Is there anything I can do short of a re-format.
- This article will explain how to install it so it will work regardless of the Office version installed.
- Searched the forum - bunch of socket issues but not this one.
- Regards. 0 Message Author Comment by:OldVB6 ID: 359106172011-06-05 Thanks for the comment, hadn't come across anything that explained the difference between design and runtime creation.
- These conditions are more likely to be indicated by the error WSAETIMEDOUT.
The file handle supplied is not valid. WSAEDQUOT 10069 Disk quota exceeded. The support for the specified socket type does not exist in this address family. Socket Error 10049 If you need any assistance while following the steps, you can contact our 24×7 Technical Support.
the winsock fix I suggested above?http://downloads.subratam.org/WinsockFix.zipDownload, unzip, run and reboot.If that doesn't do it, try it the hard way:http://support.earthlink.net/mu/1/psc/img/walkthroughs/windows_9x_nt/dialers/dun_1.2/1039.how.to.randr.tcp-ip.psc.htmlZee Flag Permalink This was helpful (0) Collapse - Low on resources? What Is A Socket Error Winsock Error 10055) and your email address into the form below and an I.T. System hangs from time to time. http://serverfault.com/questions/399311/what-causes-winsock-10055-errors-how-should-i-troubleshoot Or is this a registry hack?
Each implementation may have a maximum number of socket handles available, either globally, per process, or per thread. Socket Error 10054 Connection Reset By Peer Will just have to keep experimenting, will be looking closer at the class module api calls and see if I can purge the buffer manually...... 0 Message Accepted Solution by:OldVB6 Sorry to be dense. In some instances, it also refers to the current state of the socket—for instance, calling accept on a socket that is not listening.
What Is A Socket Error
WSAEFAULT 10014 Bad address. Patch for 1713 Error Fix Error 10061 Connection Refused. Socket Error 10054 WSAEADDRINUSE 10048 Address already in use. Socket Error 10053 It is normal for WSAEWOULDBLOCK to be reported as the result from calling connect on a nonblocking SOCK_STREAM socket, since some time must elapse for the connection to be established.
how_to/10055.txt · Last modified: 2015/09/23 13:46 (external edit) Page Tools Show pagesourceOld revisionsBacklinksBack to top his comment is here winsock error 10055 Discussion in 'Earlier Versions of Windows' started by dukie, Sep 29, 2003. There are no other winsocks on the box. A general QoS error. Socket Error 10038
Can indicate a service provider implementation error. All rights reserved. So after much pain I have managed a work around. this contact form There also appears to be a PoolUsageMaximum value that controls when the memory manager starts to trim processes which may default to 80%.
Join the community of 500,000 technology professionals and ask your questions. Socket Error 11004 Some error codes defined in the Winsock2.h header file are not returned from any function. A socket operation failed because the destination host is down.
Flag Permalink This was helpful (0) Collapse - Didn't work by buzzkutt1 / April 18, 2005 12:29 AM PDT In reply to: okay...firefox uses winsock...
An invalid policy object was found in the QoS provider-specific buffer. WSAELOOP 10062 Cannot translate name. Join & Write a Comment Already a member? Socket Error Codes Linux The following tools can be used for troubleshooting and fixing Winsock errors.
Are you looking for the solution to your computer problem? windows-server-2003 share|improve this question edited Jun 27 '12 at 14:54 asked Jun 15 '12 at 22:52 Tom Kerr 7617 I'd say that the NIC or driver could contribute to WSA_QOS_ESDMODEOBJ 11029 Invalid QoS shape discard mode object. http://isusaa.org/socket-error/winsock-error-10051.php This is the first lesson in a 3-part series that uses code to loop through an Excel spreadsheet in VBA and then fix errors, taking advantage of error handling code.
But the scope of this project requires a status update every <20 secs, which basically means a continuous connection. Once reported, our moderators will be notified and the post will be reviewed. An operation on a socket could not be performed because the system lacked sufficient buffer space or because a queue was full. Could that be something to do with this problem? 0 Message Author Comment by:OldVB6 ID: 359300022011-06-08 The data received is of varying lengths, the code always retrieves all data in
Cheers OldVB6 0 Message Author Closing Comment by:OldVB6 ID: 359942572011-06-13 Issue was in a third party control, the experts help was great, but ultimately it was resolved without a specific Usually this occurs when a socket descriptor to a socket that cannot support this operation is trying to accept a connection on a datagram socket. The paged and nonpaged pools are areas of memory for certain Windows kernel-mode allocations such as the Windows kernel itself (e.g. WSAENETDOWN 10050 Network is down.
A result of Schützenberger "adjective" or "noun" for answering the question word "What" Are there any lawyers mentioned in Harry Potter? Login. I hope someone is familiar with this. The requested protocol has not been configured into the system, or no implementation for it exists.
We appreciate your feedback. Advertisements do not imply our endorsement of that product or service. 2.5 Share?Profiles ▼Communities ▼Apps ▼ Blogs My Blogs Public Blogs My Updates Kevin Grigorenko's IBM WebSphere SWAT Blog Log in When you finish using a socket, do you close it ? 0 Message Author Comment by:OldVB6 ID: 359110082011-06-05 Well this is an issue, the hardware I am interfacing with will WSAEPROTONOSUPPORT 10043 Protocol not supported.


text:
Montelukast Added to Budesonide in Children with Persistent Asthma: a Randomized, Sdouble-Blind, Crossover Study
Purpose of the Study. The possible additive effects of leukotriene antagonists and inhaled corticosteroids have not been studied in children. This study sought to determine whether the addition of montelukast to budesonide would improve asthma control in children with inhaled glucocorticoid-dependent persistent asthma.
Study Population. A total of 279 children with asthma with persistent asthma on inhaled corticosteroid therapy.
Methods. This was a multicenter, randomized, double-blind, crossover study. After a 1-month run-in on budesonide 200 μg twice daily, children were randomized to receive montelukast 5 mg daily or placebo over the next 4 weeks, after which they were crossed-over to the opposite treatment for the next 4 weeks.
Results. The mean age was 10.4 ± 2.2 years, the mean forced expiratory volume in 1 second (FEV1) was 77.7% ± 10.6% predicted, and reversibility was 18.1% ± 12.9%. Compared with adding placebo to budesonide, adding montelukast produced significant improvements in the mean percent change from baseline FEV1 (P = .062 [P = .010 for per-protocol analysis]), mean absolute change from baseline FEV1 (P = .040), mean increase from baseline in morning (P = .023) and evening (P = .012) peak expiratory flows, decrease in exacerbation days by approximately 23% (P < .001), decreased β2-agonist use (P = .013), and reduced blood eosinophil counts (P < .001). There were no significant differences with regard to safety.
Conclusion. The addition of montelukast to budesonide improved asthma control significantly, with improvements in lung function, symptoms, and the need for rescue medication.
Reviewer's Comments. Although a relatively short-term study, the data provided here clearly support the additive effect of montelukast and budesonide. This may allow for the use of lower steroid doses to achieve the same level of asthma control.
- Simons FE, Villa JR, Lee BW, et al. J Pediatr.2001;138 :694– 698
- Copyright © 2002 by the American Academy of Pediatrics


text:
News – Wet 2 and Naughty Bear 2 Announced
November 8, 2010 by Simon Wigham
Filed under News
Behaviour Interactive (formerly known as Artificial Mind and Movement) has confirmed that it's working on sequels to both Wet and Naughty Bear.
Save for their existence, nothing is known about the games. But Wet 2 will probably offer even more of the slick, OTT action of the original, whilst Naughty Bear 2 should be the same somewhat disturbing mixture of teddy bears and murder, but hopefully a bit less average this time around.
The developer is still seeking a publishing deal for the games, so no release date is currently known for either.


text:
I was recently asked on Twitter by a friend how I managed to start up my game and get it working, as he has had an idea for a game for a while. Although I would like this to be a sort of tutorial on how to start making a game, I wouldn't have a clue where to start describing what I did, but I got it to work.
To be honest, I have tried to create several games over the years, but there are two main titles that I am working on again. More to come later on? No ideas, stay tuned for that, folks.
I started with an idea. Everyone does, and this point is so simple it doesn't need explaining. If you don't have an idea, watch television, read a book, play another game, sit in a dark room with a six-pack of beer and a notepad until you have an idea – just do whatever gets those creative juices flowing.
Think about that idea for a while. How does the idea sit in your head? How many players is this game for? What is the game about? How would you win, or how would you lose?
Once you have the basic premise of the game set, think about how it would play. Is there an order of turns? Do players move? How do they move? How are their characters/items utilised? Can they work strategically, is it luck or do you make the rules and they dance to the tune you play?
You also need to consider what your skills are, and what tools are available to you. If you are some sort of modern genius, you could probably code your own game, bang it onto Steam under the Indie section and make a tidy fortune (fortune making is not guaranteed). If you are like me, you may be stuck using unusual game creating software. I made all of my own artwork with a variety of auto-shapes and shading options in Microsoft Word – as mine works out as a card game, each card would have easily had between sixty and eighty auto-shapes, possibly more, each placed precisely using the CTRL/Shift buttons to manoeuvre.
If you have even less tools, such as just a pen and paper, then I'm not sure how you are reading this article, but clearly you are very inventive. Use that!
What I did at this stage was decide how they would move, and then work out attacks and defenses and general play. This part is pretty important, but don't expect it to be staying this way permanently – you will tweak this many times as you work towards finishing your project.
So, you have the premise of the game and how it is played, and have a vague idea on the rules or boundaries of your game. Now begins the arduous slog, I'm afraid. Creating all of the different part in your game should be fun, yes, but it is more work than you might imagine. It is all about balancing out attacks, leaving and skills or special abilities open to allow players to form their own strategies, and designing every single part individually.
If you happen to know someone who is a real wiz at graphic design, or can hire one, work out the stats of the items on a spreadsheet and discuss with them what you would like doing.
All parts of the game will be tweaked to offer a variety of play styles. In my games, I like to offer a real sense of fair-play – everything that has one excellent stat will have an Achilles heel in another – it means that anyone could pick up the game and win, with the only advantage being more strategic.
So, a quick checklist of what you will need to have done:
· Ideas! Have one.
· Tools! Assess what you have, how well you can use what you have, and how you can begin building your game. Remember, work out the details before building. A good carpenter will measure twice and cut once, and building a game should be the same (changes can be made during the build, but just get as much down for this draft as you can!)
· Rules! What are the parameters of your game? A basic list of things a player cannot do and things that they are encouraged to do will help form the rest of the rules later on.
· Content! A long list of items or a select few, you will need to have something that the game revolves around, the breakdown of your idea. Remember, everybody loves customisation and personalisation, as well as Raymond.
· Tweak! Make the game fair. Or unfair if you like, it's your game. Make it play the way you want it to. This can take some time, so gather a few good friends and take it for a spin. They might even be able to contribute to your goal, which would be lovely. Make sure they are good friends, or they might pinch your idea, which wouldn't be lovely. Rules and ideas will brainstorm quickly here, so keep a notepad handy.
And that should be it. Even at this point, don't expect to put a pricing sticker on it, it will most likely need polishing up, content added and further testing, but do be realistic and do not be a perfectionist; there is a reason why my game has never been finished. Set a calendar date that it should be ready by, and stick to it as closely as you can.
And that's it. Pretty good advice from someone who has never published their own game. Talking about your idea helps keep it alive, and this I can guarantee. I have started probably five different games since I was fourteen, two of which I'm looking to make into fully fledged games.
But, until then, there is always the polishing…


text:
mizo bible free download
Related searches
Mizo Bible Free Downloadat Software Informer
The Amplified Bible provides a new experience to understanding the Bible.
The Amplified Bible is a translation
49 user rating
4 Word Of God Ministries 17 Freeware
This Tamil Bible module for e-Sword Bible Software is completely free of cost.
More Mizo Bible Free Download
Mizo Bible Free Download in introduction
10 Logos Bible Software 2,475 Freeware
A very comprehensive free program to read and study the Bible.
5 Digital Catholic Bible Development Team 422 Freeware
Gives you access to the digital form for the Old and New Testaments.
7 Olive Tree Bible Software 23 Freeware
Read and study different Bible versions and other texts with this program.
1 Bible Explorer 2 Proprietary
Search for the definition of words and names appearing in the Bible.
Phil Stone - Bible Time Press 1 Freeware
An interpretation of the Bible times extrapolated to modernity.
1 Bible Believers Fellowship, Inc. 72 Shareware
Simple but beautiful screensaver featuring good photos and Bible verses.
Additional titles, containing mizo bible free download
Laridian 1 Commercial
Bible Maps has 13 Bible maps which covers almost all major places in Bible.
14 Larry Pierce 1,656 Shareware
Online Bible is a powerful, comprehensive Bible research software.
4 Laridian 2 Commercial
NKJV is a pocket Bible available with the Pocket Bible Program.
1 John Theodore Kiapos 229 Freeware
Let your computer read the Bible for you with Bible Reader.
2 BibleMapper.com 93 Shareware
Bible Mapper is a fully interactive, highly accurate Bible mapping system.
2 MoNooN 86 Freeware
MoNooN Bible Reader is the software that enables that you read the Bible.
5 StudyLamp Software 468 Shareware
Daily Bible is a application for personal devotion, prayer, and Bible reading.
7 Philippine Bible Society. 311 Commercial
The Electronic Filipino Bible (E-Bible) contains 20 versions and translations.
11 Youthim 120
5 Xixxy 263
Mizotec Software Solutions
Articles of interest› All articles


text: Chris had quite a few cosmetic ops lined up for today, so he actually put in a day's leave from his government job. I thought it was Zoe's last swimming lesson today which means that visitors are welcome to come and watch. Chris used to take Zoe swimming, when she still did lessons with a parent in the pool with her. As from the start of this term though, she has started to swim in a small group of 4/5 children and the teacher and we don't watch her except for the last 5 minutes of the lesson. She goes twice a week and my mom and I take her alternately so Chris hasn't seen her swim for ages. He actually had a break between his morning and afternoon lists and was all set to come and watch. Zoe was very excited that he was going to be there but then a trauma case cropped up and it was going to be very touch and go if he was going to make it. I then asked Zoe if it was okay if Nana came and watched but she said that she wanted Grandpa there. My dad is always hectically busy at work but I phoned him anyway and he said he'd definitely be there. As we arrive at swimming, there is my dad and Chris both waiting for us. Zoe was beside herself with excitement. Only problem, it wasn't the last lesson and so not visitors day!!!! Bummer, I felt so bad as somehow between my mom and I, we got it a bit mixed up. They did let them watch, although it is rather distracting for the children. Zoe is doing very well but she is very much in her own little world and doesn't seem to focus very well – definitely doesn't get that from me!!!! Her "crawl"/freestyle wasn't great but she swam a whole width of breast stroke on her own. Quite scary how quickly they grow up and become independent.


text:
Vicoprofen - Consumer Medicine Information
|United States
|Narcotic analgesic combinations
|Hydrocodone, Ibuprofen, colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, propylene glycol and titanium dioxide.
What is the Most Important Information I Should Know About Medicines Called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.
This chance increases:
- with longer use of NSAID medicines
- in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:
- can happen without warning symptoms
- may cause death
The chance of a person getting an ulcer or bleeding increases with:
- taking medicines called "corticosteroids" and "anticoagulants"
- longer use
- smoking
- drinking alcohol
- older age
- having poor health
NSAID medicines should only be used:
- exactly as prescribed
- at the lowest dose possible for your treatment
- for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
- different types of arthritis
- menstrual cramps and other types of short-term pain
Who Should not Take a Non-Steroidal Anti-Inflammatory Drug (NSAID)
Do not take an NSAID medicine:
- if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
- for pain right before or after heart bypass surgery
Tell your healthcare provider:
- about all your medical conditions.
- about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
- if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
- if you are breastfeeding. Talk to your doctor.
What are the Possible Side Effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
|Serious side effects include:
|Other side effects include:
Get emergency help right away if you have any of the following symptoms:
- shortness of breath or trouble breathing
- slurred speech
- chest pain
- swelling of the face or throat
- weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms
- nausea
- there is blood in your bowel movement or it is black and sticky like tar
- more tired or weaker than usual
- unusual weight gain
- itching
- skin rash or blisters with fever
- your skin or eyes look yellow
- swelling of the arms and legs, hands and feet
- stomach pain
- flu-like symptoms
- vomit blood
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1–800–FDA-1088.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
- Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
- Some of these NSAID medicines are sold in lower doses without a prescription (over the counter). Talk to your healthcare provider before using over the counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
|Generic Name
|Cataflam, Voltaren, Arthrotec (combined with misoprostol)
|Lodine, Lodine XL
|Nalfon, Nalfon 200
|Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone)
|Indocin, Indocin SR, Indo-Lemmon, Indomethagan
|Mefenamic Acid
|Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)
|Tolectin, Tolectin DS, Tolectin 600
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.
Manufactured by Halo Pharmaceutical Inc.
Whippany, NJ 07981 U.S.A.
for AbbVie Inc.
North Chicago, IL 60064 U.S.A.


text:
Novel Role of Silent Information Regulator 1 in Myocardial Ischemia
Jump to
The incidence of cardiovascular diseases is increasing at an alarming rate throughout the world. According to the World Health Report 2010, cardiovascular disease accounts for 17.1 million global deaths per year, or 29% of total deaths worldwide. It is predicted that this number will increase to 23.6 million by 2030. Myocardial ischemia, which is reported to induce irreversible damage to the myocardium, causes a number of cardiovascular diseases, such as myocardial infarction, myocardial hypertrophy, atherosclerosis, and heart failure. Medical treatment that effectively prevents ischemic injury would alleviate the consequent development of cardiac remodeling and failure. Previous studies have indicated that ischemic preconditioning (IPC), caloric restriction, resveratrol preconditioning, and some related factors can prevent ischemic injury to the heart and are cardioprotective.1 The underlying mechanisms of these interventions appear to be controlled by a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase called silent information regulator 1 (SIRT1).
SIRT1 is a member of the class III group of histone deacetylases, collectively called sirtuins.2 The mammalian sirtuin family consists of 7 members, designated SIRT1 through SIRT7, which are characterized by a conserved 275-amino-acid catalytic core and unique additional N-terminal and C-terminal sequences of variable length.3 Previous studies have shown that SIRT1 can deacetylate many transcription factors, including forkhead box O (FOXO) transcription factors, p53, nuclear factor-κB (NF-κB), liver X receptor, peroxisome proliferator–activated receptor γ, and brain and muscle Arnt-like protein 1, and nuclear coactivators, as well, including peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), cAMP-responsive element-binding protein–regulated transcription coactivator 2, and period homolog 2.4,5 SIRT1 also deacetylates serine/threonine kinase 11, endothelial nitric oxide synthase (eNOS), and histones H1, H3, and H4.2 It has been reported that SIRT1 performs a wide variety of functions in a variety of biological systems, including obesity-associated metabolic diseases, cancer, aging, cellular senescence, cardiac aging and stress, prion-mediated neurodegeneration, inflammation, and placental cell survival.5 Most importantly, SIRT1 is involved in cardioprotection.
Several studies suggest that SIRT1 plays a role in myocardial ischemia. Pillai and colleagues6 found that SIRT1 was involved in the effect of fructose feeding on myosin heavy chain (MHC) gene expression and cardiac protection. Additionally, the localization of SIRT1 has been reported to change during cardiac development and under stress conditions.7 Moreover, Sciarretta and colleagues8 have reported that SIRT1 plays a role in the cardiac autophagy signaling pathway. In these mechanisms, SIRT1 is controlled by several upstream molecules, such as fructose, Longevinex, nicotinamide phosphoribosyltransferase (Nampt), and microRNA (MIR)-199a. Meanwhile, SIRT1 regulates many downstream factors, including the α-MHC gene promoter, FOXOs, hypoxia-inducible factor (HIF)-1α, PGC-1α, mitogen-activated protein kinase, NF-κB, eNOS, and p53. These results indicate that SIRT1 participates in cardioprotection via a complex signaling network.
The focus of this review is to summarize the latest progress regarding the protective effects of SIRT1 in myocardial ischemia. First, we discuss some important actions of SIRT1 in myocardial ischemia. We then introduce some upstream mediators of SIRT1 and some downstream signaling pathways. Furthermore, we highlight the role of SIRT1 in human heart diseases. Finally, we show several novel potential directions of SIRT1 studies. Collectively, the information compiled here will serve as a comprehensive reference for the actions of SIRT1 in the cardiovascular system identified to date and will hopefully aid in the design of further experimental research and increase the potential of SIRT1 as a therapeutic target in the future.
Role of SIRT1 in Myocardial Actions
Autophagy is a catabolic process whereby long-lived proteins in the cytosol and organelles are sequestered into double-membrane vesicles, termed autophagosomes, and transported to lysosomes for degradation.9–11 Autophagy occurs at basal conditions and mediates homeostatic functions in cells. However, autophagy is also induced by stress, such as nutrient starvation, hypoxia, endoplasmic reticulum stress, and oxidative stress.11 Autophagy is progressively activated in mice after 3 days of fasting, which is paralleled by a progressive decline in heart weight.12,13 Sciarretta and colleagues have found that fasting activates FOXO through SIRT1-mediated deacetylation, which in turn induces Rab7 expression, thereby stimulating autophagosome-lysosome fusion. The downregulation of FOXO1 or the suppression of FOXO1 deacetylation inhibits starvation-induced autophagy and promotes cardiac dysfunction during fasting.14 These results suggest that starvation-induced autophagy activated through the SIRT1-FOXO–dependent mechanism is adaptive for the heart and the cardiomyocytes therein and broadly support the hypothesis that, in response to ischemia and reperfusion, autophagy can maintain the energy status, protein quality control, and organelle function observed under better conditions.
Nucleocytoplasmic Shuttling
Nucleocytoplasmic shuttling of SIRT1 takes place in cardiomyocytes during stress and has a role in cardioprotection. SIRT1 is expressed in all mammalian cells and was originally identified as a nuclear protein.15 However, recent studies have shown that the subcellular localization of SIRT1 differs from cell to cell. Although some cells show nuclear localization of SIRT1, others express it either both in the nucleus and the cytoplasm or in the cytoplasm alone.
In the heart, the nuclear and cytoplasmic localization of SIRT1 was found to be regulated developmentally and during stress conditions.16 In the mouse embryonic heart at embryonic day (E) 10.5 and E12.5, when the 4-chambered heart appears, a high level of SIRT1 has been found in the nucleus of myocytes in both the atria and ventricles. SIRT1 expression in the heart further declines with organogenesis. At E16.5, SIRT1 levels in the heart are 21% of E12.5 levels, and after birth, they remain constant until 27 months of age. In the adult rodent heart, SIRT1 is localized primarily in the cytoplasm and moves to the nucleus during stress conditions. The nuclear localization of SIRT1 in cardiomyocytes was inhibited by the use of the phosphatidyl inositol 3-kinase inhibitor, LY294002, which also blocked Akt activation, thus suggesting a possible role for phosphatidyl inositol 3-kinase/Akt-mediated phosphorylation in the nuclear translocation of SIRT1.17 Likewise, the c-Jun N-terminal kinase 1–mediated phosphorylation of SIRT1 also promotes its translocation into the nucleus.18 SIRT1 nuclear translocation was found to be essential for its cytoprotective effects against oxidative stress through the activation of manganese superoxide dismutase (MnSOD),19 suggesting that phosphorylation-mediated shuttling in and out of the nucleus could be 1 mechanism by which SIRT1 activity is regulated. These studies also reported the presence of nuclear SIRT1 in different models of heart failure, including the failing hearts of TO-2 hamsters, post–myocardial infarction in rats, and dilated cardiomyopathy in human patients.17 Because the nuclear presence of SIRT1 is a feature of the fetal heart and SIRT1 is translocated to the nucleus under pathological conditions, it is intriguing to consider that the nuclear translocation of SIRT1 could have a role in ischemia/reperfusion (IR)–related cardiovascular disease.
α-MHC Expression
Pillai and colleagues found that SIRT1 might participate in the expression of α-MHC. Fructose feeding has been shown to induce cardiac α-MHC expression and protect the heart from IR-mediated cell injury. The study was designed to investigate the mechanism involved in the effect of this sugar on MHC gene expression and cardiac protection. Adult mice were fed a 6-propyl-2-thiouracil (PTU) diet or PTU combined with a fructose-rich diet. PTU treatment made animals hypothyroid, which resulted in the total replacement of cardiac α-MHC with the β-MHC isoform. The addition of fructose to the PTU diet led to a significant level of reexpression of the α-MHC isoform. A similar induction of α-MHC expression was also observed when the PTU diet was combined with resveratrol, an agonist of SIRT1 deacetylase. An analysis of the heart lysate of these animals indicated that fructose feeding augmented the NAD-to-NADH ratio and the cardiac SIRT1 levels, suggesting a role for SIRT1 in the fructose-mediated activation of the α-MHC isoform. To determine whether SIRT1 has a direct effect on MHC isoform expression, Pillai and colleagues also generated transgenic mice expressing SIRT1 in the heart. Treatment of these transgenic mice with the PTU diet did not lead to the disappearance of α-MHC, as it did in the nontransgenic animals. SIRT1 overexpression also activated the α-MHC gene promoter in transient transfection assays, thus, confirming a role of SIRT1 in the induction of α-MHC expression. α-MHC has high ATPase activity and accounts for a faster shortening velocity of cardiac myofibers, whereas β-MHC, having low ATPase activity, leads to greater economy of force generation.6 Previous studies conducted with transgenic mice and rabbits have indicated that α-MHC hearts have an advantage in stress conditions in comparison with hearts primarily expressing the β-MHC isoform.19,20 These studies have indicated that the induction of α-MHC expression in a failing heart may be beneficial in terms of increasing the myocardial contractility of a hemodynamically challenged heart, thus suggesting that SIRT1 may protect the heart from IR injury via the induction of α-MHC expression.
Myocardial Hypertrophy
SIRT1 has been confirmed as a key factor in myocardial hypertrophy. An initial study conducted with SIRT1 overexpression in cardiomyocytes showed that it protected cells from death in response to serum starvation, but, at the same time, it caused an overall increase in cardiomyocyte size.21 This study also showed that blocking SIRT1 activity with inhibitors increased the propensity of cardiomyocyte to die but prevented myocyte hypertrophy in response to stress stimuli, thus implying that SIRT1 promotes cardiomyocyte growth under stress conditions through cytoprotective effects. These observations are supported by other reports demonstrating increased SIRT1 levels in hypertrophied and failing hearts.22,23 Studies performed with a cardiac-specific SIRT1 transgenic mouse model showed that SIRT1 exhibits hormesis; depending on the magnitude of SIRT1 expression, it can be either beneficial or harmful. Low to moderate SIRT1 expression (2.5- to 7.5-fold over endogenous levels) was found to be protective against the age-dependent increase in cardiac hypertrophy, apoptosis, and cardiac dysfunction, whereas 12.5-fold SIRT1 overexpression induced dilatation, hypertrophy, and cardiac failure.24 A low level of SIRT1 overexpression was also shown to reduce infarct size and improve cardiac function in a mouse model of myocardial infarction.25 These observations strengthen the perception that SIRT1 is a progrowth and prosurvival molecule for cardiomyocytes, and, hence, its expression needs to be tightly controlled to obtain desirable effects. The study also showed that the SIRT1 homozygous knockout mice were more susceptible to cell death induced by IR injury.26 Sundaresan and colleagues7 demonstrated that whole-body SIRT1-knockout mice have smaller hearts than their wild-type littermates and are resistant to the development of cardiac hypertrophy induced by hypertrophic agonists. These mice also show reduced activation of the fetal gene program, a lack of cardiomyocyte hypertrophy, and impaired Akt-signaling following the infusion of hypertrophic agonists, thus suggesting that SIRT1 is needed for the induction of the cardiac hypertrophic program and implying that SIRT1 mediates compensated myocardial hypertrophy during IR.7
Upstream Mediators
Nicotinamide Phosphoribosyltransferase
Nampt is a rate-limiting enzyme in the mammalian NAD+ salvage pathway and has been proposed to be a functional equivalent of pyrazinamidase/nicotinamidase 1 in mammals.26 Nampt upregulation increases the cellular NAD+ level and enhances the transcriptional regulatory activity of the catalytic domain of SIRT1 in mouse fibroblasts.27 Because the histone deacetylase activity of SIRT1 is NAD+ dependent, Nampt downregulation causes SIRT1 suppression.
It has been reported that the action of SIRT1 in autophagy is mediated by Nampt. Recent evidence suggests that SIRT1 stimulates autophagy through the deacetylation of antithymocyte globulins in cancer cells.28 SIRT1 downregulation increased p62 accumulation, suggesting that it suppresses autophagic flux, thereby mimicking the effect of Nampt downregulation in cardiomyocytes. Furthermore, downregulation of both Nampt and SIRT1 did not show additive effects on the inhibition of autophagic flux, consistent with the notion that Nampt may inhibit autophagic flux through SIRT1 suppression. Further investigation is required to elucidate the role of SIRT1 in mediating the effect of Nampt downregulation on autophagy in cardiomyocytes. An electron transport chain present in lysosomes maintains a proton gradient at the expense of NADH.29 Decreases in NAD+ may directly inhibit the function of lysosomes, which may also contribute to the suppression of autophagy induced by Nampt downregulation.
One study reported that Nampt expression in the heart significantly reduced the size of a myocardial infarction after ischemia and IR, thus suggesting that Nampt has a protective function in the heart via SIRT1. Because the downregulation of endogenous Nampt after ischemia and IR is normalized in Tg-Nampt, the results suggest that Nampt downregulation has a causative role in mediating myocardial injury during ischemia or IR. Because Nampt downregulation decreases cellular ATP content, increases apoptosis, and inhibits autophagy, researchers speculate that all of these contribute to myocardial injury after IR. Reperfusion after prolonged ischemia causes a release of NAD+ from mitochondria through the mitochondrial permeability transition pore opening and the subsequent downregulation of NAD+,30 which would exacerbate myocardial damage by IR. Because the detrimental effects of Nampt downregulation in cardiomyocytes appear to be rescued by exogenously applied NAD+, increasing the cellular level of NAD+ by targeting Nampt may be a promising strategy to reduce IR injury. Increased Nampt provides protection against cell death and requires an intact mitochondrial NAD+ salvage pathway. These results demonstrate that Nampt is an important upstream factor of SIRT1 and accelerates cardioprotection during ischemic stress.
In addition, Nampt may exert cardioprotection via another signaling pathway. It has been demonstrated that the NADH/NAD ratio can regulate the expression of sulfonylurea receptor 2A, a KATP channel regulatory subunit.31 Researchers have found that the sole overexpression of the sulfonylurea receptor 2A protein generates a cardiac phenotype with more sarcolemmal KATP channels, which is essential for preconditioning-induced cardioprotection, thus, increasing resistance to hypoxia and ischemia.32–36 Therefore, it is possible that the sulfonylurea receptor 2A–mediated pathway that is regulated by Nampt acts assists in SIRT1-related cardioprotection.
The discovery of resveratrol stems from an interesting phenomenon. The population of France consumes foods high in saturated fats, yet experiences fewer cardiovascular pathologies. This is known as the French paradox and may be explained in part by their daily consumption of red wine.37 Resveratrol (3,5,40-trihydroxystilbene) is prominent in red wine, and it is an antioxidant that has been shown to have many beneficial effects and to function as a caloric restriction mimetic. Similar to caloric restriction, resveratrol can maintain mitochondrial integrity, reduce insulin-like growth factor-1, activate SIRT1, and increase the lifespan of organisms from yeast to mammals.38,39 Resveratrol also improves the outcome after ischemic episodes in the heart and brain40,41 and requires SIRT1 to mediate ischemic protection.42,43 Resveratrol-activated pathways have been shown to protect against ischemia by modulating excitotoxicity, mitochondrial functioning, blood vessel integrity, and nitric oxide signaling.41,44–46
The effect of the endogenous SIRT1 activation achieved by resveratrol treatment has been studied in different models of cardiac hypertrophy. Resveratrol treatment limits the phenylephrine-induced hypertrophic response of isolated cardiomyocyte cultures.47 Resveratrol also reduces fatty lesions, myocardium vacuolization, degeneration, and inflammation in mice on a high calorie diet.38 The prefeeding of rats for 14 days with resveratrol resulted in the protection of hearts from the deleterious effects of pressure overload–mediated cardiac hypertrophy.48 Likewise, resveratrol feeding improves cardiac function in diabetic mice.49 Further, the oral administration of resveratrol to TO-2 hamsters has been shown to suppress fibrosis, preserve cardiac function, and significantly improve survival.17 All these studies correlated the cardioprotective effects of resveratrol with its ability to activate SIRT1. Based on the data available to date, it appears that resveratrol treatment may be beneficial in the management of cardiac hypertrophy and cell death.
One significant action of resveratrol treatment under ischemic conditions is the mediation of inflammatory signaling pathways. Inflammation during IR causes the breakdown of the vascular endothelium, leading to increased membrane permeability and hemorrhage. Resveratrol has been reported to maintain blood vessel integrity after ischemic injury by modulating leukocyte activity and reducing the expression of inflammatory enzymes. For example, matrix metalloproteinase-9 is an endopeptidase expressed during ischemia that induces inflammatory signaling and leads to blood vessel degradation.50 A major source of matrix metalloproteinase-9 during ischemia is leukocytes,50,51 which bind to the endothelium, infiltrate the ischemic tissue, and initiate the inflammatory response. After myocardial ischemia, resveratrol has been shown to suppress molecules that mediate leukocyte adhesion, such as NF-κB,41 a major mediator of inflammatory signaling. It has been reported that NF-κB can be inhibited by SIRT1 deacetylation,52 which suggests that SIRT1 may have anti-inflammatory effects. Resveratrol has been further shown to protect coronary arterial endothelial cells against oxidative stress by activating nuclear factor-E2–related factor-2,53 a transcription factor that regulates the genes involved in antioxidant defense.
Resveratrol has been shown to strongly stimulate SIRT1 deacetylase activity in a dose-dependent manner by increasing its binding affinity to both the acetylated substrate and NAD+.39 Biochemical and structural modeling studies have shown that resveratrol binds directly to SIRT1, thereby inducing a conformational change in the SIRT1 protein configuration.54 However, recent research has suggested that resveratrol is not a direct activator of SIRT1. In vitro studies demonstrated that SIRT1 was activated by resveratrol when an artificial, fluorescent acetyl-peptide was used as a substrate for deacetylation. Otherwise, resveratrol was unable to activate SIRT1 when the same peptide substrate lacked the covalently linked fluorophore.55,56 These recent studies are highly controversial and do not exclude the possibility that SIRT1 is activated indirectly by resveratrol. For example, SIRT1 was shown to be phosphorylated on its carboxy-terminal end at serine 659 and serine 661 by the protein kinase creatine kinase 2,57 an enzyme that can be regulated by resveratrol.58 Similarly, other studies showed that sumoylation at lysine 73459 or JNK2 phosphorylation at serine 2760 increased SIRT1 protein deacetylase activity. No studies have yet observed resveratrol-mediated posttranslational modifications of SIRT1. However, resveratrol activates numerous pathways and could therefore modulate SIRT1 activity by regulating these signaling cascades.
Although resveratrol has been shown to possess diverse health benefits, several recent reports have demonstrated conflicting results on some aspects of its effects, including its antiaging properties. Considerable debate appears to exist on the dose and bioavailability of resveratrol, leading to the controversies on its effectiveness. To solve this problem, Mukherjee and colleagues61 designed a study with a resveratrol formulation that contained resveratrol supplemented with 5% quercetin and 5% rice bran phytate (commercially known as Longevinex). In their study, Longevinex-treated hearts, irrespective of the treatment duration, revealed superior cardiac performance, reduced infarct size, and the induction of survival signals, as evidenced by an increased B-cell lymphoma gene 2 (Bcl2)/Bax ratio and enhanced Akt phosphorylation. However, LC3-II and Beclin were significantly enhanced after 3 months of Longevinex treatment, suggesting that autophagy occurred only after feeding Longevinex to rats for a prolonged period of time. Corroborating the autophagy results, SIRT1 was significantly increased only after 3 months of Longevinex treatment, suggesting that enhanced SIRT1 expression correlated with the induction of autophagy. Additionally, Longevinex caused the phosphorylation and nuclear translocation of FOXO1, FOXO3a, and FOXO4, indicating the involvement of FOXOs in autophagy. Because SIRT1 and FOXOs are reliable markers of longevity, the results appear to suggest that Longevinex induces longevity after prolonged feeding via the induction of autophagy, whereas it converts death signals into survival signals and provides cardioprotection within a relatively shorter period. This research provides a novel target for decreasing IR injury by the use of Longevinex treatment.
Downstream Pathways
Forkhead Box O
One of the well-documented targets of SIRT1 in cardiomyocytes is FOXO. FOXO is the mammalian homolog of Daf16 and has been implicated in the SIRT1-mediated longevity of Caenorhabditis elegans.62 In mammals, there are 4 evolutionarily conserved FOXO family members, FOXO1, FOXO3, FOXO4, and FOXO6. They control various cellular processes such as cell cycle arrest, reactive oxygen species production, DNA repair, and apoptosis. SIRT1 regulates FOXO activity either positively or negatively depending on the target gene or cell type.63–65 SIRT1 deacetylates and activates FOXOs, which synthesize antioxidants, such as MnSOD and catalase, thereby promoting cellular resistance against oxidative stress.63,64 SIRT1-transgenic mice display a retarded aging phenotype in the heart owing to its ability to induce MnSOD and catalase expression through the activation of FOXOs.24 In a mouse myocardial infarction model, the SIRT1-mediated upregulation of FOXO prevented cellular injury by activating prosurvival factors, such as thioredoxin-1 and Bcl-xL, and suppressing the activity of proapoptotic molecules such as Bax and cleaved caspase3.25 Similarly, the resveratrol-mediated activation of SIRT1 increased MnSOD levels in cardiomyocytes and suppressed fibrosis, preserved cardiac function, and significantly improved the survival of TO-2 hamsters.17 Chen and colleagues65 researched the role of the resveratrol-SIRT1 signaling pathway in cardioprotection. They found that SIRT1 has a dual effect on FOXO1 function: SIRT1 increases FOXO1's ability to induce cell cycle arrest but inhibits FOXO1's ability to induce cell death. This effect could be reversed by SIRT1 inhibition. The results of their study indicate that resveratrol inhibits apoptosis via the SIRT1-FOXO1 pathway in H9c2 cells, thus suggesting a potential target for preventing ischemic cardiovascular disease, particularly in patients with coronary artery disease.
Hypoxia-Inducible Factors
HIFs are a group of transcription factors involved in mediating protective adaptations. SIRT1 activation of HIF-2a increases the expression of erythropoietin,66 a regulator of red blood cell production and angiogenesis. The IPC elevation of erythropoietin protein expression has been shown to play a key role in IPC-mediated protection.67 SIRT1 activation of HIF-2a has also been shown to enhance the expression of the mitochondrial reactive oxygen species scavenger MnSOD,66 which further shows that SIRT1 can regulate multiple mechanisms to mediate protection against oxidative stress. HIF-1a is regulated by MIR-199a, and SIRT1 is an additional target of MIR-199a, suggesting a conceivable relationship between HIF-1a and SIRT1.68
Peroxisome Proliferator–Activated Receptor γ Coactivator-1α
PGC-1α is a member of a family of transcription coactivators that have activities in mitochondrial biogenesis, antioxidation, growth factor signaling regulation, and angiogenesis. Tan and colleagues69 found that almost all the signaling pathways activated by resveratrol involve PGC-1α activity. Moreover, it has been demonstrated that resveratrol can mediate an increase in PGC-1α activity. These significant conditions support the hypothesis that resveratrol exerts a pharmacological preconditioning effect by activating PGC-1α. Resveratrol can strongly stimulate SIRT1 activity, thus, showing that SIRT1 prevents IR injury via a PGC-1α–related pathway. Other studies have indicated that SIRT1 directly activates PGC-1α,70 the transcriptional coactivator associated with protection against oxidative stress. SIRT1-dependent PGC-1α expression was shown to reduce infarct size and improve neurological scores after middle cerebral artery occlusion.71 Rodents lacking PGC-1α displayed enhanced hippocampal neurodegeneration in response to oxidative stress72 and exhibited decreased reactive oxygen species scavenger expression after transient global ischemia.73 This suggests that SIRT1 may protect against ischemia-induced oxidative damage by activating PGC-1α.
Other Downstream Targets of SIRT1
In addition to the previously mentioned downstream pathways, there are other downstream targets of SIRT1 in the myocardial ischemia procedure. In neonatal rat ventricular cardiomyocytes subjected to a simulated IR model, Becatti and colleagues74 demonstrated that SIRT1 overexpression positively affects the mitogen-activated protein kinase pathway. Vahtola and colleagues75 reported an increase in the number of SIRT1-positive nuclei in the infarct area of Goto-Kakizaki rats, and the acetylation of p53 at the SIRT1-preferred site was decreased. In an isolated myocardial IR model of SIRT1-overexpressing mice, Nadtochiy and colleagues76 found that the phosphorylation of eNOS was significantly higher in SIRT1+++ hearts than in SIRT1+/− hearts. Alternatively, SIRT1 is known to deacetylate and inhibit NF-κB and p6552; however, the results of Nadtochiy and colleagues also showed a significant increase in the level of p65 acetylation in SIRT1+/− hearts relative to SIRT1+++ hearts. We have provided a table to summarize these target genes (and the downstream biological effects) that are potentially regulated by SIRT1 in myocardial ischemia, along with an experimental model and bibliographic references (Table).
The Role of SIRT1 in Human Heart Diseases
Data also suggest that SIRT1 has a role in many human heart diseases. Tanno and colleagues17 found that normal human cardiomyocytes predominantly expressed SIRT1 in their cytoplasm, and chronic heart failure induced a nuclear translocation of SIRT1 in cardiomyocytes. The nuclear accumulation of SIRT1 is likely to be an adaptive mechanism of cardiomyocytes against heart failure, as indicated by the potent cell protective effect of nuclear SIRT1 against reactive oxygen species. Shan and colleagues77 reported that SIRT1 participates in the development of congenital heart disease. Carter and colleagues78 demonstrated that SIRT1 has an effect on aortic stenosis by inhibiting resistin expression. It has also been demonstrated that SIRT1 interacting with Notch signaling can participate in bicuspid aortic valve disease.79
Most importantly, SIRT1 has a significant connection with ischemia-related myocardial diseases. Research data indicated that monocytic SIRT1 expression is reduced in patients with stable coronary artery disease and acute coronary syndromes.80 Moreover, SIRT1 plays an important role in the prevention of atherosclerosis. Zeng and colleagues81 reported that SIRT1 may prevent the formation and progression of atherosclerosis by enhancing the liver X receptor-ATP–binding cassette, A1/ABCG1/C-C chemokine receptor type 7, and inhibiting the NF-κB pathways.
Above all, both animal experiments and human studies demonstrated that SIRT1 has a credible protective function on myocardial ischemia injury, manifesting the significance of the investigation of SIRT1.
Potential Directions
Among many recent studies on SIRT1, some recent findings indicate potential directions of future studies. They may be of underlying value in the treatment of IR injury.
Recently, MIRs have been shown to play a role in SIRT1-related signaling pathways. Rane and colleagues68 reported that MIR-199a is acutely downregulated in cardiac myocytes following a decline in oxygen tension. The reduction is required for the rapid upregulation of its target, HIF-1a. Replenishing MIR-199a during hypoxia inhibits HIF-1a expression and its stabilization of p53 and thus reduces apoptosis. However, MIR-199a knockdown during normoxia results in the upregulation of HIF-1a and SIRT1 and reproduces hypoxia preconditioning. SIRT1 is also a direct target of MIR-199a and is responsible for downregulating prolylhydroxylase 2, which is required for the stabilization of HIF-1a. Thus, they concluded that MIR-199a is a master regulator of a hypoxia-triggered pathway and can be exploited for preconditioning cells against hypoxic damage. These data demonstrated a functional link between the 2 key molecules that regulate hypoxia preconditioning and longevity. Additionally, Salloum and colleagues82 reported that MIRs do affect cardioprotection, and they noted that MIRs can drive SIRT1 expression to some extent. We believe that MIRs have immense potential in the treatment of cardiovascular diseases via SIRT1-related pathways.
Caloric restriction is also a research direction. Prolonged caloric restriction improves the recovery of left ventricle function and limits infarct size after IR. Additionally, it restores the protective effects of IPC. The cardioprotection afforded by prolonged caloric restriction is associated with changes in the subcellular localization of SIRT1, and nitric oxide synthase activity is necessary for the increase in nuclear SIRT1 content during prolonged caloric restriction. These results suggest a possible pathway through which caloric restriction regulates the activity of eNOS, thus mediating SIRT1 expression, leading to cardioprotection.83
In 2010, Nadtochiy and colleagues84 discussed lysine deacetylation in IPC and the upstream regulation of SIRT1. They observed more lysine deacetylation in IPC and an elevation in SIRT1 activity. The investigation demonstrated that SIRT1 protein levels do not change in IPC, although SIRT1 sumoylation does occur. SIRT1 inhibitors can restrain IPC-mediated lysine deacetylation and IPC-induced cardioprotection. The research suggests a potential relationship between SIRT1 and lysine deacetylation.
It is encouraging to know that in addition to resveratrol, another component of white wine, n-tyrosol [2-(4-hydroxyphenyl) ethanol], also exhibits cardioprotective effects. Samuel and colleagues85 evaluated the effect of tyrosol treatment on myocardial ischemic stress. Tyrosol-treated rats demonstrated reduced infarct size and improved myocardial function. They also observed a significant increase in the phosphorylation of Akt, eNOS, and FOXO3a. In addition, tyrosol induced the expression of SIRT1. These findings suggest that tyrosol induces myocardial protection against ischemia-related stress by inducing survival and longevity proteins, particularly SIRT1, and that it may be considered as a new target for antiaging therapy for the heart.
Above all, we proposed a hypothesis to connect all of the pathways and to simulate the probable process of SIRT1-related cardioprotection in myocardial ischemia. When the heart is under ischemic stress, the absence of oxygen and calories promotes the expression of SIRT1. In addition, the activation of the phosphatidyl inositol 3-kinase/Akt and c-Jun N-terminal kinase 1 pathways facilitates SIRT1 translocation to the nucleus. After nucleocytoplasmic shuttling, SIRT1 begins to regulate several target genes: (1) SIRT1 activates the α-MHC gene promoter, thus enhancing α-MHC expression, providing higher ATPase activity and a faster shortening velocity of cardiac myofibers; (2) SIRT1 activates FOXOs, which in turn induce Rab7 expression, thereby stimulating autophagosome-lysosome fusion to maintain homeostatic functions in cells; (3) activation of FOXO1 alters the cell cycle to prevent apoptosis, as SIRT1 increases FOXO1's ability to induce cell cycle arrest but inhibits FOXO1's ability to induce cell death; (4) SIRT1 promotes myocardial hypertrophy and reduces infarct size via a FOXO3a-related pathway; (5) SIRT1 increases the expression of erythropoietin via a HIF-2a-mediated pathway, leading to red blood cell production and angiogenesis, thus improving blood supply; and (6) through several pathways, such as FOXOs, HIFs, PGC-1α, mitogen-activated protein kinase, NF-κB, eNOS, and p53, SIRT1 increases the expression of various antioxidants to resist oxidative stress. In studies of obesity-associated metabolic diseases, cancer, prion-mediated neurodegeneration, inflammation, and placental cell survival, other mediators have been reported to participate in SIRT1-dependent actions, including liver X receptor, peroxisome proliferator–activated receptor γ, cAMP-responsive element–binding protein–regulated transcription coactivator 2, period homolog 2, serine/threonine kinase 11, etc.5 However, all of these mediators have not been investigated in myocardial ischemia; therefore, further investigation is necessary. Meanwhile, these activities constitute an interactive network that protects the heart against ischemia. In this network, we can find that different pathways have intersections, and these intersections may suggest new targets of myocardial ischemia.
In summary, increasing lines of evidence suggest that SIRT1 protects the heart from ischemia-related injury. Stimulating SIRT1 appears to be a promising modality for reducing the level of ischemia-related injury. At present, the data indicate that a complex network of signaling mechanisms is involved in SIRT1 mediation (Figure). Its numerous regulators and signaling pathways provide researchers with many chances to explore its mechanism. However, there are many unsolved issues regarding the function of SIRT1 in the heart. Undoubtedly, more work is needed to understand the role of SIRT1 in cardiac cell biology before it can be considered as a valuable therapeutic target for translational studies of myocardial ischemia.
Sources of Funding
This study was supported by grants from the 12th National Five Years Supporting Project of China (2011BAI11B20), the National Natural Science Foundation of China (81102687 and 81070198), the Academic Promotion Project of Xijing Hospital (XJZT09 M16 and XJZT10 M11), and Social Development Project of Shaanxi Province (2012JQ4001).
- © 2013 American Heart Association, Inc.
- 1.↵
- 2.↵
- 3.↵
- 4.↵
- Paraíso AF,
- Mendes KL,
- Santos SH
- 5.↵
- 6.↵
- Pillai JB,
- Chen M,
- Rajamohan SB,
- Samant S,
- Pillai VB,
- Gupta M,
- Gupta MP
- 7.↵
- 8.↵
- 9.↵
- 10.↵
- 11.↵
- 12.↵
- Kanamori H,
- Takemura G,
- Maruyama R,
- Goto K,
- Tsujimoto A,
- Ogino A,
- Li L,
- Kawamura I,
- Takeyama T,
- Kawaguchi T,
- Nagashima K,
- Fujiwara T,
- Fujiwara H,
- Seishima M,
- Minatoguchi S
- 13.↵
- 14.↵
- 15.↵
- Michishita E,
- Park JY,
- Burneskis JM,
- Barrett JC,
- Horikawa I
- 16.↵
- Tanno M,
- Sakamoto J,
- Miura T,
- Shimamoto K,
- Horio Y
- 17.↵
- Tanno M,
- Kuno A,
- Yano T,
- Miura T,
- Hisahara S,
- Ishikawa S,
- Shimamoto K,
- Horio Y
- 18.↵
- 19.↵
- James J,
- Martin L,
- Krenz M,
- Quatman C,
- Jones F,
- Klevitsky R,
- Gulick J,
- Robbins J
- 20.↵
- 21.↵
- Alcendor RR,
- Kirshenbaum LA,
- Imai S,
- Vatner SF,
- Sadoshima J
- 22.↵
- 23.↵
- Vahtola E,
- Louhelainen M,
- Merasto S,
- Martonen E,
- Penttinen S,
- Aahos I,
- Kytö V,
- Virtanen I,
- Mervaala E
- 24.↵
- Alcendor RR,
- Gao S,
- Zhai P,
- Zablocki D,
- Holle E,
- Yu X,
- Tian B,
- Wagner T,
- Vatner SF,
- Sadoshima J
- 25.↵
- Hsu CP,
- Zhai P,
- Yamamoto T,
- Maejima Y,
- Matsushima S,
- Hariharan N,
- Shao D,
- Takagi H,
- Oka S,
- Sadoshima J
- 26.↵
- 27.↵
- Revollo JR,
- Grimm AA,
- Imai S
- 28.↵
- Lee IH,
- Cao L,
- Mostoslavsky R,
- Lombard DB,
- Liu J,
- Bruns NE,
- TsokosM,
- Alt FW,
- Finkel T
- 29.↵
- 30.↵
- Di Lisa F,
- Menabò R,
- Canton M,
- Barile M,
- Bernardi P
- 31.↵
- Crawford RM,
- Jovanovic S,
- Budas GR,
- Davies AM,
- Lad H,
- Wenger RH,
- Robertson KA,
- Roy DJ,
- Ranki HJ,
- Jovanovic A
- 32.↵
- Du Q,
- Jovanovic S,
- Clelland A,
- Sukhodub A,
- Budas G,
- Phelan K,
- Murray-Tait V,
- Malone L,
- Jovanovic A
- 33.↵
- Budas GR,
- Jovanovic S,
- Crawford RM,
- Jovanovic A
- 34.↵
- Sukhodub A,
- Jovanovic S,
- Du Q,
- Budas G,
- Clelland AK,
- Shen M,
- Sakamoto K,
- Tian R,
- Jovanovic A
- 35.↵
- 36.↵
- 37.↵
- 38.↵
- Baur JA,
- Pearson KJ,
- Price NL,
- Jamieson HA,
- Lerin C,
- Kalra A,
- Prabhu VV,
- Allard JS,
- Lopez-Lluch G,
- Lewis K,
- Pistell PJ,
- Poosala S,
- Becker KG,
- Boss O,
- Gwinn D,
- Wang M,
- Ramaswamy S,
- Fishbein KW,
- Spencer RG,
- Lakatta EG,
- Le Couteur D,
- Shaw RJ,
- Navas P,
- Puigserver P,
- Ingram DK,
- de Cabo R,
- Sinclair DA
- 39.↵
- 40.↵
- 41.↵
- 42.↵
- 43.↵
- 44.↵
- 45.↵
- Gurusamy N,
- Lekli I,
- Mukherjee S,
- Ray D,
- Ahsan MK,
- Gherghiceanu M,
- Popescu LM,
- Das DK
- 46.↵
- Bulhak AA,
- Jung C,
- Ostenson CG,
- Lundberg JO,
- Sjöquist PO,
- Pernow J
- 47.↵
- Chan AY,
- Dolinsky VW,
- Soltys CL,
- Viollet B,
- Baksh S,
- Light PE,
- Dyck JR
- 48.↵
- Juric D,
- Wojciechowski P,
- Das DK,
- Netticadan T
- 49.↵
- Sulaiman M,
- Matta MJ,
- Sunderesan NR,
- Gupta MP,
- Periasamy M,
- Gupta M
- 50.↵
- Gidday JM,
- Gasche YG,
- Copin JC,
- Shah AR,
- Perez RS,
- Shapiro SD,
- Chan PH,
- Park TS
- 51.↵
- 52.↵
- Yeung F,
- Hoberg JE,
- Ramsey CS,
- Keller MD,
- Jones DR,
- Frye RA,
- Mayo MW
- 53.↵
- Ungvari Z,
- Bagi Z,
- Feher A,
- Recchia FA,
- Sonntag WE,
- Pearson K,
- de Cabo R,
- Csiszar A
- 54.↵
- Borra MT,
- Smith BC,
- Denu JM
- 55.↵
- Pacholec M,
- Bleasdale JE,
- Chrunyk B,
- Cunningham D,
- Flynn D,
- Garofalo RS,
- Griffith D,
- Griffor M,
- Loulakis P,
- Pabst B,
- Qiu X,
- Stockman B,
- Thanabal V,
- Varghese A,
- Ward J,
- Withka J,
- Ahn K
- 56.↵
- 57.↵
- 58.↵
- Ahmad KA,
- Harris NH,
- Johnson AD,
- Lindvall HC,
- Wang G,
- Ahmed K
- 59.↵
- 60.↵
- 61.↵
- 62.↵
- 63.↵
- Brunet A,
- Sweeney LB,
- Sturgill JF,
- Chua KF,
- Greer PL,
- Lin Y,
- Tran H,
- Ross SE,
- Mostoslavsky R,
- Cohen HY,
- Hu LS,
- Cheng HL,
- Jedrychowski MP,
- Gygi SP,
- Sinclair DA,
- Alt FW,
- Greenberg ME
- 64.↵
- Daitoku H,
- Hatta M,
- Matsuzaki H,
- Aratani S,
- Ohshima T,
- Miyagishi M,
- Nakajima T,
- Fukamizu A
- 65.↵
- 66.↵
- Dioum EM,
- Chen R,
- Alexander MS,
- Zhang Q,
- Hogg RT,
- Gerard RD,
- Garcia JA
- 67.↵
- 68.↵
- Rane S,
- He M,
- Sayed D,
- Vashistha H,
- Malhotra A,
- Sadoshima J,
- Vatner DE,
- Vatner SF,
- Abdellatif M
- 69.↵
- 70.↵
- Nemoto S,
- Fergusson MM,
- Finkel T
- 71.↵
- 72.↵
- 73.↵
- 74.↵
- 75.↵
- 76.↵
- Nadtochiy SM,
- Yao H,
- McBurney MW,
- Gu W,
- Guarente L,
- Rahman I,
- Brookes PS
- 77.↵
- 78.↵
- 79.↵
- 80.↵
- 81.↵
- 82.↵
- 83.↵
- Shinmura K,
- Tamaki K,
- Bolli R
- 84.↵
- Nadtochiy SM,
- Redman E,
- Rahman I,
- Brookes PS
- 85.↵
This Issue
Jump to
Article Tools
- Novel Role of Silent Information Regulator 1 in Myocardial IschemiaYang Yang, Weixun Duan, Yue Li, Zhenxiao Jin, Juanjuan Yan, Shiqiang Yu and Dinghua YiCirculation. 2013;128:2232-2240, originally published November 11, 2013https://doi.org/10.1161/CIRCULATIONAHA.113.002480
Citation Manager Formats


text:
Shanghai Young Sun Printing Co., Ltd. was established in 1998, located in Mountain She Economic Development Zone, Song Jiang district Shanghai.
The company has a total investment of 160 million RMB, registered capital is 50 million RMB, and covers an area of more than 32,000 square meters. The company has advanced printing equipment and professional management team with strong and comprehensive strength and production capacity. It has been 13 years since the company's foundation. It mainly provides one-stop overall packaging solutions for the world's advanced pharmaceutical companies, food companies and cosmetics companies.


text:
Ozone is formed when an electrical discharge passes through oxygen, or by the action of ultraviolet light on oxygen. It can also be destroyed by UV light, which can break it back down into an oxygen molecule, O2, plus a single "free radical" atom of oxygen. At ground level, it is a pollutant, corrosive to many materials, damaging to lungs and plants. It is found in the "smog" that is formed by the action of light on vehicle exhaust smoke.
Up in the stratosphere, ozone is more appreciated. It forms a thin layer that protects us from the carcinogenic UV part of the Sun's spectrum.
Without this protection, there would be little life on Earth. So, ozone is formed by UV, destroyed by UV, and in the process it protects us from UV.
What this means is that there is an "ozone balance" - a state in which ozone is being created and destroyed at equal rates - which keeps the ozone layer in being. The balance is naturally fragile and fluctuating, and anything that upsets it and increases the rate of ozone destruction is potentially life-threatening - hence the worry, since the 1980s, about the effect of the release into the atmosphere of chlorofluorocarbons (CFCs), such as those used in aerosols, refrigerators and air conditioners. These interfere with the ozone balance by promoting complex chemical reactions that speed up the breakdown of ozone. The problem is aggravated by the fact that CFCs were used for many years in the belief that they were inert, with no environmental penalties. Their very stability, however, means that even after they have been phased out, they will remain in the atmosphere for a long time.
Their slow migration to the stratosphere brings them into contact with the ozone layer. There is hope that ozone depletion - largely seen in the form of "holes" in the ozone layer over both Poles - has slowed and the layer is showing signs of recovery.
Another worry is the increase in "greenhouse" gases. The greenhouse effect is the name given to the increase in temperature at the Earth's surface caused by the way that certain gases in the atmosphere - notably carbon dioxide and water vapour - allow heat radiated from the Sun to pass freely to the Earth, and then absorb it when it is radiated back, heating up and thus keeping the atmosphere warm where it is closer to the Earth.
The greenhouse effect itself is natural - without it, the Earth would be in the grip of permanent ice age with an average temperature of - 15oC, 30oC below its current level.
But for 150 years, industrialisation has meant that much more carbon dioxide is being pumped into the atmosphere, and most scientists believe that this is increasing the greenhouse effect, leading to a range of radical effects such as the shrinking of the ice caps, rising sea levels and increasingly frequent extreme weather.


text:
Experiential Marketing: A Master of Engagement
April 2, 2008
This exerpt from an ARF white paper presents the findings of the January 2008 study on B-to-C and B-to-B event, trade show, and sponsorship engagement.
You do not have access to this content
Here's who has access to this content:
- Logged In Visitors
Login Now
First, one quick step. You'll need to log in to continue:
No Account?
You need an account to view this content, creating one is free and painless. Click below to create an account with us today using your business email address.


text:
NEW YORK -- Andre Agassi walked off the court at the U.S. Open yesterday and into the waiting arms of girlfriend Brooke Shields, who immediately planted a victory kiss.
It's New York. It's the Open. It's show time. And Agassi is back in the Sweet 16 here for the first time in three years.
He's also back entertaining.
Is he happy to have Brooke here?
"I like having Brooke, period, at the match or not," Agassi said. "She knows that."
Yesterday, in front of a packed Stadium Court, Agassi charmed the masses with a 7-5, 6-1, 7-5 victory over No. 12 seed Wayne Ferreira and set up a much-anticipated match with No. 6 seed Michael Chang.


text: Just joined Backyard Chickens today...after having had chickens for about 1.5 years. We love our chickens...3 Golden Comets, 2 Easter Eggers, and 2 Barred Rocks. They have definitely become part of our family identity. Kids love showing them off to their friends, I love their company when I'm working in the yard, and we all love their eggs! Love the BYC forum...I look forward to learning from all of you. Here's a pic of our coop w a bit of explanation. Thoughts? Take care, Doug...RYGblog RedeemYourGround


text:
Q: Does insurance pay for your service?
A: Non-medical homecare is very similar to Assisted Living. In most cases, our clients pay privately for our services. If the care recipient has Long Term Care (LTC) Insurance, that policy will pay for our services. All LTC benefits are unique (deductibles, waiting periods, maximums, etc), so contact your LTC provider to verify your policy's benefits. Medicare does not cover this type of service.
U.S. Veterans who were Active Duty during Wartime may also have a needs-based benefit that pays for our services. Feel free to call our office for your Veteran's Specialist's contact information.
Q: What are your rates?
A: Our rates are hourly, and are determined by the number of hours you utilize our service, and the payment method you choose. Our rates include all payroll, payroll taxes, bonding, insurance, and worker's compensation insurance. The hours required to properly care for your loved one will be based on their needs assessed during the in-home assessment and on an ongoing basis.
Q: Are there minimum hours of service required?
A: Yes, we have minimum hours required. Minimums are very helpful in providing quality, consistent care to our clients. Caregivers rely upon these hours for their livelihood, and a consistent schedule leads to consistent care. Our current minimum is three hours per shift, and nine hours per week (subject to change).
Q: What is your service area?
A: Our Glendora office serves the communities of Azusa, Bradbury, Covina, Duarte, Glendora, La Verne, Monrovia, and San Dimas. Our Upland office serves Alta Loma, Claremont, Mount Baldy, Pomona, Rancho Cucamonga, and Upland.
Q: Are your services tax-deductible?
A: Eldercare is considered dependent care (similar to childcare). Contact your accountant for more information on requirements and deduction limits.
Q: Is there an additional cost for errands and transportation?
A: If your caregiver uses their car for errands or transportation, you will be invoiced at the prevailing IRS rate per mile driven. Mileage is not charged if the caregiver drives your vehicle.
Q: Which Long Term Care (LTC) Insurance Companies recognize you as a provider?
A: We go through an application process with each LTC Insurance Company. We have gained approval from each LTC Insurance Company to whom we have applied. Here is a list of the companies that recognize us to date:
I wanted to thank all the angels who sat at night with our dad while he was in Clara Baldwin. It gave us some much needed relief during the time he was there and it was much appreciated. You all were so kind to him and we thank you for that. Blessings to all of you.
I wanted to thank all the angels who sat at night with our dad while he was in Clara Baldwin. It gave us some much needed relief during the time he was there and it was much appreciated. You all were so kind to him and we thank you for that. Blessings to all of you.


text:
Enabling a better Working World
You are not logged in
HSL is to run a 1 day course on CRD - Maximum Residue Levels Workshop.
Chemicals Regulation Division, Mallard House, Kings Pool,
3 Peasholme Green, York YO1 7PX
1st February 2018
CRD will be holding a one-day workshop on Maximum Residue Levels
(MRLs). The aim of the day will be to raise awareness, and to
provide guidance for proposing and supporting MRLs. A mixture of
formal presentations and workshops will be used to relay complete
and up to date information on current and upcoming issues that
relate to the EU MRL system.
The workshop will be presented by CRD Policy and Regulatory
Specialists who will be available to answer your questions
throughout the day.
Given the nature of
the workshop, places will be limited to a maximum of 16
The event will be targeted at technical and regulatory staff
involved in the production and submission of data into the EU
The workshop will be held at the Chemicals Regulation Division,
Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX.
Registration will begin from 9:00 am. The workshop will start at
9:30 am and finish around 4:30 pm.
The cost of this course is £430 (plus VAT) per person (includes
course notes, lunch and refreshments.
The closest date available is shown above. If you know
of other dates and wish to attend, please write this in
the Comments Box during the booking process.
Please note the invoice option is not available within 4
weeks of the course date, or for overseas customers. If you
are selecting the invoice option for payment, it will be mandatory
to input a purchase order/reference number as we are unable to
process booking forms without this.
For further dates and additional information email: email@example.com
or contact the Training & Conferences Unit
at HSL directly on +44 (0)203 028 3704.
Back to Health & Safety Training Courses
Back to the top
Contact Details
HSL Training & Conferences Unit
Harpur Hill
Buxton, Derbyshire
E: email@example.com


text:
Order Custom Flower Saddle Pad Here
Order Custom Flower Saddle Pad Here
from 42.00
This is where you can place your order for a custom English saddle pad. If you would like an oversize pad or pony sized pad, please contact us directly. Our standard pad size is 23 1/2" top length, 20" girth and 27 1/2" longest length.
If you choose Other as a color option, you will be contacted within 24 hrs with a few fabric styles to choose from. Your satisfaction is guaranteed!
Saddle Pad Options:
Add To Cart


text:
Industrial automation based on a distributed control system (DCS)
Would you like to upgrade your processes? Develop new processes? Continuous developments will allow you to push your boundaries of industrial automation and process control for even more efficiency, production continuity, quality and safety.
Independent solutions for DCS systems
Today, we mainly see industrial automation evolving in the following direction:
- Centralisation
- Real-time information
- Big data (data collection and analysis for decision support)
- Links with workflow management tools
- Visualisation for more efficient/effective jobs by operators and engineers
Intation develops state-of-the-art solutions for production environments based on DCS and/or PLC.
Intation as a one-stop shop
Intation essentially develops, tests and implements software for distributed control systems (DCS). Of course, you can also use Intation as a one-stop shop. If that is the case, we will also handle your industrial IT budgeting, arrangements and coordination.


text: David Greely, genius fiddler, singer and saxophonist, founding member of the modern Mamou Playboys with Steve Riley, has put out his own solo CD, Sud du Sud, or South of the South. Information is available on his web site: http://www.davidgreely.com. You can purchase if from him and, soon, CD Baby. MP3 downloads are on Amazon. The CD has 14 tracks, and they look mostly like older tracks, with a few originals. Samples on his web site. Should be great! Now if we can only get the long-promised CD of four-part a capella singing from Vieille, another of Greely's groups.


text:
Save on FOTGA products at PLR Articles Now. Hurry! Limited time offers. Offers valid only while supplies last.
Fotga DP500III 15mm Standard Rail Rod Filmling System Quick Release Set Up Camera Rig Cage Follow Focus Matte box for 5DII III A7S A7R2 A7RM2
In Stock
mpn: Fotga, ean: 0761710154772,
Specifications: Material: sturdy metal Compatible with industry standard follow focus whip or crank. Mounts onto industry standard 15 mm rod support :60mm center to center MOD drive gear: industry standard 0.8.can work with different size gear to...
Fotga DP500 III Filming System Camera Gears Kits for Dslr Cameras Camcorders Photography (DP500 III Follow Focus Set)
In Stock
mpn: DB768, ean: 0780411054204,
Description: Adjustable locking systems Quick-release version,easily attach and detach. The white mark ring is included. Made of magnet material, easy to be detached and attached. Compatible with industry stand 15mm rods Rail distance: 60mm Ra...
Viewing Page 1 of 1
Feel free to Browse Our Catalog.


text:
2011 60 FORD TRANSIT CONNECT 1.8 T220 TREND LR VDPF 1d 89 BHPFACELIFT VAN+NO VAT TO PAY+GREAT VALUE
- 108000 Miles
- Diesel
- Manual
- TBC CO² (g/km)
- £TBC 12m Tax
- £TBC 6m Tax
- 47.1 Avg. MPG
- Group 0 Ins.
Vehicle Information
- Features
- Description
- Finance
- Gallery
Vehicle Summary
- Body stylePanel Van
- Engine size1753cc
- Engine capacity1.8 L
- Fuel typeDiesel
- Number of doors4
- Number of seats2
- TransmissionManual
- Insurance group0
Performance & Economy
- Fuel consumption (urban)39.2 mpg
- Fuel consumption (extra urban)53.3 mpg
- Fuel consumption (combined)47.1 mpg
- 0 - 60 mph17.4 seconds
- Top speed94.0 mph
- Engine power89 bhp
- Engine torque177 lbs/ft
Interior / Exterior
InteriorNo features available.
ExteriorNo features available.
ComfortNo features available.
Safety / Other
SafetyNo features available.
OtherNo features available.
Factory Fitted Extras
For more info on this vehicle call our showroom on 01752 876715
Every effort has been made to ensure the accuracy of the above information but errors may occur. Please check with a salesperson.
- Registered: 2011
- Mileage: 108000 miles
- Engine Size: 1.8 L
- Fuel Type: DieselGearbox: ManualBody Style: PANEL VANColour: WhiteOwners: 2
For more info on this vehicle call our showroom on 01752 876715
FACELIFT VAN+GREAT VALUE, NO VAT TO PAY, MOT 29TH JAN 2019, LOTS OF SERVICE HISTORY WITH 5 SERVICES, INCLUDING CAMBELT CARRIED OUT IN JAN 2018. - Part exchange is welcome on any car, even if its worth more, or out of MOT. We can take anything in p/x - cars, vans or motorbikes. We are now open 7 days a week, 9 til 6pm Monday til Fri, 9-5 Saturday, and 11- 4pm on Sunday. Credit cards and Debit Cards accepted-Debit card is prefered payment method, which is free, there is a charge for credit cards..,, due to current very busy period occasionally some cars may not have been fully valeted or fully prepared for sale when you first see them. Although we are a trade centre we do sell to the public as well, PLEASE CALL TO BOOK APPOINTMENT BEFORE COMING TO VIEW AS CARS ARE KEPT OFF SITE IN SECURE YARD. UP TO 40 PHOTO'S ON OUR WEBSITE www Ivybridge trade centre co uk
PLEASE CALL TO BOOK APPOINTMENT BEFORE COMING TO VIEW CARS-THEY ARE KEPT OFFSITE IN SECURE COMPOUND. UP TO 40 PICTURES ON OUR WEBSITE, PLUS OVER 100 CARS, PLEASE LOOK AT ivybridge trade centre co uk. PLEASE NOTE, CREDIT CARDS NOT ACCEPTED. We do have limited customer parking onsite, alternatively there is free parking opposite us in the watermark car park, or Ivybridge Leisure Centre Car park is £0.60pence an hour, which we will reimburse with any purchase.
Every effort has been made to ensure the accuracy of the above information but errors may occur. Please check with a salesperson.
|HP Representative Example
|Total Payable
|Fixed Rate
|Representative APR
|1st Payment
|Monthly Payment
|Final Payment
|48 mths
|£69.62 p/m* x 46
|Hire Purchase
|Total Payable
|48 mths
|Fixed Rate
|Representative APR
|1st Payment
|Monthly Payment
|£69.62 p/m* x 46
|Final Payment
Additional Information
Finance is subject to status. Terms and conditions apply. Applicants must be 18 or over. Guarantees / indemnities may be required.
*The Acceptance & Option fees that may apply can vary from time to time and from lender to lender, fees are already accounted for within the payments displayed and are also included within the total amount payable.
We work with a number of carefully selected credit providers who may be able to offer you finance on your purchase. We are only able to offer finance products from these providers.
Due to changing interest rates and market conditions, the Finance Calculator provides an estimate and should be used for guidance only.
The following documents are available for this vehicle:


text:
Leader: KPMG's cuts set out harsh truth about profits
A dip in profits, as well as more partners, set the tone for KPMG's future direction. But is cutting non-partners right? asks Accountancy Age
A dip in profits, as well as more partners, set the tone for KPMG's future direction. But is cutting non-partners right? asks Accountancy Age
HOW HAS A FIRM posting £418m in profits found itself in a position where it needs to look at cutting 3% of its workforce?
For KPMG, it would appear to be a case of simple maths.
The profit figure, relating to its last financial year (ending 30/09/11), equated to an average profit per partner (PPP) of £690,000.
The previous year saw a higher profit and fewer partners, hence £750,000 per partner.
Where are the cuts coming from at KPMG? Below partner level.
Big Four firms can talk all they like about the efforts they make in recruiting grads and opening up opportunities for the non-university-educated, as they have in response to KPMG's travails.
But from the outside, it seems clear that the engine room of KPMG's business is likely to take a hit. The cost-cutting will no doubt look to improve the PPP figure, yet surely the most important thing is that quality of service to the client is maintained.
Bearing in mind that PwC and Deloitte partners saw a fall in PPP during the last year (E&Y doesn't supply figures), KPMG's latest action does send a shiver down the spine.
As an aside, one wonders how new KPMG chairman Simon Collins felt about fronting up to staff on this issue, bearing in mind he was initially meant to take over from John Griffith-Jones in October.
Kevin Reed is editor of Accountancy Age


text:
H&M's Mickey Mouse Mom Jeans are a Disney Style Must-Have
It's no new news that the '90s are back in a big way, and mom jeans are a major part of the trend. We love these Mickey Mouse mom jeans for the perfect retro Disney style.
We are a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for us to earn fees by linking to Amazon.com and affiliated sites.


text:
What Is TANI Spreadsheet
Thank you for coming to us in looking for "What Is TANI Spreadsheet" online.
Many individuals would rather use a money deflation, particularly people who desire to save. Despite the criticism and disbelief, a cryptocurrency coin may be better suited for some uses than others. Monetary seclusion, for instance, is amazing for political activists, but more problematic when it comes to political campaign financing. We need a steady cryptocurrency for use in trade; should you be living paycheck to paycheck, it would happen within your riches, with the remainder reserved for other currencies.
For most users of cryptocurrencies it is not essential to comprehend how the procedure operates in and of itself, but it is simply important to comprehend that there is a process of mining to create virtual currency. Unlike monies as we know them now where Authorities and banks can simply select to print endless numbers (I am not saying they're doing so, just one point), cryptocurrencies to be operated by users using a mining software, which solves the sophisticated algorithms to release blocks of monies that can enter into circulation.
Ethereum is an incredible cryptocurrency platform, nevertheless, if growth is too quickly, there may be some difficulties. If the platform is adopted quickly, Ethereum requests could improve dramatically, and at a rate that surpasses the rate with which the miners can create new coins. Under such a scenario, the whole stage of Ethereum could become destabilized due to the raising costs of running distributed programs. In turn, this could dampen interest Ethereum stage and ether. Instability of demand for ether can lead to an adverse change in the economic parameters of an Ethereum based business that could result in business being unable to continue to manage or to cease operation.
What Is TANI Spreadsheet
The wonder of the cryptocurrencies is that scam was proved an impossibility: because of the nature of the method in which it's transacted. All transactions over a crypto currency blockchain are irreversible. When youare paid, you get paid. This is not something short-term wherever your web visitors could dispute or desire a concessions, or employ unethical sleight of palm. In practice, many merchants would be a good idea to utilize a fee processor, because of the irreversible nature of crypto currency orders, you must ensure that security is difficult. With any kind of crypto currency may it be a bitcoin, ether, litecoin, or the numerous different altcoins, thieves and hackers could potentially get access to your individual keys and so grab your money. However, you probably can never obtain it back. It's vitally important for you really to adopt some excellent safe and secure methods when working with any cryptocurrency. Doing this can guard you from all of these adverse events.
Mining cryptocurrencies is how new coins are put in circulation. Because there's no government control and crypto coins are digital, they cannot be printed or minted to produce more. The mining process is what creates more of the coin. It may be useful to think about the mining as joining a lottery group, the pros and cons are exactly the same. Mining crypto coins means you will get to keep the total benefits of your efforts, but this reduces your chances of being successful. Instead, joining a pool means that, overall, members will have a much higher possibility of solving a block, but the benefit will be divided between all members of the pool, depending on the amount of "shares" won.
If you're considering going it alone, it's worth noting the software configuration for solo mining can be more complex than with a pool, and beginners would be likely better take the latter course. This alternative also creates a secure stream of earnings, even if each payment is small compared to fully block the wages.
Cryptocurrencies such as Bitcoin, LiteCoin, Ether, YOCoin, and many others have been designed as a non-fiat currency. Put simply, its backers argue that there is "real" value, even through there is absolutely no physical representation of that value. The value grows due to computing power, that's, is the lone way to create new coins distributed by allocating CPU power via computer programs called miners. Miners create a block after a period of time that is worth an ever declining amount of currency or some form of reward in order to ensure the shortage. Each coin contains many smaller units. For Bitcoin, each component is called a satoshi. Operations that take place during mining are exactly to authenticate other transactions, such that both creates and authenticates itself, a simple and elegant solution, which will be among the appealing aspects of the coin. Once created, each Bitcoin (or 100 million satoshis) exists as a cipher, which is part of the block that gave rise to it. The one who has mined the coin holds the address, and transfers it to some value is supplied by another address, which is a "wallet" file stored on a computer. The blockchain is where the public record of all transactions dwells.
The fact that there is little evidence of any growth in using virtual money as a currency may be the reason there are minimal attempts to regulate it. The reason behind this could be simply that the marketplace is too little for cryptocurrencies to warrant any regulatory effort. It is also possible that the regulators just don't understand the technology and its consequences, expecting any developments to act.
Here is the trendiest thing about cryptocurrencies; they usually do not physically exist everywhere, not even on a hard drive. When you examine a specific address for a wallet containing a cryptocurrency, there is absolutely no digital information held in it, like in the exact same way a bank could hold dollars in a bank account. It is simply a representation of value, but there is no genuine tangible sort of that value. Cryptocurrency wallets may not be seized or immobilized or audited by the banks and the law. They would not have spending limits and withdrawal restrictions enforced on them. No one but the owner of the crypto wallet can determine how their wealth will be managed.
When searching online for what is TANI spreadsheet, there are many things to think about.
What Is TANI Spreadsheet
Click here to visit our home page and learn more about what is TANI spreadsheet.
Bitcoin is the primary cryptocurrency of the internet: a digital money standard by which all other coins are compared to. Cryptocurrencies are distributed, international, and decentralized. Unlike traditional fiat currencies, there's no governments, banks, or some other regulatory agencies. Therefore, it truly is more immune to outrageous inflation and corrupt banks. The benefits of using cryptocurrencies as your method of transacting cash online outweigh the security and privacy risks. Security and privacy can readily be reached by just being intelligent, and following some basic guidelines. You'dn't set your whole bank ledger online for the word to see, but my nature, your cryptocurrency ledger is publicized. This can be secured by removing any identity of ownership from the wallets and thus keeping you anonymous.
This mining activity validates and records the trades across the entire network. So if you're attempting to do something illegal, it's not a good idea because everything is recorded in the public register for the rest of the world to see forever.
Cryptocurrency is freeing people to transact money and do business on their terms. Each user can send and receive payments in the same way, but in addition they take part in more complex smart contracts. Multiple signatures enable a trade to be supported by the network, but where a certain number of a defined group of people consent to sign the deal, blockchain technology makes this possible. This permits innovative dispute arbitration services to be developed in the foreseeable future. These services could enable a third party to approve or reject a trade in the event of disagreement between the other parties without checking their money. Unlike cash and other payment methods, the blockchain consistently leaves public evidence that the transaction occurred. This can be potentially used in a appeal against companies with deceptive practices.
Only a fraction of bitcoins issued so far can be found on the exchange markets. Bitcoin markets are competitive, which suggests the cost a bitcoin will rise or fall depending on supply and demand. Many people hoard them for long term savings and investment. This limits the amount of bitcoins that are actually circulating in the exchanges. In addition, new bitcoins will continue to be issued for decades to come. Consequently, even the most diligent buyer couldn't purchase all present bitcoins. This situation isn't to suggest that markets usually are not vulnerable to price exploitation, yet there exists no need for large sums of cash to move market prices up or down. The merest events on the planet economy can change the cost of Bitcoin, This can make Bitcoin and any other cryptocurrency volatile.
Since one of the earliest forms of making money is in money lending, it is a fact which you can do this with cryptocurrency. Most of the giving sites now focus on Bitcoin, many of these sites you're needed fill in a captcha after a particular time frame and are rewarded with a bit of coins for visiting them. You are able to visit the www.cryptofunds.co website to locate some lists of of these sites to tap into the money of your choice. Unlike forex, stocks and options, etc., altcoin marketplaces have quite different dynamics. New ones are constantly popping up which means they do not have a lot of market data and historical outlook for you to backtest against. Most altcoins have rather poor liquidity as well and it is hard to think of a reasonable investment strategy.
If you are looking for what is TANI spreadsheet, look no further than TAN.
What Is TANI Spreadsheet
Entrepreneurs in the cryptocurrency movement may be wise to research possibilities for making massive ammonts of cash with various kinds of internet marketing.There could be a rich reward for anyone daring enough to endure the cryptocurrency marketplaces.Bitcoin structure provides an informative example of how one might make lots of money in the cryptocurrency marketplaces. Bitcoin is an incredible intellectual and technical accomplishment, and it has created an avalanche of editorial coverage and venture capital investment opportunities. But not many people understand that and pass up on quite lucrative business models made available as a result of growing use of blockchain technology.
It's certainly possible, but it must be able to understand opportunities regardless of market behaviour. The market moves in relation to cost BTC … So even supposing it's in a BTC trend down can make money by buying the altcoins which are altcoin oversold trading ratios-BTC. Sure, your purchasing power in DOLLARS may be lower, but as long as your purchasing power in BTC is still growing you will be okay.


text:
Today a bomb targeted the Syrian PM Wael al-Halqi and killed only one or two of his bodyguards (This need to be confirmed). The PM walked from the explosive to the corner of the street when he was taken to the hospital as one of the citizen of that area said, but he was okay and nothing happened to him.
Only in Syria, the prime minister is targeted in a huge car bomb, then he continue to his office to keep working.
The Syrian TV podcast live from a meeting in the PM office, the PM of course stated the date just in case you were questioning whether or not it is recorded or not as some smart Arab journalist claimed.