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All About Jobs In Darjeeling, Kalimpong ,Kurseong, Mirik, Sikkim, Siliguri & Other Informations.
The DarjeelingForYou.com, Is Especially For Those Who Wants To More About The Darjeeling, Kalimpong, Kurseong, Mirik, And More....And We Provides Our Visitors The Following Information, Listed Down Below.
We Will Provide Our Visitors The Informations About "Darjeeling, Kalimpong, Kurseong & Mirik.
We Will Share You The Informations About The Schools & Colleges Of The Darjeeling, Kalimpong, Kurseong, Mirik Etc.
Darjeeling News Today, Kurseong News Live, Kalimpong News Today, Mirik Darpan News, Mirik News, National News, International News, Sports News And Many More.
This Is Our Main Motives To Inform You About Job Recruitments, We Will Provides You With The Best Jobs Notifications From All Over India & More.....All Indian Government Jobs News Updates.
Remember We Are Not A Jobs Recruitment Agency Or Consultancy, We Only Provides You The Latest Jobs Notifications From All Over India.
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"timestamp": "2019-04-26T05:39:47",
"url": "https://www.darjeelingforyou.com/p/about-us.html",
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Soft drinks can be bad for your waistline, your teeth, your bones, and more. (Yes, even diet ones!) Here's how to make giving them up easier.
You know soda's not exactly good for you—but at the same time, it can be hard to resist. Its sweet taste, pleasant fizz, and energizing jolt often seems like just what you need to wash down your dinner, get you through an afternoon slump, or quench your thirst at the movies.
But the more soda you consume (regular or diet), the more hazardous your habit can become. And whether you're a six-pack-a-day drinker or an occasional soft-drink sipper, cutting back can likely have benefits for your weight and your overall health. Here's why you should be drinking less, plus tips on how to make the transition easier.
The biggest risk for regular soda drinkers is the excess calories, says Lona Sandon, RD, assistant professor of clinical nutrition at the University of Texas Southwestern Medical Center. "The calories in regular soda are coming entirely from added sugar, and you're not getting any value in terms of vitamins or minerals, or even good quality carbohydrates," she says.
But soda may also be causing other types of harm. Studies have shown that its consumption is linked with tooth decay and diabetes, and it also seems to be bad for your bones. "It may have something to do with the phosphorus in soda, or it could be that people are drinking soda instead of other beverages—like milk—that have nutrients necessary for healthy bones," Sandon says.
But what about diet soda?
Plus, diet drinks have many of the same health risks as regular soft drinks, including tooth decay and bone thinning, and they've also been linked to heart disease and depression in women. Switching to diet sodas may be a smart first step if you're trying to eliminate excess calories, says Sandon, but your best bet is to eventually give them up, too.
RELATED: Should You Rethink 0-Calorie Drinks?
That news may be enough to convince you that you should stop drinking soda, but it could still be easier said than done. "People really can become addicted to soda, so you have to be a realist and not an idealist," says nutritionist Stefanie Sacks, author of the forthcoming book What the Fork Are You Eating?. "I don't recommend going cold turkey; you need to wean yourself off, just like you would anything you've become dependent on."
If you typically drink multiple servings of soda a day, Sacks suggests first cutting back to one a day. Give that two weeks, then switch to three sodas a week. "It gives you a chance to adjust gradually, which should lead to real, sustainable change," says Sacks.
Sandon also recommends weaning yourself slowly off soda, and sometimes suggests that her clients start drinking half-soda, half-water. "You're automatically drinking less and hydrating and filling up with water, which is a good thing," she says.
But there's an added advantage, as well: "It cuts back on the sweetness you get from soda, which is one of the things people get really used to. If you're drinking less sugar, your taste buds will change and soon you won't need that sweetness anymore."
Downloading a calorie-tracking app may help you realize just how much those beverages can affect your daily calorie consumption—as long as you actually log in and record each serving. Instead of pouring yourself refill after refill, start paying attention to how much you're actually drinking; once you do, you may be more willing to cut back.
Another way to quantify the calories you're drinking is by thinking about how much exercise it would take to burn them off. In a 2014 Johns Hopkins University study, researchers placed signs in corner stores stating that a 20-ounce bottle of soda would take 5 miles of walking or 50 minutes of jogging to burn off.
These "advertisements" worked: When teenager customers saw these signs, they were more likely to buy a smaller soda, a water, or no drink at all. "When you explain calories in an easily understandable way such as how many miles of walking needed to burn them off, you can encourage behavior change,” said the study authors.
Need that jolt of caffeine to wake up in the morning? If you're not a coffee drinker, Sandon suggests sipping on unsweetened iced tea instead. "It can be just as refreshing, and there are real health benefits to drinking the phytochemicals in tea," she says.
If you don't like the taste of plain tea, mix in some lemon, mint, or a small amount of sugar or artificial sweetener—at least during your transition-from-soda phase. The important thing is that you're aware of, and in charge of, exactly what's going into your drink and how much is added.
Whenever the urge to drink a soda hits, fill up a big glass of ice water and finish that first. "A lot of times, people drink soda just because they're bored, or they're thirsty, and that's what's available or that's what they're used to," says Sacks.
When Sacks has successfully weaned her clients down to just a few sodas a week, she often recommends they switch to a brand with fewer artificial ingredients. "They're more expensive, but you'll be drinking them less often," she says. Sacks likes Grown Up Soda, Santa Cruz Organics, and Blue Sky because they don't contain high-fructose corn syrup or artificial ingredients, and generally contain less sugar than the big brands. "They're an overall healthier choice, especially if you're only drinking them occasionally."
If it's carbonation you crave, try drinking plain or flavored seltzer water, suggests Sacks. You can buy seltzer by the bottle, or make your own at home with a SodaStream machine ($69, amazon.com).
"Toss a little fruit juice in there for flavor, and eventually change that juice to fresh-squeezed citrus," says Sacks. "That way you still get the bubbles that you love in soda, but you're in control of how much sweetness and sugar is added."
Even still water (or non-bubbly) can be made more palatable with the addition of some fruit or natural flavors. "People tell me they don't like water, but often they just need to experiment with new ways to drink it," says Sandon.
She recommends adding lemon, orange, or cucumber slices to a pitcher of water in your refrigerator, which can serve as a detour when you go hunting for a cold soda. Frozen berries and fresh mint can also be tasty additions to a cold glass of H2O.
If you drink a lot of soda and you're not quite ready to give it up, try buying caffeine-free versions instead. You may start drinking less without even realizing it, suggests a 2015 study published in the British Journal of Nutrition. In the study, participants were split into two groups and all told to drink as much soda as they'd like for the next 28 days. (One group got regular, one group got caffeine-free.) Even though there was no noticeable taste difference between the two, the caffeinated group drank 53% more over the next month—about 5 ounces a day. When our bodies get used to regular caffeine, we crave more of it, say the study authors, prompting us to drink more.
You may notice that you only drink soda in certain places or situations: In the afternoon at the office, for example, or when you eat at a certain restaurant. You may not be able to completely avoid these scenarios—you've still got to go to work and should still enjoy eating out—but you may be able to change those bad habits.
If it's the office vending machine that tempts you to buy a soda every day, try to stay away from it in the afternoon—and pack your own healthy beverage or a refillable water bottle so you have an alternative. Or if you tend to crave soda with a certain type of food, try restaurants that offer other options instead.
Weaning yourself off something gradually works best for most people, says Sacks, but some may want to try the cold turkey approach. If you plan to go that route, think of it as a temporary change: Giving soda up for two weeks or a month may be easier and more manageable than ditching it forever.
Once you're able to break your regular soda habit and the drink loses its grip on you, it can be treated just like any other junk food: If you really love the taste, there's nothing wrong with an occasional indulgence, says Sacks. "If it's your gotta-have-it food, then by all means splurge on a soda now and then," she says. In fact, knowing that you can have a soda on your cheat day or during a special night out may help you resist them on a more regular basis. "Just do it from a place of education: If you understand that soda is essentially just sugar and artificial flavorings, then you can be more smart about when or if you're going to drink it."
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{
"timestamp": "2019-04-23T15:00:50",
"url": "https://www.health.com/health/gallery/0,,20902395,00.html",
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This 12.5" wide Seaside Faux Moss wreath is a wonderful addition to your home. Designed to be hung indoors. It is 2.5" thick and the middle is 4" wide.
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{
"timestamp": "2019-04-20T22:29:17",
"url": "https://quickcandles.com/seaside-faux-moss-wreath-12.html",
"language": "en",
"source": "c4"
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|
7 years 7 months re-enable copying of SetFile, add line to copy fdisk440 to relevant package script folders. Add correct path to where fdisk440 for script to work. Next problem to sort is find where org.chameleon.Boot.plist is created??
7 years 7 months Sync these with trunk (r1485).
7 years 7 months Issue 163, FSB Detection cparm Branch !
7 years 7 months Change custom_ports to max_ports. Small tweaks and 2 max values added.
7 years 7 months Add brackets... fixes build.
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{
"timestamp": "2019-04-23T14:30:15",
"url": "http://forge.voodooprojects.org/p/chameleon/timeline/all/?_px_sk=creation_dtime&_px_so=a&_px_p=145",
"language": "en",
"source": "c4"
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Tracking gas prices are like having a roller coaster ride, at one moment they are down a little and the other they are up again. At times they even shoot up to around 50% in a year. One other strange fact about gasoline prices is that they are different everywhere; different in different countries, in different states and even different in different cities. Americans have an unquenchable thirst for gas. Just by looking at the traffic around you can imagine what it would be like if there is a shortage of gas. America is definitely going to cripple if there is no gas.
Department of Energy reported that Americans consume around 19 million barrels of oil products every day, half of this amount is used by motors all over America whereas the other half is used as fuel oil, jet fuel, residual fuel and other oils (Department of Energy, 2010). The factors that affect the prices of gasoline are the cost of crude oil, taxes associated to it, refining of crude oil and its distribution. Out of these four factors the major factor is the cost of the crude oil from which the gasoline is extracted.
In recent years the demand of gasoline and diesel has grown globally causing a steep demand for crude oil and as we all know when the demands go high prices are also increased in order to control the increasing demand. The demand growth is the main cause that has taken the price of crude oil and gasoline on a record level (Rowe, 2008). As the cost of crude oil is increasing it is causing the cost of delivery to rise as well. The delivery of the gasoline within the country is done through large fuel trucks that are needed to be fueled by gasoline in order to run.
Along with the transportation cost the heavily implied taxes on gas is also causing its price to go out of hands of the consumers. Since the prices of gas are constantly on a rise some people prefer driving to gas stations where they can save few cents on per gallon of gasoline. It is one of the ways to save dollars on the gas budget, if one acts smart and follow a few sensible steps then he or she can save a lot on gas prices. Gas prices vary from state to state. There are several reasons behind it, the most important being the tax factor.
Different states imposes different amount of taxes on gasoline. So, one of the options can be to get the tank full from a nearby state which imposes less tax on gas and offers slightly lower price. But it is only possible if one is living near to that state else driving all way the long to a different state just to save few dollars will be not smart enough. One other way can be to look on the internet for nearby gas stations that offer lowest available gases prices. There are several websites on the internet that displays rates offered by different stations in different cities and states.
By doing a little search on the internet one can easily figure out that at which nearest stations he or she can get lowest gas prices. Competition is one of the factors that cause gas pumps to offer lower prices. If there are a lot of stations situated in some specific region than there are chances that there will be a price war between them and each one of them will be trying to offer lowest possible gas price. Keeping an eye on such crowded areas can also help one save few dollars.
Distance from oil refineries is also one of the reasons that affect the prices at the gas stations situated near to them. As the refineries are situated nearby the pumps have to pay a very small amount of transportation cost. The reduction in transportation cost allows these gas stations to charge lower prices from their customers as compare to other pumps in the country. So having car fueled from such stations can also help one save few dollars. Although following the above mentioned ways can help one save a few dollars on gas, but it is not necessary that these situations are present all the time.
There may be circumstances where these options may turn out to be not so feasible therefore instead of relying on these options one should try to drive less. Instead of driving one can opt for different mode of transportation like travelling through bikes, buses, trains or may be having a walk to the desired location if the distance is walk able. This will not only help us saving money but also our environment which is getting polluted by the fumes that are coming out of our vehicles (Girard, 2008). References Department of Energy. (2010).
Crude Oil Is Getting Cheaper- So Why Isn’t Gas?
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{
"timestamp": "2019-04-19T20:23:54",
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To read more about Sundet Industrier and its companies, click here.
Sundet business group consists of 6 companies, distributed within the business areas Industrier and Handel. The companies are engaged in subcontract manufacturing, trading of industrial supplies and e-commerce with bicycles.
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{
"timestamp": "2019-04-21T20:31:22",
"url": "http://www.sundet.se/en/?page_id=158",
"language": "en",
"source": "c4"
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I’m located in London in the UK.
Technology means we can work together, wherever you are. Get in touch.
From my first job in London designing retail magazines I was then fortunate to be offered the chance to art direct Creative Review magazine.
Three years and a redesign later I left Creative Review when I was offered the deputy art director job on TIME magazine in London. TIME produced four international weekly editions in London and this exciting job saw me dealing with weekly schedules instead of the monthly ones and working closely with the US team on the NY edition.
After another three years on TIME I was hired as launch art director for ‘The Business’ for the Weekend FT. I came to the post with a full book of illustrators and I produced a very different business magazine.
The Financial Times closed the magazine in a round of cost-cutting some years later and I set myself up as Cook Design. I’ve worked for a lot of publishers and have enjoyed winning pitches for them, freshening up their titles or just working day-to-day on longer term design contracts. I am strong conceptually and have worked for consumer magazines and customer publishing houses.
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{
"timestamp": "2019-04-21T06:41:51",
"url": "http://www.cookdesign.co.uk/about-me/",
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I would like to wish you and your family a Happy New Year. With this letter, I hope to provide you with a brief overview of how investment markets have performed over the past year, as well as some perspective for evaluating your portfolio’s results in this context.
How did the markets do last year?
Well…not very well. It can easily be referred to as the year that no investment strategy worked. After an unusually calm year of solid performance for capital markets in 2017, investors experienced a much bumpier ride in 2018. Downward volatility resurfaced in the first quarter. Though markets moved generally higher through the summer months, a sharp sell-off in the fourth quarter meant that most asset classes registered negative returns for the year. For Canadian investors in foreign markets, losses were mitigated somewhat by the weakness of the Canadian dollar, which declined about 8% relative to the U.S. dollar for the year.
U.S. equities posted some of the best results among global assets in 2018, with the S&P 500 Index reaching an all-time high and setting a record for the longest bull market on record in the third quarter. After the fourth quarter sell-off, however, the index finished the year with a loss of 4.4% (a gain of nearly 4% in Canadian dollar terms). Canada’s S&P/TSX Composite Index, meanwhile, was weighed down by themes that included plunging energy prices as well as weakness in materials and financial services. The Canadian benchmark finished the year with a loss of 8.9%. From January 1, 2018 to Jan 1, 2019 the TSX went from 16,310 to 14,347.20 (a loss of 12.03%) and the Dow Jones fell from 24,824.01 to 23,346.24 (a loss of 5.95%). The MSCI World Index, a broad measure of developed market equities, fell 8.2% in U.S. dollars (-0.2% in Canadian dollars).
Central banks in North America continued to gradually raise interest rates throughout 2018. Ten-year U.S. and Canada government bond yields rose and peaked early in the fourth quarter, but fell through November and December to end lower for the year. The FTSE TMX Canada Universe Bond Index, which broadly reflects results for the Canadian government and investment-grade corporate bond market, gained about 1.4% over the 12-month period.
Although it is always difficult to pinpoint a single reason, several economic and geopolitical developments have been linked to 2018’s market gyrations. These include increasing trade friction between the U.S. and its trading partners, particularly China, and the fraught Brexit negotiations between the U.K and the European Union. Rising short-term interest rates in North America are leading to tighter financial conditions, while slower economic activity has weighed on commodity prices – particularly oil – and the materials and energy sectors.
Regardless of the cause, there is no doubt that market turbulence can be unsettling for investors, and last year’s volatile performance was particularly surprising following last year’s steadiness. The reality, however, is that downside market volatility is normal.
The chart below shows that in most years, the S&P 500 will experience several days in which the value of the index drops by 2% or more. In this context, 2017 was an outlier with nearly non-existent volatility. Last year, with 15 days registering losses of 2% or more, the level of volatility for the index returned to a more “normal” range.
Furthermore, it is nearly impossible to predict when market swings will occur. Studies have shown that investors who attempt to time the market – that is, sell before a downturn and reinvest when markets are poised to rise – often end up missing the best upside days and underperform relative to those who stay invested. Markets do not advance in a straight line, but historically the long-term direction for equities has been up.
In contrast to last year’s consensus outlook that pointed to a synchronized global economic expansion, many experts now believe we are in the late stages of the economic cycle, with global growth slowing and downside risks increasing. Nevertheless, developed economies are expected to grow throughout the coming year and inflation remains moderate. Global interest rates are low by historical standards, allowing corporations the flexibility to strengthen their balance sheets and invest in the future of their businesses. These conditions suggest a cautiously optimistic outlook for markets in 2019.
It can be difficult to set aside short-term distractions and maintain a long-term perspective when negative headlines dominate as they have in recent weeks. But looking back over the longer term, the most recent market decline can be seen as a setback in a strong run upward. From its lows reached following the financial crisis in March 2009 to the end of last year, for example, the S&P 500 was still up more than 270%.
I believe the most important action to take as an investor is to create a sound, diversified investment plan that takes your time horizon and tolerance for risk into account, and then to stick to that plan through periods of short-term volatility. As asset classes do not typically perform in a correlated fashion, diversification can help to insulate your portfolio from the highs and lows, and provide a smoother experience over time.
In closing, I would like to thank you for the opportunity to work with you as your Investment Advisor. If you have any questions or concerns about your investments, or if your personal circumstances have changed, please do not hesitate to contact my office, toll free at 1-866-860-4190 or directly at 613-491-3344.
Filed Under Investing · Comments Off on How did the markets do in 2018?
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{
"timestamp": "2019-04-24T07:58:35",
"url": "https://creatingwealth.ca/2019/01/",
"language": "en",
"source": "c4"
}
|
N avigate Morningside South Dakota map, Morningside South Dakota country map, satellite images of Morningside South Dakota, Morningside South Dakota largest cities, towns maps, political map of Morningside South Dakota, driving directions, physical, atlas and traffic maps.
With interactive Morningside South Dakota Map, view regional maps, road map, transportation, geographical map, physical maps and more information. On Morningside South Dakota Map, you can view all states, regions, cities, towns, districts, avenues, streets and popular centers' satellite, sketch and terrain maps.
On upper left Map of Morningside South Dakota (+) beside zoom in and (-) sign to to zoom out via the links you can visit. Morningside South Dakota Map move the mouse over it via (left click) and clicking the image you can drag. Right upper Map, Satellite, Terrain icons via the map view, satellite, hybrid and terrain map can be switch between images.
Please Not : You can find local businesses, public places, tourist attractions via map view, satellite image, hybrid view, driving directions in Morningside South Dakota Map. You'll also find a varity map of Morningside South Dakota such as political, administrative, transportation, demographics maps following Google map.
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{
"timestamp": "2019-04-21T04:46:27",
"url": "https://www.turkey-visit.com/map/Morningside-south-dakota-Map",
"language": "en",
"source": "c4"
}
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I love the soft colors in the picture, and isn't that afghan a work of art? I don't have experience with crocheting or knitting, but the pieced afghan reminds me of a quilt (which I have done). So for my card, I did kind of a honeycomb quilt pattern. I'm absolutely obsessed with hexagons and honeycomb style quilts are some of my favorite. I love they way they are vintage and modern all at once. So the pieces of my "quilt" are made from 5 different patterned papers.
Ever since I got my hexagon dies, I've had this card in my head. To mimic the soft look of the inspiration image, I pieced the hexagons on a layer of vellum. The entire piece of vellum is layered over the card base including the sentiment.
And a side note...this is the first time I used my new vellum adhesive runner. I was a bit skeptical at first, so I tried it out on some scrap vellum. It works perfectly! On my card, I put the adhesive over the sentiment so the vellum would really stay close to the cardstock. The adhesive is virtually undetectable even in person.
Now I'm off to go peek at all the wonderful other Moxie Fab cards! Thanks for looking!
This is beautiful and a wonderful idea!
Gorgeous card design!! Truly fabuulous!!
Just beautiful! Thanks for the vellum adhesive tip, too!
Wow, JJ! This is a fantastic card! So beautiful. I love the idea of using the vellum that way, and the patterned papers are just wonderful.
Thanks for popping over to my blog, I really appreciate your visit.
I love this!!! The colours, the patterns, the fantastic layout framing the pretty sentiment, the softness of the vellum... gorgeousness!
Awesome news about the adhesive - I'm gun-shy since I've bought so many vellum adhesives that didn't work that way.
|
{
"timestamp": "2019-04-26T11:47:45",
"url": "http://www.jjbolton.org/2011/08/moxie-fab-squares-to-cherish.html",
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1. Preheat the oven to 150°C, gas mark 2. Place the egg whites in an electric mixer and whisk on high until stiff peaks form. Gradually add the caster sugar, one tablespoon at a time, waiting 30 seconds before adding another. Once all the sugar is in, whisk for a further 6 minutes or until the mixture is stiff and glossy. Scrape down the sides of the bowl, add the cornflour and vinegar, and whisk until just combined.
2. Shape the mixture into a 22cm round on a baking tray lined with non-stick baking paper. Reduce the oven temperature to 120°C, gas mark 1, and bake for 1 hour 30 minutes. Turn the oven off and allow the pavlova to cool completely in the oven.
3. To serve, place the cream, icing sugar and vanilla paste into a bowl, and whisk until soft peaks form. Spoon the cream over the pavlova. Top with sliced stone fruits, berries and passion fruit. Serve immediately.
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{
"timestamp": "2019-04-24T18:11:03",
"url": "https://www.waitrose.com/content/waitrose/en/home/recipes/recipe_directory/d/donna-hay-s-pavlovawithvanillacreamsummerfruits.html",
"language": "en",
"source": "c4"
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Starting this fall, Windows 10 will be available as a subscription service for Windows 10 Enterprises. It was widely speculated, about Microsoft selling Windows 10 as a service someday as the company constantly referred it new OS “as a service” more than a product. Now, the company has finally announced subscription service offerings for Windows 10 along with its Surface tablets.
“Today, we are announcing Windows 10 Enterprise E3 in CSP. Starting this fall, businesses can get enterprise-grade security and management capabilities at just $7 a seat per month for the first time through the Cloud Solution Provider channel”.
Microsoft’s CSP partners will be able to provide a subscription to Windows 10 Enterprise Edition as part of a managed service offering. The company says that subscription is ideal for businesses who do not have dedicated IT resources or limited IT staff, and want their licensing and IT needs to be managed by a trusted and experienced partner.
Subscriptions are only for the businesses and not the retail consumers. Businesses are free to purchase Windows 10 copies and use if they do not want to opt for a monthly subscription. However, as an organization, if you want to use the whole bunch of Microsoft products without taking the additional burden of buying them and managing their keys and validity, a subscription is a good alternative to consider.
Through Microsoft Partners you get to choose from a bunch of Microsoft products or “call it services now” including Windows 10, Office 365, Dynamics Azure and CRM as a per user, per month offering through a single channel that you can change whenever needed.
Increased Security: Windows 10 features help businesses secure sensitive data and identities. It also helps to ensure devices are protected from cybersecurity threats.
Simplified Licensing & Deployment: Subscription would eliminate the need for time-consuming device counting and audits, and would make it easier to stay compliant with a subscription-based, per-user licensing model.
Partner-managed IT: Configuring and managing devices by a partner experienced in Windows 10 and cloud deployments would relieve organizations of maintaining IT staff.
Microsoft also introduced the Surface as a Service Program and Additions to the Surface Enterprise Initiative. Microsoft’s Cloud Solution Providers (who are also Surface Authorized Distributors) will now offer Surface devices through a managed service offering to all of Microsoft’s resellers and customers, alongside managed cloud services, Office 365, Windows OS and relevant ISV software.
For more information on the subscriptions, click here.
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{
"timestamp": "2019-04-26T08:47:49",
"url": "https://news.thewindowsclub.com/windows-10-and-surface-will-be-available-as-subscriptions-84924/",
"language": "en",
"source": "c4"
}
|
This Refrigerator Water Filter is used in Whirlpool® and KitchenAid® side-by-side and top mount refrigerators with filter access inside the refrigerator. Simply turn the Refrigerator Water Filter 1/4 turn to remove and replace. While retaining beneficial fluoride, this NSF® Certified Refrigerator Water Filter reduces cysts, asbestos, chlorine taste and odor, particulates (class I), lead, and mercury. The contaminants or other substances removed or reduced by this water filter are not necessarily in all users' water. Replacing this Refrigerator Water Filter every 6 months ensures clean, safe drinking water. This package includes three Refrigerator Water Filters.
|
{
"timestamp": "2019-04-22T11:00:37",
"url": "https://www.kitchenaid.com/major-appliances/refrigeration/accessories/ice-makers/p.refrigerator-water-filter-interior-turn-cyst-3-pack.8171414t.html",
"language": "en",
"source": "c4"
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|
Want to play cricket at one of the most dominant clubs within the Box Hill Competition? Please click on the image above or click here to register to play cricket at Heatherdale Cricket Club.
Heatherdale Cricket Club has a very proud history and is one of the key clubs in the Box Hill Reporter District Cricket Association. You can learn more about the clubs history by clicking here.
No club can survive without the support of sponsors. This section is dedicated to the businesses that support our club and players.
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{
"timestamp": "2019-04-23T10:52:46",
"url": "http://www.heatherdalecricketclub.com.au/",
"language": "en",
"source": "c4"
}
|
Please see below the positions we are actively recruiting for.
Looking for a reliable and hardworking lettings manager. Preferably with previous experience working within a lettings/estate agency.
Roles will include rental valuations, tenant referencing and day to day lettings management and organisation.
If you are interested in the role based in Longridge Lancashire, please email your CV and cover letter to: sales@goestateagency.co.uk.
|
{
"timestamp": "2019-04-24T08:47:25",
"url": "http://www.goestateagency.co.uk/careers",
"language": "en",
"source": "c4"
}
|
0%84°60°Partly cloudy with a high of 84 °F (28.9 °C). Winds variable.Night - Clear. Winds from E to ESE at 2 to 6 mph (3.2 to 9.7 kph). The overnight low will be 65 °F (18.3 °C).
75%75°65°Thunderstorms today with a high of 75 °F (23.9 °C) and a low of 65 °F (18.3 °C). There is a 75% chance of precipitation.
Tonight - Clear. Winds from E to ESE at 2 to 6 mph (3.2 to 9.7 kph). The overnight low will be 65 °F (18.3 °C).
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{
"timestamp": "2019-04-18T17:59:51",
"url": "https://www.yahoo.com/news/weather/paraguay/san-pedro/yataity-del-norte-379153",
"language": "en",
"source": "c4"
}
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This web site is updated daily. Hit refresh if it looks the same as yesterday.
The following photos are absolute proof they drained the dams on purpose, causing severe flooding and NEVER gave california growers a SINGLE DROP for the sole purpose of killing all the orange orchards, grape vineyards and almond groves. It is important to note that with any war effort waged by the usurpers of a conquored government, that fake documentation will be produced by the government to support the lie. That is when you have to use photos to prove that the documents, which show a drought and reduced out flows, are fake.
HERE IS THE PROOF. 2011 was called a drought year that was so bad they could not give the farmers any water (heads up, this is good).
WELL, People noticed that, so they hatched the lie that the flooding happened because the rain was selective, and all fell in the valley and not in the mountains, which is why the dams were "empty" and they could not give the growers any water. And the media stuck with the lie, and the people trusted the media. BIG MISTAKE.
CHECK MATE, THE ENEMY OF AMERICA, THE NEW WORLD ORDER AGENDA 21 ZIONIST, HAS BEEN BUSTED. HOW CAN YOU GO FROM HAVING THE DAMS BE LIKE THIS, ABOVE, IN 2011, GIVE THE GROWERS NO WATER AND THEN HAVE THE DAMS LOOK LIKE THIS, BELOW IN 2013? THEY DON'T JUST DRY UP, YOU ARE BUSTED.
My guess for all of this? It is possible they are bankrupting all the growers by killing all the legacy trees via denial of water, trees which are not GMO, so that one billionaire can move into the valley, buy it all, plant it entirely with GMO and ram GMO down America's throat. It could also be that they are planning a mass starvation of the American people, and the San Joaquin, which produces practically everything from almonds to grapes to strawberries to oranges, enough for much of the world, has to be killed before they can actually succeed in starving America. With much of what the San Joaquin produces, you can't get it back in a year, it will take decades so it won't do any good to just start managing the water properly once everyting is dead, it will take years to come back. By then the starve off will have been accomplished.
They responded to this article QUICKLY. There is no underground water left as some state, all of it was pumped out in 2009 and 2010 to save the orchards when they cut the water off, and now the ocean has back flowed all the way to the valley and they can only pump salt. The water is GONE. And WHY was the San Joaquin at flood stage for three consecutive years during a "drought" if they were not letting the dams go to kill the San Joaquin valley ON PURPOSE as I clearly show below?
DO NOT fall for the lies which have been and will no doubt continue to be hatched to bury this act of war, a little common sense will go a LONG WAY here. The original reason for the water shortage was to save the "delta smelt", and they evolved it into a lie about a drought which never happened. The truth is that in the bay there were salinity problems with certain species due to too much fresh water entering the bay. Its all documented here folks, read it and weep for the California Orange.
I am re-posting this with updates because it is so important.
I was actually in the San Joaquin valley when the effort to destroy it started. In 2008 I saw the Sacramento river carrying all the water from the dams straight to the ocean, it was obvious they opened the dams to intentionally drain them. During this time, when the river should have been at a low point, it was at flood stage and even after having a lot of experience with dangerous rivers such as the Mississippi, and having seen the Yukon at flood stage, the Sacramento river was absolutely spooky to see at this time - obvious death for even an experienced swimmer.
During this time, the media was pushing the lie about how water was limited, all the while they were draining it to the ocean - "limited" because "there was a drought." But reality is that the rain in California has been within a perfectly normal range for the last 10 years, there has been no drought and even if there was a drought the reservoirs that were built to supply the San Joaquin had enough reserve, absent being drained, to keep California agriculture alive for a full five years with no rain at all.
Now, (for the last six months) there really has been less rain than usual, and it is obviously caused by chem trails and Haarp. They are manufacturing a real drought at this time in the hopes that people will not realize that prior to now the rain has been perfectly normal over the last 10 years and STARTING NOW, the San Joaquin should with a truthful lack of rain be able to hold on for five years. Unfortunately the dams are already drained so they will succeed at killing the San Joaquin this summer, the summer of 2014.
After draining the dams on purpose was done by the "elite" to destroy the San Joaquin valley, Haarp is being used to finish the job with a real drought. Read on, I have proof that this has been in the works for six years.
Many of the orchards and prime agricultural zones have already been intentionally killed via denial of water by the choice of the elite. This was caused by draining all the dams and flushing all the water out to the ocean ON PURPOSE. And if you believe the lies in all the stats and charts used to cover up this horrific fraud of a drought on America,TAKE A LOOK AT THIS VIDEO AND ASK YOURSELF,WHY WOULD THEY LET THAT MUCH WATER GO IF THE DAMS WERE EMPTY? THAT FLOOD SHOULD HAVE BEEN USED TO FILL THEM.
America's enemies which have taken control of the country by the throat obviously want the San Joaquin gone from America's list of assets. The San Joaquin is a natural desert, which was only brought to life via irrigation projects and reservoirs. No "drought" can change this fact. Several people who are among the "elite", most notably Warren Buffet bought all the reservoirs in violation of law (at least the original law the reservoirs were agreed to be built under) and drained them into the ocean rather than give the water to the farmers (which also violated the water contracts the farmers signed onto) in the name of an imported and not native fish called the Delta Smelt. These fish were brought into California around 100 years ago and are not natural to the area at all.
There has ALWAYS been plenty of water in California. The irrigation projects were vastly overbuilt and were more than enough to handle an extended drought, (which there in fact has not been despite claims) up until now. But once America's enemies among the elite got control of the dams, they simply opened the floodgates and sent all the collected water straight to the ocean down the Sacramento river, causing a large amount of flooding and draining the water supply that California orchards and agriculture needs to survive. And they did it in the name of a fish that did not belong there anyway, an obvious act of war. Since the farmers subsequently did not get their water, a lie of drought was hatched in the mainstream media (including mainstream fake alternative media), a lie laid waste by the rainfall chart that even Rense posted.
This was an act of war against the American people, launched by NWO elitists to destroy America's most prime agricultural zone. Make no mistake, the New World Order crowd absolutely HATES America, and will be America's "friend" only to whatever extent it takes to deceive an ignorant populace long enough to have that populace stand idly by as America's greatest assets are WIPED OUT.
The San Joaquin agricultural zone was far too much of an asset for America's conquerors to tolerate having around, so they just took control via government corruption afforded by rigged elections and shut off the water.
Now there are hundreds of miles of dead orchards there, stretching as far as the eye can see. And the State mandates that the growers cut these dead orchards down, so six years into this war there are equally vast expanses of dead earth that were only a short time ago fertile orchards.
So when you hear MANY in the so called "truth movement" haarp all about how the San Joaquin died because of Fukushima, KNOW THE LIE. MANY IN THE "TRUTH MOVEMENT" HAVE EVOLVED INTO BEING THE ENEMY OF TRUTH. Let's PROVE IT RIGHT NOW, with a few pictures of the San Joaquin from MORE THAN A YEAR AGO, LONG before this so-called "drought" which happens to be Haarp caused and actually is real. REAL BUT IRRELEVEANT, THE SAN JOAQUIN IS ALREADY DEAD.
Here is the California precipitation chart everyone is now quoting. Look at the history here, there have been plenty of other periods that were a little bit dry. The only dry period on the chart is the recent Haarp attack that has spanned five months, since September of 2013 (when the water year starts) up until now, in Feb of 2014. The real drought, the HAARP drought has only been going on for FIVE MONTHS. 5 months won't empty the dams or kill orchards. LOOK AT THE CHART BELOW, AND THEN TRY TO EXPLAIN THE FOLLOWING PHOTOS OF EMPTY DAMS. WHY ARE THEY EMPTY ALREADY, WHEN UP TO SEP OF 2013 THE RAIN WAS WITHIN A NORMAL RANGE?
The chart from Forbes PROVES: These orchards are NOT dead because of drought and the dams are NOT empty because of drought, they are empty because a few priviledged enemies in the New World order got into America's government and chose to drain them so they can get America by the throat in a future catastrophe THEY ENGINEERED. The enemy would surely love to blame it on Fuku, DO NOT let a lack of knowledge draw you into that trap.
The photo to the left, which Rense posted clearly shows that Haarp is indeed being used to stop the rain from reaching California. But this is being done to create a real drought only AFTER the San Joaquin has been severely damaged from lack of water. 2011 gave the orchards another year, up until 2010 the farmers were able to pump wells to water the valley. But the wells went mostly dry by the end of 2010, and 2011 was a godsend because they had no other water, and were denied it from the reservoirs, water which they got from a very wet year that should have filled the reservoirs. I know, I WAS THERE DURING IT. It rained all the time and this saved the orchards. But after 2011, the orchards took a severe beating from being denied water during a normal precipitation year following a very wet year that should have filled the reservoirs, and this haarp blockage will no doubt be the final death sentence for the San Joaquin, because even if there is an agreement to save the orchards, the NWO crowd already emptied the dams. There is no where to go now.
Wow. Finally I am validated. You said exactly what I have been saying, that we have NOT been in a drought, that our water has been normal for years, that yes we had little rain this year but we could see blatant chemtrailing which caused it. I live in Santa Barbara where our Lake Cachuma has gone almost dry. I have considered it might be partly due to fracking, but the water system has no particular connection to oil wells here. When we moved here, SB had been in a drought for 7 years, still the Lake was fairly full. It was, they said, the first day of rain they had had, although they did have a few inches every year prior, just not much. I came from LA where I participated in 3 or 4 dry times when water was rationed. I AGREE WITH YOU that this has been done on purpose. I am a lifelong Californian. I know my environment.
But, I had zero idea, had not heard at all, that they were draining the dams into the ocean. Makes total sense. I do remember one year (1970-ish) when Lake Shasta was almost dry, but it came back the next year. Lake Shasta currently seems to be the focal point of destroying our environment according to Dane Wiggington.
So, Thanks for your article, but I think even if I print it out and give it to my friends and family they will likely dismiss it -- I am continually amazed at how extremely educated people do not see what is happening!
The bankers have propped up the American dollar and made sure everyone got their antidepressants and stayed fat and happy. That keeps them from asking any questions. Hungry people ask questions, and when the hunger starts, the elite want there to be NO WAY to make it go away. That's how wars are often fought, and it will all be blamed on nature because people have been educated into blind stupidity as a preparatory move before killing them like idiots.
I am a Southern-California resident. I wanted to give you some supporting facts in regards to the California "drought."
I have been living in California for over 20 years. According to this site http://d35brb9zkkbdsd.cloudfront.net/wp-content/uploads/2014/03/20140304_CA_trd-638x501.jpg, I live in a "D3 Extreme Risk" Zone for drought, the second worst risk in the state. Despite these assertions by the State and the weather "authorities," I have not seen any evidence of drought, not in the last few years as compared to the last few decades, nor in this last year as compared to the last few years. Meaning: I haven't noticed these past few years to be any drier than the past 20 years. Nor have I noticed that this last year, 2014-2015, has been any drier than than the years between 2010-2014. In fact, about two years ago I moved to a new house. I was told that during rainy season, a small waterfall sometimes formed in a secluded part of the property. However, I never saw it form during the rainy season of 2013 - 2014. This year, though? This year a waterfall DID form, and it was beautiful, and flowing. So apparently the drought is not bad enough to prevent a seasonal stream/waterfall from forming in one of the most dry parts of the state.
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Daniel J. Costa joined Pircher, Nichols & Meeks in 2015 and is an associate in the firm’s real estate department.
Mr. Costa represents institutional investors and developers in connection with complex real estate transactions, with an emphasis on acquisitions, dispositions, financings and development. Mr. Costa’s experience includes a wide range of asset types, including office buildings, land for residential development, and retail, mixed-use, and hospitality projects.
Representation of a private investment firm in the lending of funds pursuant to mortgage and mezzanine loan facilities to facilitate the acquisition of a hotel located in Indianapolis, Indiana, secured by the hotel property and equity interest of the mortgage borrower.
Representation of a national casino chain in the disposition of real property formerly used as a hotel and casino to a state university for future development as a university campus.
Representation of a pharmaceutical company in the acquisition, and partial leaseback, of a pharmaceuticals production facility in Corona, California.
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"timestamp": "2019-04-23T02:56:13",
"url": "https://www.pircher.com/attorneys-daniel-costa.html",
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Our advocates offer advice on all aspects of commercial and contractual disputes. From the interpretation of contractual terms to representation at arbitrations and in the commercial court, members of Compass are alert to the commercial and economic considerations of clients.
As such, Compass encourages the early involvement of members in providing advice. Members are willing to recommend and appear at mediation when appropriate.
Agents are actively encouraged to discuss and agree fee structures in advance of instructions thereby providing some level of certainty in relation to costs.
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{
"timestamp": "2019-04-20T14:30:56",
"url": "https://www.compasschambers.com/practice-areas/other-areas/contract-and-commercial-litigation/",
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Anxiety is an emotional state of chronic, non specific persistent fear, worry and over concern about everyday matters not focused on any particular object or situation.
Do you cancel engagements at the last minute?
Homeopathy can do unbelievable wonders. Everyone experiences anxiety to some degree. Most people feel anxious before exams, before results, first date, interview, public appearance or speech.
Mild to moderate degree of anxiety is normal and beneficial. It helps people to prepare and be focused.
Superficial attempts to change one’s lifestyle may not work in severe cases of anxiety because they fail to address the root issues that lead to symptoms of anxiety.
Numerous well proved homeopathy medicines are available for cure of anxiety.
Homeopathy offers excellent treatment for anxiety neuroses in early stages, chronic cases and also in severe cases where the dose of conventional medicine is ever increasing.
Patients already on medications are asked to continue same along with homeopathy initially.
Homeopathy helps to improve sleep, regulate appetite, reduce panic attacks and negative thoughts bringing peace and sense of well-being.
Homeopathy is safe, gentle, free from side effects and not habit forming.
It helps to reduce the dose of conventional medicines over time.
Homeopathy makes you peaceful and brings you in the present.
Classification – generalized anxiety disorder, phobias, panic disorder, obsessive compulsive disorder, post trauma stress disorder, separation anxiety, situational anxiety (that something harmful will happen).
Causes – drugs (alcohol, caffeine, benzodiazepine), stress (financial worries, physical illness, death of loved one, social interaction, self image), genetics.
Symptoms – excessive worry, restlessness, fatigue, difficulty in concentration, irritability, sleep disturbance, muscle tension, tremors, headache, sweating, palpitation, weight loss, and impotency.
Depression is a state of persistent sadness that affects thoughts, behavior, feelings and sense of well being. People with a depressed state of mind can feel anxious, hopeless, helpless, worthless, guilty or ashamed. They lose interest in activities that were once pleasurable.
Do you feel sad, tired and miserable for no reason at all?
Homeopathy is one of the most popular holistic system of medicine. It calls for individualized homoeopathic prescription of remedy to each patient.
Homeopathy is deep acting and addresses root cause of depression.
Homeopathy prescription takes into account not only medical history but family history, past history, physical & psychological characteristics of the patient. This helps to find the cause, precipitating factors and hereditary tendencies in cases of depression.
It is gentle, safe and free from side effects.
Homeopathy and counseling go hand in hand. Every patient of depression receives constant support and motivation at Global Homeopathy.
Patients find improvement at work, personal and social life. It is persistence and perseverance of treatment along with support of family members that helps to uproot depression.
Causes – Depression is caused by a combination of genetic, biological, nutritional, environmental and psychological factors.
Symptoms – loss of appetite or overeating, difficulty in concentration and decision making, may attempt or commit suicide, insomnia or increased sleep, fatigue, aches and pains.
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"timestamp": "2019-04-23T14:36:47",
"url": "https://globalhomeopathy.in/anxiety-depression/",
"language": "en",
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Deep green, broken-cell chlorella has 78% digestibility. It contains 12 naturally occurring nutrients including beta-carotene, vitamins B1, B2, B3, and B12, and biotin. It contains chlorophyll and nucleic acids, plus organic germanium. It is rich in protein. This broken-cell chlorella is of the highest quality.
Take 1 teaspoon (2.5 g) twice daily mixed in with water or juice, with food, or as directed by your health-care practitioner.
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{
"timestamp": "2019-04-24T18:36:24",
"url": "https://purepharmacy.com/products/new-roots-chlorella-150g",
"language": "en",
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Hand drawn advertisement in the style of vintage Côte d'Azur travel posters for the Plaza Hotel's Provence at the Plaza activation.
Illustrated advertisement for Dream Hotel Group's Meatpacking hotel, Dream Downtown. I created this ad when I was an art director at Dream Hotel Group working under the brilliant visionary and one of hospitalitydesign.com's Next Gen Brendan McNamara. I drew this ad using the digital illustration app Procreate on the iPad. Brendan and I brainstormed the concept with Nylon Magazine's demographic in mind. The ad depicts a romantic fall sunset on the hotel's PH-D Rooftop Lounge.
The editor, Nahid El Massnaoui, is a Moroccan professional surfer*, a sharp entrepreneur, and has an impeccable eye for beauty & fashion. She balances work and play as brilliantly as she balances on a surfboard. She has a positive attitude to life too, “As soon as I step into the water, a big smile draws on my face and whatever the conditions are like I feel accomplished.” Read on at theworkingsurfgirl.com.
*Nahid is also the first Moroccan surf girl to be featured on the cover of a surf magazine! Check out the story at: Surf Girl Magazine.
Illustration featured on How You Glow’s Social media channels. This dual portrait was created in collaboration with How You Glow founders Jessie Groveman and Tara Sowlaty who believe in the positive vibrational energy that makes us GLOW from the inside out. HOW YOU GLOW is the lifestyle source for health-driven individuals seeking inspiration, nourishment, tips, tricks, and solutions on how to get the GLOW. HYG gives readers access to health trends, shoppable stories, product/restaurant/fitness/book reviews, monthly emails, and inventive nourishment. But most importantly, they empower their readers to live delicious lives that make them light up from within.
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"timestamp": "2019-04-23T08:59:22",
"url": "https://liastrasser.com/news",
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Everyone here has a different role to help us all move forward. Some will make you face your truth by triggering you, some will pamper you, some will do both.
The fallacy is in expecting everyone to see/do the same thing.
You may not always like the answers you are given especially if you are looking for validation. Often in retrospect you will find that the truth of the situation that someone else saw, is a truth you simply were not ready for.
You may need to ask yourself "is there an element of truth here that I need to hear right now?
If so, what is it?" And do some honest digging.
Many right now are getting triggered and tested more and more often. The closer to Union the faster and more furious the triggers to clear out what you need to heal.
See these triggers are opportunities, not a need for alarm. In this opportunity it is important to be honest with yourself.
If you are triggered there is a reason: You need to GROW.
How do you know when you are triggered?
You are angry, offended, sad, you need to make the other person see your point of view and agree with it. These are all elements you need to heal within from your past, not for others to tiptoe around (which would be control).
Where have I felt this before?
Is this something I have experienced many times with many people?
Where does this come from in my childhood/past?
What do I need to change in order to move forward and not blame others for my reactions?
What do I need to heal?
This journey is meant to teach us recognition, truth and to release what no longer serves us. What no longer serves is usually FEAR/EGO based reactions to things. This fear manifests as rejection, abandonment, the need to be right, being easily offended/taking everything personally, etc.
Not all are on the same path, not all are Twin Flames, and not all need to agree on every tiny detail.
You cannot make a Zebra a Bear.
They are both animals, but they are not the same type of animal.
Not all lightworkers are Twin Flames for a reason, all have a different purpose to move this planet forward to evolve.
Accepting yourself for who you are and accepting differences in others is vitally important on this journey.
Expecting all to be and think exactly alike only holds you back.
Go WITHIN as that is where your TRUTH lies. Not in what others have to say.
If you are worried what others say or do, or need validation from others for your own truth, you are on the wrong path.
Once you KNOW your truth, nothing anyone says or does will bother you, and you will be triggered less and less.
the freedom to be yourself and accept that others can also be themselves and not be wrong.
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"timestamp": "2019-04-21T10:40:23",
"url": "https://www.heartsinbalance.com/coming-into-balance---blog/triggers-and-the-freedom-of-letting-go",
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This final development of the Beocord 8000 range offered Dolby C NR in addition to the B type fitted to previous models. Dolby C did not prove very popular, certainly pre-recorded tapes were never encoded this way, and few other recorders offered it. This limited the usefulness of the system then to making good recordings to be played back on the Beocord 8004 itself only, even the lesser models in B&O’s own range did not have Dolby C decoders. Text copyright © Beocentral. Unauthorised reproduction prohibited.
The end of Beocord 8004 production marked the end of the series, though by this time the Beocord 5000 had appeared, but even though this offered Dolby B and C, and the HX Pro system, this is the last that would be seen of the real time tape counter, direct access to any time on the cassette and the built in programming facility. Text copyright © Beocentral. Unauthorised reproduction prohibited.
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"timestamp": "2019-04-21T04:24:24",
"url": "https://beocentral.com/beocord8004",
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Fate/stay night [Heaven’s Feel] II. Lost Butterfly will be showing at selected SM Cinemas beginning April 3. It is a Japanese anime film which focuses on the story of the Holy Grail War and explores the relationship between Shirou Emiya and Sakura Matou, two teenagers participating in this conflict.
The story continues immediately from Fate/stay night: Heaven's Feel I. presage flower, following Shirou as he continues to participate in the Holy Grail War even after being eliminated as a master. It is the second film in the Fate/stay night: Heaven's Feel trilogy.
Ticket price ranges from ₱170 ~ ₱285 depending on the location.
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"timestamp": "2019-04-19T17:23:06",
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Martin Mooney’s poems are darkly comic, muscular, inventive and highly charged. Politics simmer beneath the surface of poems that find their energy in the everyday urban experience, be it work at the shipyards, an early morning fishing expedition, the building of houses, or a visit to the local pub. A patently Irish humor, replete with shadows and irony, informs the poet’s observations—and the second part of the collection is a kind of novella through poetry that follows the exploits of a young Irish expatriate and a cast of people on the fringe as they stumble through daily unpleasantries.
MARTIN MOONEY’s poetry, short fiction, reviews, criticism and cultural commentary have been published in Irish and British periodicals. Following Grub, which on its original release in Ireland won the Brendan Behand Memorial Award, Mooney published Bonfire Makers, Operation Sandcastle, and Rasputin and His Children. His poems have appeared in Field and The Gettsyburg Review. He was writer-in-residence as the Brighton Festival and the Aspects Festival of Irish Writing, and twice was appointed a member of the resident faculty at The Robert Frost Place Poetry Festival in Franconia, NH.
fine collection . . . lyrical but never precious, moving but never mawkish, political but never hectoring . . . a very impressive debut.
and worship the god machinery.
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How To Build Perfect Arms in Dubai, detailed step by step Plan. In this comprehensive info on building perfect arms, we will cover, how to get An Upper-Body Boost, Upper Body: Pilates Chest Expansion, Swimming moves to build arms, Upper Body: Active Cat, Arms: Plie with Bicep Curls, Arms: Tricep Press and much more. Below we also provide you with contact details to get in touch with one of Trainer.ae personal training experts who can help create a personalised plan just for you.
Your arms and shoulders take part in almost everything you’ll do this summer, from carrying a cooler to the beach to playing tennis to performing Downward Facing Dog. But unless you’re lugging around lots of heavy objects on a daily basis, they’re probably not reaching their full potential.
To build strength, endurance, and resilience in your upper-body muscles, try the following exercises twice a week. Your newfound strength will give you a boost of confidence — not to mention, you’ll look great in a tank top.
What it does: Strengthens the triceps and deltoids, as well as core muscles. Increases lung capacity, expands the chest, and strengthens back muscles.
How to do it: Hold a 2- to 3-pound weight in each hand. Stand with heels touching and toes pointed out about 45 degrees (don’t force your feet apart beyond their natural range). Squeeze thighs together and engage the buttocks and abdominal muscles, creating one long line with the body. With your arms extended forward at shoulder height, take a deep breath, filling out the chest, and press the arms straight back as high as you can, maintaining your position. Holding your breath, turn your head left, center, right, and back to center. Exhale and lower arms. Repeat 4 to 6 times.
What it does: Works the muscles of the back, deltoids, legs, and triceps. Increases shoulder stability. Engages and strengthens the core.
How to do it: Stand with feet parallel, hip-width apart. Bend over at 90 degrees (or less if this is too difficult). Keep knees slightly bent and engaged. With weights by your ears, inhale deeply and extend the left arm out straight in front of you (palm down), and the right arm behind you (palm up). Draw arms back in. Repeat on the other side. Do 4 to 8 times.
What it does: Strengthens the entire front and back of the upper body, as well as the lower back and glutes in a Vinyasa-type flow.
How to do it: Start in a modified push-up position, knees on the floor. Inhale and lift your right leg up and back, opening up the hip and working the lower back. Exhale, lowering the upper body to 3 to 5 inches above the mat. Inhale and return to push-up position, and then exhale, curling your body under and drawing your right knee into your forehead. (See next slide.) Repeat with the other leg. Alternate, doing 3 to 5 reps on each side.
What it does: Works the biceps; strengthens legs and arms together for faster results.
How to do it: Stand with legs 3 feet apart, toes rotated out, knees pointing over the toes. Hold a 2- to 3-pound weight in each hand. (For a greater challenge, increase to 5 pounds.) Engage your core and buttock muscles. Bend your knees to a challenging (but not painful) degree, keeping your spine tall and your knees aligned with your second and third toes, as you raise your hands to your collarbone. (See next slide.) Hold for 3 breaths, and return to starting position. Repeat 10 to 15 times. Do 3 sets.
What it does: Tones and develops the triceps.
How to do it: Hold a 2- to 3-pound weight in each hand. (For a greater challenge, increase to 5 pounds.) Stand with feet shoulder-width apart, bending at the hips with a flat back. Let your arms hang down, palms back. Take a breath and then exhale, pressing the arms back until they’re slightly raised above the hips. (See next slide.) Repeat 10 to 15 times. Do 3 sets.
What it does: Improves upper-body strength without strain.
How to do it: Press your belly into the top of a stability ball. Extend your arms down to the floor. Position yourself on the ball so all of your torso and hips are in front of the ball and your shoulders are directly aligned above your wrists. Keep fingers pointing forward. As you inhale, bend your elbows and lower your upper body toward the floor, keeping abdominals strong. (See next slide.) On an exhale, straighten your elbows. Repeat 8 to 10 times.
What it does: Works the rhomboids and latissimus dorsi as well as the biceps, making it easier to pick up heavy items. Also wards off age-related loss of flexibility in the shoulder joint.
How to do it: Stand with your left side facing the front of a chair that has no arms (you can also use a bench), holding a weight in your right hand. Bend and rest your left knee on the chair, grabbing the side edge of the chair with your left hand; your right arm should extend down toward the floor. Keep your spine straight and core tight. Moving to a three count, bend the right elbow and lift the weight straight up. Slowly return to the starting position using a three count. Complete 8 to 12 reps. Switch sides and repeat with weight in left hand.
What it does: Works the deltoids and trapezius, along with the triceps. Builds strength for overhead lifting and movements, making it easier to perform actions such as retrieving items off high shelves or powering up a tennis serve.
How to do it: Stand tall with a weight in each hand. Keeping your core tight, raise the weights until your hands are at the same level as your ears; palms facing forward and elbows pointing out. This is the starting position. Press the weights straight up to a count of three (see next slide), then lower them back to the starting position to a count of three. Do 8 to 12 reps.
What it does: Builds strength and endurance in the trapezius and rhomboids, as well as in the levator scapulae. Helps prevent injuries when performing overhead actions such as lifting luggage into a bin, and makes it easier to carry heavy items for long distances.
How to do it: Stand with feet hip-distance apart, arms by your sides and weights in your hands. Keeping your body stationary, core engaged, and shoulders down, draw your shoulder blades back so they reach toward each other. Now, to a count of three, slowly lift your shoulders up toward your ears as far as you can go without compressing your neck. (See next slide.) Then lower them back to the starting position, also for a count of three. Repeat for 8 to 12 reps.
Get in touch with us today, Group fitness classes and one on one personal training from male and female personal trainers available in Dubai, Abu Dhabi, Sharja, Ajman, Al Ain or RAK. Your health is more important than you know.
Posted on 5th September 2015 by admin. This entry was posted in Fitness plans Dubai and tagged Arm Exercises for women in Dubai, Arm exercises for women in UAE, Arm Exercises with Stability Ball, Upper Body: Pilates Chest Expansion Dubai. Bookmark the permalink.
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There are currently no Elmwood Bloomdale, OH notable alumni listed. Be the first to add an EHS famous alumni.
This section is to remember Elmwood High Bloomdale, OH alumni who have passed away.
There are currently no memorials for Elmwood Bloomdale, OH alumni.
Even if alumni from Elmwood High School have moved away from Bloomdale, Ohio, they can use this site to find and contact high school friends. Elmwood High School alumni can relive their experiences from high school by sharing memories and pictures, reconnecting with those alumni listed, and more. If you are a former student of Elmwood High in Bloomdale, Ohio, register now to add your name.
Cynthia Bishop has someone searching for them.
Edward Smith 111 has someone searching for them.
Carol Weekman has someone searching for them.
Luanne Lyons has someone searching for them.
Micheal Smith updated his profile picture.
Micheal Smith registered as a EHS Class of 1973 alumni.
Micheal Smith added photos to their personal photo gallery.
Chris Garner Barnett updated their profile picture.
Chris Garner Barnett registered as a EHS Class of 1993 alumni.
Chris Garner Barnett added photos to their personal photo gallery.
Gail Sweeting updated her profile picture.
Gail Sweeting registered as a EHS alumni.
Gail Sweeting added photos to their personal photo gallery.
Wilms Kelly Jean updated her profile picture.
Wilms Kelly Jean registered as a EHS Class of 1981 alumni.
Wilms Kelly Jean added photos to their personal photo gallery.
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The breeze stirred the neatly cut bushes of Tisovaya Street, silently lying under the ink- black sky. Lo Hobbit - La desolazione di Smaug ( The Hobbit: The Desolation of Smaug) è un film fantasy del diretto da Peter Jackson e scritto dallo stesso Jackson Fran Walsh Philippa Boyens e Guillermo del Toro. Liberamente tratto dalla parte centrale del romanzo Lo Hobbit e dalle Appendici de Il Signore degli Anelli di J. Of all the streets in the world, this street was the least suitable for amazing events.
The hobbit an unexpected journey trailer free download. Tolkien è il secondo capitolo della trilogia de Lo Hobbit che.
The Hobbit: An Unexpected Journey is a epic high fantasy adventure film directed by Peter is the first installment in a three- part film adaptation based on J. Tolkien’ s 1937 novel The is followed by The Desolation of Smaug ( ) and The Battle of the Five Armies ( ), and together they act as a prequel to Jackson' s The Lord of the Rings film trilogy. Directed by Peter Jackson.
With Martin Freeman, Ian McKellen, Richard Armitage, Andy Serkis.
A reluctant Hobbit, Bilbo Baggins, sets out to the Lonely Mountain with a spirited group of dwarves to reclaim their mountain home, and the gold within it from the dragon : The Hobbit: An Unexpected Journey ( Two- Disc Special Edition) : Ian McKellen, Martin Freeman, Richard Armitage, James Nesbitt, Ken Stott, Cate Blanchett. The adventure follows the journey of title character Bilbo Baggins, who is swept into an epic quest to reclaim the lost Dwarf Kingdom of Erebor from the fearsome dragon Smaug.
The Hobbit: An Unexpected Journey Blu- ray delivers truly amazing video and audio in this exceptional Blu- ray release A curious Hobbit, Bilbo Baggins, journeys to the Lonely Mountain with a. The Hobbit is a film series consisting of three high fantasy adventure films directed by Peter Jackson.
They are based on the 1937 novel The Hobbit by J. Tolkien, with large portions of the trilogy inspired by the appendices to The Return of the King, which expand on the story told in The Hobbit, as well as new material and characters written especially for the films.
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Energy systems from POLYMA do their job reliably far away from all electricity grids. Be it as an independent electricity supplier to clients in the event of transformer separations from municipal suppliers and energy suppliers or for the supply of electricity and light at building sites and in civil protection – the range of applications is extremely manifold.
This is why we simply listen at the beginning so as to learn which tasks you as our clients need to perform, about your ideas, your wishes and the individual conditions. This information, combined with the know-how and experience of our specialists, results in long-lasting solutions that have been proven all around the world. A large number of our units have been operating for more than 30 years already.
At first glance it seems that one and the same solution is always the right one for a specific job. But, the talks we have with our clients on site, the analysis of the technical circumstances and the local conditions often reveal new insights. This then calls for the development of a solution which satisfies this client`s requirements individually. In the end, it makes a crucial difference whether a mobile electricity generator or a floodlight system shall be used somewhere in the countryside, in the mountains or in the narrow winding alleys of an old town.
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Pet owners across Ashford and the surrounding area will be breathing a sigh of relief as Kent Fire and Rescue Service (KFRS) takes delivery of new animal oxygen masks, to boost pet safety.
The specially designed pet masks were donated by Smiths Medical Specialty Team and not-for-profit organisation Smokey Paws, and were officially handed over on Wednesday 27 July 2016. The masks will be carried on fire engines in Tenterden, Wye, Aldington, Dymchurch and Hythe, and form part of a county-wide initiative for every fire engine in Kent to carry a set.
In the 12 months to 23 July 2016, 48 cats or dogs have been caught up in domestic fires that KFRS has attended, some of which have resulted in the pets being given oxygen. As recently as the weekend a pet dog was rescued from a house fire in Gravesend and was treated for the effects of breathing in smoke. Firefighters used their new oxygen masks to save the beloved pet.
Smiths Medical Senior Business Manager Specialty Business, Linda Wilmin said: “Today is a ‘pawfect’ day for pet safety in Ashford. Smiths Medical has a desire to contribute positively in the communities in which we operate. This was the ‘purrfect’ opportunity to support such a great cause. It has been a delight working with Smokey Paws and their commitment to have masks on all fire engines to save pets is remarkable. We are honoured to donate to KFRS and support Smokey Paws in the future.
Lynn Carberry from Smokey Paws said: “The five sets of masks being given to KFRS supports the fantastic efforts that has already equipped 75% of Kent’s fire stations and were made possible by Smiths Medical Surgivet®, who actually manufacture the masks.
Firefighter plea: "Make sure we can get through"
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This is a common question amongst modern entrepreneurs, many of which have heard about the attributes of blogging and are ready to launch probably their own. Therefore in this brief tutorial, I can explain how to begin a business weblog without wasting a lot of time in the research and setup process. In fact , information will show you how to get up and running rapidly when compared with13623 couple of days.
Specialized notes: This lesson is going to focus on the self-hosting model of blogging. In other words, it will teach you how to set up a web hosting account for going through your brilliant blog (as opposed to hosting this with WordPress, Blogger, and so forth ). This is actually best form of setup for the business as well as company blog page.
This will become your web address. If you already have a company website online, you could simply put your blog on the main site. In this hosting scenario, your website would become an extension of the existing internet site, and all of the supporting documents would be written and published into a sub-folder or sub-directory.
Once more, even if you have a website and will be adding your blog for the reason that an extension of this site, you may skip this task. Web hosting simply identifies the web servers (big computers) that will hold all of your blog page files. You are likely to pay among $7 and $10 every month for internet hosting.
Many of the same companies who offer website registration services can web host a business blog page / web-site as well. Make an effort to to use one of many big names stated under Step #1 to help you enjoy dependable service with minimal down time.
Some bloggers will claim until their particular blue hard about which blog system is first-class, and how come. In my opinion, weblog programs each and every one do the same task – they will publish your content onto the internet, quickly and easily, in addition to an arranged manner.
I recommend employing either Blogger or WordPress. If your weblog is going to be fairly simple, you might select Blogger. If you feel you might be “tweaking” the blog code to achieve several effects (not necessary, by the way), you might prefer the WordPress platform.
Now you currently have a authorized domain name, a website hosting plan, and a blogs program every picked out. The next phase is the set up process. Below you will set up the blog on your hosting consideration. If you decided Blogger, this technique will be simply. You just login your Blogger account and tell it where to reveal the blog (onto your domain). If you selected WordPress, you are likely to actually mount the program straight onto your world wide web domain as well as hosting accounts. It’s a straightforward process, however you might want to obtain help from somebody who has performed it.
Now you decide to start blogging away. When you do, it’s a good idea to make a few test articles or blog posts. A “post” is fresh information circulated to the blog page, like an document. You can make a few test posts to learn how your selected program functions. Experiment with back links, formatting the written text, adding images, etc . You can always delete your practice articles and reviews when you’re done.
Congratulations. Get tackled the technical side of things and you are at this moment ready to begin writing and publishing information online. Once you have a blog up and running, and you’re comfortable with how to use that, you can begin “loftier” topics, such as increasing your traffic and growing the web presence.
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#frapalymo is hosted by @FrauPaulchen and is translated by Bee on her blog Just Fooling Around with Bee. Today’s prompt is “the day after”.
What a delightful poem. Yes, there is nothing like carrying a child. You become so close to that baby before he/she is born. Thanks for the beautiful thoughts. I thought I already commented on this one, but it is not here.
I read it again and yes it is different. Holding your new born child is one of the greatest joys after giving birth.
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Holiday season got you uptight and anxious? Cold weather getting you down? Why not join us for a relaxing hour of hot yoga on Saturday, December 16th and help out the families of children fighting cancer?
Hot Yoga Carle Place has offered to have a fund raising event to help you get your stretch and strength on at their beautiful facilities. The funds raised during this class will go to help A Mother’s Kiss and the families.
Your $20 donation gets you an hour of hot yoga led by expert instructors.
“Hot Yoga is a complete system of wellness, restoration and rejuvenation. Bringing hot yoga into your life cleanses the body and calms the mind. The studio is HOT (over 100 degrees) to facilitate deeper stretching, prevent injury, relieve stress and tension and to detoxify the body.
Space is limited so book your place early. Use our link below to make your donation.
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Discoverering the right car rental in Kenya is essential, you want to find the best one to suit your needs. If you are travelling in to Kenya and need a great vehicle to meet you travel requirements, or if your car is off the road and you need suitable short term transportation? We can offer the best prices with 24/7 customer service. At CarHire4Lower.com, we can offer a sporty SUV, a luxury auto or a fairly basic run about and with our simple and quick search engine. Great value car rental is only a few clicks away.
The moment you collect your reservation, you can relax, knowing you're in good hands. We compare Low Prices from trusted suppliers, such as Avis, Hertz and Enterprise, that attain very high standards of safety, cleanliness and value. When your online booking is complete, you can relax, knowing you'll be picking up a great Rental Car in Kenya, and you can focus on more important matters.
With your Car Rental booking in Kenya, you are able to include some additions with your reservation. These extras are aimed at making your experience that little bit better. You are able to add an extra driver or if you are travelling with infants, include a child seat, if wish to get greater insurance cover this is also available. All you have to do is select the items you require via our easy to use booking process. We provide comprehensive support, so if any issues arise regarding you reservation or you wish to make any changes to your booking, CarHire4Lower.com help is available online or you can contact us by phone.
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Driving under the Influence (DUI) is a severe crime that would probably impact a large number of variables of a person's life. Employment opportunities might possibly be damaged, legal costs may have an affect on money and driving rights may be revoked. There are a great many irrevocable aftermaths to driving a car under the influence that may cause terrible harm to a person's lifestyle. If charged for a Drunk driving, legal representation is considered necessary to attain a minimized sentence and keep away from jail time. Judges are giving harder sentences for the crime, as well as, higher fines.
At present, the lawful drinking age in the United States is 21 years old. A substantive section of Driving Under the Influence charges are acquired by persons under the age of 21. Quite a few DUI's were accompanied by accidents and fatalities. States cognizant of the numbers are issuing underage drinkers, who drive under the influence, felony charges and lengthy jail sentences.
Currently, in all 50 states, DWI is classified by law as possessing a blood alcohol concentration (BAC) of 0.08% or greater. However, in some states intoxicated drivers may be charged with a lesser offense if the BAC is lower than 0.08%. Laws for drunk driving charges vary from state to state. Therefore, individuals must learn the rules of every single state before driving a car.
Alcohol is a depressant that decreases the response or response time of the motorist. Brain indicators are under control when drinking. Some indicators do not arrive to the brain while drunk. Consequently, drivers may not react swiftly enough to avoid an obstacle in the highway, a stopped vehicle or an animal. Men and women that are drunk or inebriated may see truth differently than reality. This makes it tough to manage the auto and drive within the white and yellow lines on the highway. Drunk drivers routinely bring about catastrophes and crashes when they cannot discern or keep the truck in the path.
Numerous impaired people have caused fatalities or severely injured themselves or another person. Drivers under the age of 24 are more likely to die in a car accident than from any other cause, according to the Center for Disease Control and Prevention. Forty percent of these fatalities are related to alcohol. Both drivers and passengers are likely to expire in an liquor connected driving a vehicle incident.
A blood alcohol content of one tenth or 0.10 boosts the probability of a deadly car accident by seven times. Equally, the likelihood for death will increase 25 times for individuals whose blood alcohol level is increased to 0.15. Operating a vehicle with a legal blood alcohol level of 0.04 will increase the probability of being engaged in an auto accident by 1.4 times. If this number doubles, the possibility of an car crash raises by 11 times. Additional drinks could have lethal repercussions, if the driver proceeds to operate a car. Those who decide to commence may live with the effects of their actions, if they live through the auto accident.
Drivers in Georgia may be charged with a DUI if the BAC level is 0.08 or significant. Any amount of contraband drugs or unlawful blood levels will be grounds for a DUI charge in the state of Georgia. Drivers that exhibit erratic driving behavior and a blood alcohol content of over 0.08 may be convicted of a Driving while intoxicated. In some instances, individuals may also be taken to jail.
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More than just a bit skeptical and uneasy, she is strongly considering whether or not she will even attendthe wedding. But when Scott makes a strong case for supporting her father on his big day, she eventually relents. Soon enough, she learns that she’s not the only one who opposes this union. In fact, the two families seem ready to go to war over it!
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If you live in the Boston area and ride public transit, you should check out this iGoogle Gadget that makes tracking buses easy. You can set up to 3 stops (perhaps near your home/work) and it will show all the latest arrivals in real-time. Note that it only serves a few lines currently (click here to see the list of lines served). The number of lines/stops served will increase as MBTA adds more tracking services.
Once you have added the gadget to your homepage you will see instructions on how to add stops. You can click on the link at the bottom of the gadget to search for stops (on the NextBus website). If you like the gadget you can use the link at the bottom of the gadget to give feedback or promote it (on Twitter, Facebook, your blog, etc…).
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Read all about Jannora and Miles' love story, romantic poetry-reading proposal, and wedding experience. Featuring the event planning work of MunaLuchi Coterie member ValiaRose Events.
Tell us how you met and all about the proposal: We met in 2012 in Miami during spring break while I was in school at The University of Maryland and Miles was at Alabama A&M. I was with my girlfriends and a few guy friends who are in the same fraternity as him. Miles and his frat brothers saw us and joined us on the beach. Later that night, we randomly saw each other again and exchanged information.
We continued to keep in touch and then in 2013 when I was leaving Maryland to move to Texas, Miles happened to be in the area for an engineering conference and was able to make it to my going away party. We hung out the whole weekend. After that we would talk on the phone every day, all day. I even stopped in Alabama to visit before moving to Texas. We became really great friends and would visit one another in our respective states. A few months later, we went to New Orleans for Miles' birthday and decided to take our friendship to the next level the same day he told me he loved me for the first time.
In May of 2015, we went to New York for my birthday where our friends came to celebrate with us for the weekend. We went to a poetry spot, Nuyorican Poets Cafe, and he got up and read a poem he wrote for me after midnight when it was officially my birthday. He performed for me the previous year so I figured we were starting a tradition. I was on the stage with him because he told me he had some dialogue I would be a part of for his poem. The title of the poem was "Mary and Me" and during the last line he pulled a ring box out of his pocket and asked, "So how do you feel about marrying me?" I was literally speechless. I just couldn't get the word “Yes” out because I was so surprised and thankful that this man God sent to me felt as strongly about me as I do him. He must have been on his knee for about five minutes because I was so busy crying and in a state of shock. Then he pointed and showed me that my whole family was there to witness and the tears started pouring out even more. I'm getting emotional now just thinking about it. It was so perfect! I’m usually the planner in the relationship and it was such a surprise to know he made sure the most important people in my life were present for our special moment.
Describe your wedding dress. My wedding dress was a beautiful, ivory Allure gown with satin material and beading. I found my dress at the first place I went to. I didn't know it at first, but once I went to the second boutique, I realized I couldn't stop thinking about it and didn't even want to look any longer. I told my mother and grandmother I was ready to go back and get the dress I knew Miles would love seeing me walk down the aisle in.
Describe your wedding style? Our wedding fit us and our style perfectly. We made sure to do things we knew represented us and the couple we are. From the music we chose to the food we served, everyone knew whose wedding they were attending. We made it our own and didn't want to follow anyone else's traditions; we even came out for the reception to Gucci Mane in matching gold grillz.
Bridesmaids and Groomsmen gifts: Bridesmaids - Floral rompers and jewelry. Groomsmen gifts: Cigars, custom bowties, pocket squares, and lapel flowers.
What is your best memory from the wedding? The best memory from our wedding is one we can both agree on ... the dances with our parents! Miles and his family are originally from East Chicago and he was able to two step with his mother to their favorite Stevie Wonder song. I danced with my dad to "Ether" by Nas for the father-daughter dance and everyone looked around thinking it was a mistake until they realized how turned up my dad was.
What is the best wedding advice you can give to engaged couples? The best wedding advice we can give to engaged couples is to have a wedding that reflects you both. Pick a wedding planner like ValiaRose Events that listens and understands your vision. They stood behind our vision and values of not impressing anyone else. Our planner strived for quality, not quantity, and we invested the rest!
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Dynasty's Fast n Furious "Zayn" showing in Juniors at his first AKC show in November 2015 at the Savannah Kennel Club. He is shown by Danny White and you can see they are both having a great time. Zayn earned his first 5 AKC points during that weekend including a Best of Winners.
GCH Dynasty's Triple Crown "Remi" is the first AKC Champion in the history of MAS, and is also the 2nd AKC Grand Champion. Remi has also had several group placement in the herding group with a Group 1 under Dr. Sophia Kaluzniacki at the Jacksonville Dog Fanciers Show in September.
CH Dynasty's Designed to Impress earned his AKC Championship after two weeks of showing in July 2015.
Rio has moved to Hawaii and is loving her new island paradise. She is doing lots of hiking and looks like she loves it.
In Juniors, Danny White and Dynasty's Designed to Impress have moved out of Novice Juniors with three wins and are now competing in Open Juniors. Desi and Danny are one of the top-ranked Junior teams in the breed.
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Triple Nickel just celebrated its third anniversary under proprietors Marc Blanke and John Fleming.
Nooks and crannies are very much a part of the decor at the stylish restaurant in the high-rise at 555 S. Old Woodward. Diners may choose a cozy table tucked next to a big window, or a corner alcove on the lower level of the room, or a perch at the bar under the big buffalo head trophy that is a symbol of the place, along with the buffalo nickel.
Triple Nickel just celebrated its third anniversary under proprietors Marc Blanke and John Fleming. Those names may sound familiar, because they worked together for years at Sindbad’s on Detroit’s waterfront before taking on the Birmingham spot.
The two restaurants do have some similarities, of course, including an emphasis on seafood. Triple Nickel, while comfortably casual, is not as informal as its waterfront cousin, and the menu under chef Fleming is more ambitious. There’s also a focus on dishes from a calorie perspective.
The menu includes a selection of entrees that are 325 calories or less at lunch, 475 at dinner, and it includes a number of appealing dishes regardless of that aspect. For instance, seared scallops topped with Thai chili sauce, char-grilled salmon with house-made salsa, and 4-ounce filet mignon at a surprising calorie count of just 300. That stems, says Fleming, from the patrons of the neighboring fitness and exercise studios.
The chef also serves a vegan burger, as well as half-pound buffalo and prime beef versions on the wide-ranging American menu. He is particularly proud, however, of the fresh seafood brought in directly from the source. As a case in point, you won’t find a better fish and chips than his version of Atlantic haddock lightly beer-battered and served with thin, crisp fries and coleslaw, and he can also do it gluten-free. House soup is New England clam chowder, and there are two additional soups each day.
Service is friendly and accommodating by a competent staff that doesn’t mind if an occasional patron roams the room for just the right table.
Hours: 11 a.m.-10 p.m. Mon.-Wed., 11:30 a.m.-11 p.m. Thurs.,11:30 a.m.-midnight Fri.-Sat., 11 a.m.-9 p.m.Sun.
Prices: Lunch appetizers $9-$16, soups and salads $5-$12,sandwiches $10-$14, entrees $12-$19; dinner appetizers $9-$16, soups and salads $6-14, entrees $16-$31, desserts $5-$8.
Parking: Attached structure and street.
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Book Arts Club is mainly about making Artist's Books. Its when we get together to explore the world of books and play around with ideas. We also make the books produced by Firestation Print Studio as part of our projects and fundraising endeavours. We meet on the fourth Saturday of the month 1-4pm. The first meet in 2017 is on Feburary 25th. This Club is open to all Firestation Print Studio members. Cost is $10/$5 concession.
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Maquina cuya herramienta, ... Metal mecánica- Torno paralelo universal Meuser. ... Otros- Rectificadora de Cilindros Modelo: TX200A .
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The End Of Life date (EOL, sunset date) for Python 2.7 was initially set at 2015, ... single quote marks and double quote marks function identically.
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Faculty in the College or Arts and Science and the School of Engineering offer an interdisciplinary minor in Scientific Computing to help natural and social scientists and engineers acquire the ever-increasing computational skills that such careers demand.
Computation is now an integral part of modern science and engineering. In science, computer simulation allows the study of natural phenomena impossible or intractable through experimental means. In engineering, computer simulation allows the analysis and synthesis of systems too expensive, dangerous, or complex to model and build directly. Astronomers studying the formation of massive black holes, neuroscientists studying neural networks for human memory, mechanical engineers studying the designs of turbines and compressors, and electrical engineers studying the reliability of electronics aboard spacecraft are united both in the computational challenges they face and the tools and techniques they use to solve these challenges.
Students in the program in Scientific Computing are taught techniques for understanding complex physical, biological, and social systems. Students are introduced to computational methods for simulating and analyzing models of complex systems, to scientific visualization and data mining techniques needed to detect structure in massively large multidimensional data sets, to high performance computing techniques for simulating models on computing clusters with hundreds or thousands of parallel, independent processors and for analyzing terabytes or more of data that may be distributed across a massive cloud or grid storage environment.
Scientific Computing at Vanderbilt is supported by faculty and includes students from a wide range of scientific and engineering disciplines. While the content domain varies, these disciplines often require similar computational approaches, high-performance computing resources, and skills to simulate interactions, model real-life systems, and test competing hypotheses. Scientific Computing embodies the computational tools and techniques for solving many of the grand challenges facing science and engineering today.
The minor in Scientific Computing prepares students for advanced coursework that combines computational approaches with a substantive area of science or engineering. It prepares students for directed or independent study with a faculty member on a research project. It prepares students for advanced study in graduate school. It provides skills that will be attractive to many employers after graduation.
The minor in Scientific Computing is distinct from the minor in Computer Science. Scientific Computing uses computation as a tool to solve scientific and engineering problems in research and application. As such, it is more focused on simulation, numerical techniques, high performance computing, and higher-level methods than the minor in Computer Science, which is focused on the algorithms, systems, and technologies that enable such methods to be developed and employed.
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Double-Helix_Cone_Mixer - Mixing equipment series - Jiangyin Jiayuan Pharmaceutical Equipment Co., Ltd.
Overview：This machine is a new , efficient, high-precision mixing equipment, widely used in pharmaceutical, chemical and feed industries mixture of various powdered materials.
4. The material fell by its own gravity. Those four movements in the mixer create convection, shearing, diffusion, so as to achieve rapid and uniform mixing purposes.
This machine is widely used for mixing powder and powder (solid-solid), powder and liquid (solid-liquid), liquid and the liquid (liquid-liquid) in chemical, pharmaceutical, foodstuff, biotechnology, healthy products, fertilizer, dyestuff, pigment, metallurgy, mine, building materials, plastic, and other industries.
6. The mixing function of the mixer has a better effect on the chemical reaction for the materials.
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"timestamp": "2019-04-18T20:43:58",
"url": "http://www.jyjiayuan.com/products/230.html",
"language": "en",
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Educational qualification : Candidates should possess standards to MCI .
How to Apply : Eligible candidates may visit University of Health Sciences , Sec the interview together with a curriculum vitae and all original documents including experience certificate on 04/09/2019 9:00 to 15:00 in Rajasthan. 18, Kumbha Marg, Pratap Nagar, Sanganer , Jaipur .
Date & time of interview for II ( 1 ) & III ( 1) posts: 09.04.2019 from 09.00 .
Date & Time of Interview for IV ( 1) posts: 09.04.2019 to 09.30 clock .
Date & Time of Interview for IV ( 2) posts: 04/09/2019 till 10.00 clock .
Date & time of interview for II (2) posts: 09.04.2019 to 10.30 clock .
Date & time of interview for II ( 3) Posts: 09.04.2019 to 11.00 clock .
Date & Time of Interview for IV ( 3) posts: 09.04.2019 to 11.30 clock .
Date & time of interview for II (4 ) Posts: 4.9.2019 by12 00 clock .
Date & time of interview for II (6) , III (2 ) and IV ( 5) posts: 04.09.2019 at 13.00 clock .
Date & time of interview for V Posts: 04.09.2019 at 14.00 .
Date & time of interview for VI posts: 09/04/2019 by 3:00 .
Venue: – Rajasthan University of Health Sciences , Sec. 18, Kumbha Marg, Pratap Nagar, Sanganer , Jaipur .
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"timestamp": "2019-04-22T14:58:44",
"url": "https://www.ind91.com/university-of-health-sciences-ruhs-walk-in-jobs/",
"language": "en",
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I'm selling my RX-8 as I have moved from the UK to Western Europe and the car just isn't practical over here with the steering wheel on the "wrong side".
It's in mint condition and is a very loved car, but my missus is Swiss and so its time to get one with a steering wheel on the other side.
Please PM me and I can send more photos etc.
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{
"timestamp": "2019-04-24T08:20:31",
"url": "https://www.rx8club.com/europe-sale-wanted-148/2007-231-all-extras-254408/",
"language": "en",
"source": "c4"
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Alright Glam Gals, these Sequin Joggers are the party pants you've been waiting for! Our "Sequins Joggers” are black and have a slim jogger pant fit which makes them great to wear with slim fit shirts and over-sized tees. The dazzling sequined fabric makes for a glamorous look, with the sheen of the sequins gleaming with movement from the pants. You can pair these joggers with a nice black, clear, purple or green heel to have a ohhh so glamours night or you can put on a flat & have a comfortable chic night. Which ever you decide you will definitely be the spot light of the day.
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"timestamp": "2019-04-20T18:32:10",
"url": "https://barcodeglam.com/products/sequin-joggers",
"language": "en",
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I have used a calculation field to refer to a date field in another app. Sometimes the reference is invalid because the item does not exist or is not filled with a date or time. What I want is the calculation field to be empty ... or return another value like >> no appointment made.
is the calculation field date type (does it show the date like a real date field)? If so, you can't display a text like >> no appointment made.
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{
"timestamp": "2019-04-22T14:41:10",
"url": "https://help.podio.com/hc/en-us/community/posts/360042891932-Leave-calculation-field-empty-when-referring-to-invalid-empty-data",
"language": "en",
"source": "c4"
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Many homeowners believe that once they make the decision to install hardwood flooring, the difficult part is over. Simply choose a wood and be done. However, this is oversimplifying the process a bit. There are a number of factors that will determine the type of hardwood flooring a home is able to accommodate and what is going to look best with the existing decor and furnishings. Some questions to help determine the best type of Wood Floors in Nassau County for a home are found here.
Where is the wood going to be installed?
Installing wood flooring on a second floor is different than installing it in the basement. The space below the ground level is called below grade. Grade is when the floor is even with the ground outside and the floor above the ground is above grade. Where the wood is being installed will limit the available options. For example, solid wood should never be put below grade since the moisture that comes up through the ground can create a number of issues. Engineered wood flooring is ideal for this space.
What is the subfloor composed of?
The three most common types of subfloors include particleboard, plywood, and a concrete slab. When a homeowner knows what their subfloor is made of, it will help determine if solid wood flooring can be installed or if engineered wood would be the right option.
• Concrete: Only engineered wood can be installed.
• Plywood: Offers more versatility and is ideal for both solid and engineered wood.
• Particleboard: It should be replaced with plywood and then the Wood Floors in Nassau County installed.
What are the living habits of the residents?
It is important to think about how much abuse the floors will take and learn about how durable the options are. For example, if a homeowner has pets or kids or hosts big parties often, they will need a more durable wood, than if they are single and away often.
Wood flooring is a popular option for many homes. However, prior to having it installed, it is a good idea to think about the type that is needed. Additional help and information can be found by visiting the Anthonysworldoffloors.com website.
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{
"timestamp": "2019-04-19T00:38:05",
"url": "https://www.articlebay.us/questions-to-ask-prior-to-purchasing-wood-floors-in-nassau-county/",
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Although Canterbury does not have many mineral resources, some places such as Birdlings Flat, south of Banks Peninsula, are popular among rockhounds. The beach is rich in gemstones, particularly agates, which are sought-after for making jewellery. Inset are polished gemstones from Birdlings Flat: greywacke (grey), quartz (white), volcanic pebbles (pinkish brown), and jasper (reddish brown).
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"timestamp": "2019-04-22T00:25:51",
"url": "https://teara.govt.nz/en/photograph/10297/looking-for-gemstones-birdlings-flat",
"language": "en",
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Whether you're competing for a fresh haircut, or are only trying to combine things up a bit. Hold your facial form, your hair, and your styling wants in your mind and you will find a great hairstyle. That you do not must be an expert to have perfect classy pinned pony hairstyles all day. You simply need to know a couple of tips and get your practical to the right ponytail hairstyles.
The key to selecting the ideal classy pinned pony hairstyles is balance. Other suggestions you should think about are how much effort you wish to put to the ponytail hairstyles, what type of look you want, and whether you want to play up or play down particular features. Modify is excellent, a new and fresh ponytail hairstyles could provide you with the energy and confidence. The classy pinned pony hairstyles may change your outlook and self-confidence all through a period when you might need it the most.
These represent the the classy pinned pony hairstyles that could you have completely to create an appointment with your stylist or barber. These hairdos and hairstyles are the most popular throughout the world. Many are everlasting and may be classic in just about any era. Take it easy and enjoy yourself, many of these hairstyles are easy and simple to realize and were pick pertaining to their unique classiness, and enjoyable style. We recommend selecting the most truly effective three you want the best and discussing what type is best for you personally together with your hairstylist.
For some of us, the classy pinned pony hairstyles is important to maneuver from a old trend to an even more sophisticated look. Our haircuts may add or withhold years to our age, therefore select properly, relying on which way you wish to get! Most of us only wish to be in style and updated. Finding a new haircut raises your self-confidence, ponytail hairstyles is an easier solution to recreate your self and put in a great appearance.
Make your classy pinned pony hairstyles being better, given that you have got an amazing hair-do, time to show off! Make sure you do your hair regularly. Notice to the products or items you buy and put in it. Messing with your own hair frequently may result in damaged hair, hair loss or split ends. Hair is just a symbol of beauty. So, the hair also provides a lot of hair-dos to make it more spectacular.
Classy pinned pony hairstyles seems easy, however it is actually quite complicated. Many variations must be made. Exactly like when you're choosing the best style of gown, the hair also needs to be effectively considered. You have to know the tricks of finding the perfect style of clothes, and there are some of them for you to use. To try this hair is not too difficult, you can even do it yourself at home. It can be an interesting option.
Classy pinned pony hairstyles is really a fairly powerful, it is able to raise your great facial features and get the accent far from weaker features. Listed here is how to change your ponytail hairstyles in the ideal way, your hair structures your appearance, so it's really the second thing persons notice about you. When picking a hairstyle, it is frequently important to look a pictures of identical hairstyles to get what you want, select images of ponytail hairstyles with matching hair type and face shape.
Get yourself a latest classy pinned pony hairstyles, take advantage of your latest step to get gorgeous ponytail hairstyles. Before you go to the salon, use your time for browsing the magazines and figure out that which you want. If at all possible, it's best to show the hairstylist an image as illustration so you may be near fully guaranteed to obtain it in which you want it. Some ponytail hairstyles remain favorite over time for their ability to work well with the trends in fashion.
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"timestamp": "2019-04-20T06:22:18",
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“Our college kids are scared,” one mother admitted to me as she grabbed ten copies of The Story of Reality to purchase for her young people and their friends. A Christian teacher once confessed it was easy in church to stand for God, but with her non-Christian friends she could not muster the courage to speak the truth.
It’s natural to be scared when we’re facing threat. I’ve felt it many times myself. It’s one reason that the third part of STR’s vision for you is Courage and grace for every encounter. We all need to develop our courage—to nurture our ability to step up to danger. But how do we do that? How do we stand tall when all our instincts tell us to lay low? I have some ideas that have helped me, and I think you may find them helpful, too.
My first tip is the most important one: Face up.
In Matthew 10, Jesus didn’t mince words when He gave his disciples a “pep talk” before sending them on their first short-term mission. He told them they would be persecuted, hated, maligned, beaten, betrayed, and murdered. Hard facts? Yes. Frightening? Of course. Why was Jesus so blunt?
“Do not fear”—in the final reckoning all will be known and you will be vindicated. “Do not fear”—the worst anyone can do is kill your body, but God will save your soul. “Do not fear”—you are not alone. You are cherished. God has your back.
So decide today—mark your calendar—that you are already dead in this fight. You will not survive this war. You are fully in. You are fully His. You accept the consequences. Let the ridicule and rejection come. You are ready for it. You expect the worst from men, and you expect the best from God. Do not fear.
Here’s my second tip: Prep up.
For cold-case homicide detective, J. Warner Wallace, weapons training wasn’t just shooting at targets; he fired rounds into his bulletproof vest, too. Why? Because he needed to know, firsthand, that his vest stopped bullets. It gave him the confidence to stand in the line of fire when circumstances got intense.
Do you like tests? Most people don’t…unless they know the answers. Then there’s little fear. That’s because knowledge breeds courage. As you spend more time with the kind of training STR provides, you’ll realize that Christianity can stand up to the challenges. Put simply, our vest stops bullets.
Another part of STR’s vision for you is Confidence for every Christian. So prep up. If you take a hit in a conversation, you’re alerted to where you need to bone up on for the next round. The more you know, the braver you’ll be. As the Marines say, the more you sweat in training, the less you bleed in battle.
Here’s my final tip: Step up.
You may be surprised to know that, ironically, pluck and nerve often come immediately after you get going, not before. Your courage surges once you’re moving.
The best way to do that is to plan your first few moves in advance so when a particular challenge comes up you can step out immediately. I know of no better way to do this than to start with questions. Take small steps forward, if you need to. Probe. Inquire. Investigate. Get the lay of the land. As you do you’ll discover the other side is not as frightening as you thought.
So first, face up. Make peace with the fact that you may be a victim of the war in the short term, but you’ll be a victor in the long run. Second, prep up. You’ll be amazed at the pluck you’ll feel when you’ve done your homework. Finally, step up. Motion matters, so put on your game face and get moving.
And always remember, do not fear. The Lord is there for you.
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{
"timestamp": "2019-04-26T07:40:27",
"url": "https://www.str.org/article/how-stand-tall-when-your-instincts-say-lay-low-mentoring-letter-october-2017",
"language": "en",
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Spend time with an Avalara trainer and other students in an online classroom. Perform hands-on exercises to experience Returns real-world settings, tools, and best practices. As long as you have a quality internet connection, you can learn anywhere.
Learn how Avalara Returns works, what to have on hand before you get started, and how to set up your account.
Attend this session if Avalara files returns for you. An expert from Avalara's filing team will walk you through what you need to know and do to prep for your filing. Learn tips for reviewing and approving your tax liabilities.
Learn how to keep your Avalara Returns settings up to date and reflective of your business. Learn to manage filing calendars, account users, and your filing responsibilities.
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"timestamp": "2019-04-18T18:58:46",
"url": "https://training.avalara.com/upcoming-workshops-avalara-returns-essentials",
"language": "en",
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A mobile app designed in Pensacola is helping people find out which nutrients they need based on their dietary conditions, activity levels and more.
A married couple in Pensacola is starting to see a return on the hard work they put into developing a nutrition tracking mobile app.
Marcus and Maria Vlahovic designed and developed Nutritrack, a free app that tracks consumer-specific health and fitness and places emphasis on nutrients.
Two weeks after launching the app on March 24 the current University of West Florida students saw a major spike in downloads when the Apple App Store listed Nutritrack as one of their "new apps we love."
"We freaked out," Marcus said. "We were getting just sort of normal, 50 downloads a day or 100 downloads a day, nothing to be super excited about. Then one day I noticed there's a lot of traffic on our server and I see there's thousands of accounts being created. I thought, 'This can't be right, what is happening?'"
The Vlahovic's learned that Apple had been experimenting with promoting Nutritrack in other countries and Marcus said he saw tons of accounts popping up from overseas. Three days later, the App Store featured Nutritrack on its homepage.
At its peak in April, Nutritrack was being downloaded 3- to- 4,000 times per day, according to Maria. The total amount of downloads is currently around 40,000.
"I looked for an app that would help me overcome the deficiencies that I had and get all the nutrients that I needed from my food, and I couldn't find anything," Marcus said. "We started brainstorming and realized it'd be really great to have for ourselves and for other people. Even the most historically popular nutrition trackers out there, they'll only track like calories, carbs, fat, protein and maybe a few more nutrients. But we track, on the dot, 30 nutrients."
Customization is the top priority for Marcus and his wife, who did the majority of the work on Nutritrack at The Stables office space on North Guillemard Street in Pensacola. Marcus said they are working on a major update now.
"The cool thing is when you enter in what you've eaten you actually get food suggestions to tell you, like, 'Hey, your diet's pretty low in this particular nutrient, try eating more avocados to hit your goals," Marcus said. "We let you know exactly why you need the nutrients we're suggesting, and in addition to that we customize it to your lifestyle, whether you're gluten-free, a vegetarian, an athlete and so on."
A version of Nutritrack initially launched a year ago, but it didn't do very well, leading the couple to conduct more market research so they could work out the kinks and create a more effective app.
Marcus said he believes it was the hard work he and his wife put into honing Nutritrack, as well as the Apple-friendly nature of the app, that sparked the App Store to promote it on its homepage.
"We make the best use of Apple's technologies," Marcus said. "You can sync with Apple Health with our app, we run perfectly on iPhone X, and I think Apple, when they feature apps, they feature apps they want to build long-term relationships with and that best showcase the products that they sell."
Nutritrack is available for download on the iPhone, iPad and iPod. Marcus said he and Maria are aiming to launch an Android version of the app by the end of 2018.
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{
"timestamp": "2019-04-20T11:13:19",
"url": "https://www.pnj.com/story/news/local/2018/07/13/nutritrack-mobile-app-designed-pensacola-couple-apple/779298002/",
"language": "en",
"source": "c4"
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Is Social Media Affecting Your Child Custody Case?
It’s no surprise that social media is a huge part of many peoples’ lives. And, some people tend to vent about anything and everything on their social media channels, without necessarily thinking about potential consequences down the line. One of these potential consequences can become a real concern if you find yourself in the middle of a custody battle and/or a messy divorce. Your social media can play an influential role in time-sharing schedule arrangements.
When you’re going through a divorce or a child custody battle, everything in your life comes under a strong microscope. Assets and expenditures are far from the only things that your ex’s lawyer is interested in. If you’re active on social media and post about your personal life a lot, the other side can try to use even seemingly innocent things against you.
It should seem like common sense, but photos of you intoxicated and sitting on some person’s lap at that friend’s party on a Monday night may not look so well blown up in court. Making disparaging remarks about your ex’s parenting style, or even passive aggressive comments, can be misconstrued and interpreted incorrectly. Dating someone new? It’s pretty much a given that the other side is going to look into that person and their social media as a way to suggest that you are keeping your child around unsavory individuals.
You may be tempted to remove old photos or posts in anticipation of an upcoming hearing; however, the other side may ask for those deleted posts and photos to be produced during proceedings. Deleted or not, remember that the other side is looking for any opportunity to take a post or photo out of context to help support their contention that you are a bad parent.
Now, there is a silver lining here. Just as social media has the potential to affect you negatively during a custody battle, it can have the same effect on your ex as well. Your ex will be under the same microscope, and you may be able to help collect critical information that helps support your petition for custody. This is why it’s crucial to hire a skilled Florida family law attorney to represent you in a custody battle and/or divorce.
Remember in situations where a protective order is active, you are prohibited from contacting each other for any reason. Contacting them via social media can be construed as a violation, and so can posting something about your ex in a public social media post. There are instances where judges have determined that a public post about an ex-partner can be a form of harassment.
In addition to comments and posts on your social media channels, text messaging can be a source of problems as well. It’s easy to say something you regret in the heat of the moment, but when you text those thoughts, there is a permanent record that can be used against you. Threatening your ex-spouse/partner via text message with messages that threaten them with never seeing their child/children again or demanding they stop seeing someone new, etc., may be admissible in court.
If you’re preparing for a child custody dispute and/or divorce, our team of Boca Raton child custody attorneys work tirelessly to get the desired parental custody agreement for their client(s). However, you need to not help the other side’s case by posting unflattering information and photos on social media. Contact the Law Offices of Schwartz | White at 561-391-9943 or online to schedule a consultation.
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{
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"url": "https://www.schwartz-white.com/is-social-media-affecting-your-child-custody-case/",
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This application claims the benefit of U.S. Provisional Application Serial No. 60/955,895, filed on August 15, 2007 .
A The invention relates generally to the field of immunology and immunotherapy applications using oligonucleotide-based compounds as immune modulatory agents. More particularly, the invention relates to chemically-modified oligonucleotide-based compounds that modulate immune regulation through TLRs and methods of use thereof.
The immune response involves both an innate and an adaptive response based upon the subset of cells involved in the response. For example, the T helper (Th) cells involved in classical cell-mediated functions such as delayed-type hypersensitivity and activation of cytotoxic T lymphocytes ("CTL"s) are Th1 cells, whereas the Th cells involved as helper cells for B-cell activation are Th2 cells. The type of immune response is influenced by the cytokines and chemokines produced in response to antigen exposure. Cytokines provide a means for controlling the immune response by affecting the balance of T helper 1 (Th1) and T helper 2 (Th2) cells, which directly affects the type of immune response that occurs. If the balance is toward higher numbers of Th1 cells, then a cell-mediated immune response occurs, which includes activation of cytotoxic T cells (e.g. CTLs). When the balance is toward higher numbers of Th2 cells, then a humoral or antibody immune response occurs. Each of these immune responses results in a different set of cytokines being secreted from Th1 and Th2 cells. Differences in the cytokines secreted by Th1 and Th2 cells may be the result of the different biological functions of these two T cell subsets.
Th1 cells are involved in the body's innate response to antigen (e.g. viral infections, intracellular pathogens, and tumor cells). The initial response to an antigen can be the secretion of IL-12 from antigen presenting cells (e.g. activated macrophages and dendritic cells) and the concomitant activation of Th1 cells. The result of activating Th1 cells is a secretion of certain cytokines (e.g. IL-2, IFN-gamma and other cytokines) and a concomitant activation of antigen-specific CTLs. Th2 cells are known to be activated in response to bacteria, parasites, antigens, and allergens and may mediate the body's adaptive immune response (e.g. IgM and IgG production and eosinophil activation) through the secretion of certain cytokines (e.g. IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13 and other cytokines) and chemokines. Secretion of certain of these cytokines may result in B-cell proliferation and an increase in antibody production. In addition, certain of these cytokines may stimulate or inhibit the release of other cytokines (e.g. IL-10 inhibits IFN-γ secretion from Th1 cells and IL-12 from dendritic cells). The balance between Th1 and Th2 cells and the cytokines and chemokines released in response to selected stimulus can have an important role in how the body's immune system responds to disease. For example, IFN-α, may inhibit hepatitis C, and MIP-1α and MIP-1β (also known as CCL3 and CCL4 respectively) may inhibit HIV-1 infection. Optimal balancing of the Th1/Th2 immune response presents the opportunity to use the immune system to treat and prevent a variety of diseases.
The Th1 immune response can be induced in mammals for example by introduction of bacterial or synthetic DNA containing unmethylated CpG dinucleotides, which immune response results from presentation of specific oligonucleotide sequences (e.g. unmethylated CpG) to receptors on certain immune cells known as pattern recognition receptors ("PRR"s) . Certain of these PRRs are Toll-like receptors (TLRs).
Toll-like receptors (TLRs) are intimately involved in inducing the innate immune response in response to microbial infection. In vertebrates, a family of ten proteins called Toll-like receptors (TLR1 to TLR10) is known to recognize pathogen associated molecular patterns. Of the ten, TLR3, 7, 8, and 9 are known to localize in endosomes inside the cell and recognize nucleic acids (DNA and RNA) and small molecules such as nucleosides and nucleic acid metabolites. TLR3 and TLR9 are known to recognize nucleic acid such as dsRNA and unmethylated CpG dinucleotide present in viral and bacterial and synthetic DNA, respectively. Bacterial DNA has been shown to activate immune system and antitumor activity (Tokunaga T et al., J Natl Cancer Inst (1984) 72:955-962; Shimada S, et al., Jpn H cancer Res, 1986, 77, 808-816; Yamamoto S, et al., Jpn. J Cancer Res, 1986, 79, 866-73; Messina, J, et al., J Immunol (1991) 147:1759-1764). Other studies using antisense oligonucleotides containing CpG dinucleotides have shown stimulation of an immune response (Zhao Q, et al., Biochem Pharmacol 1996, 26, 173-82). Subsequent studies showed that TLR9 recognizes unmethylated CpG motifs present in bacterial and synthetic DNA (Hemmi H, et al., Nature (2000) 408:740-5). Other modifications of CpG-containing phosphorothioate oligonucleotides can also affect their ability to act as modulators of immune response through TLR9 (see, e.g., Zhao et al., Biochem Pharmacol (1996) 51:173-182; Zhao et al., Biochem Pharmacol (1996) 52:1537-1544; Zhao et al., Antisense Nucleic Acid Drug Dev (1997) 7:495-502; Zhao et al., Bioorg Med Chem Lett (1999) 9:3453-3458; Zhao et al., Bioorg Med Chem Lett (2000) 10:1051-1054; Yu et al., Bioorg Med Chem Lett (2000) 10:2585-2588; Yu et al., Bioorg Med Chem Lett (2001) 11:2263-2267; and Kandimalla et al., Bioorg. Med. Chem. (2001) 9:807-813). In addition, structure activity relationship studies have allowed identification of synthetic motifs and novel DNA-based structures that induce specific immune response profiles that are distinct from those resulting from unmethylated CpG dinucleotides. (Kandimalla ER, et al., Proc Natl Acad Sci U S A. (2005) 102:6925-30. Kandimalla ER, et al., Proc Natl Acad Sci U S A. (2003) 100:14303-8. Cong YP, et al., Biochem Biophys Res Commun (2003) 310:1133-9. Kandimalla ER, et al., Biochem Biophys Res Commun (2003) 306:948-53. Kandimalla ER, et al., Nucleic Acids Res. (2003) 31:2393-400. Yu D, et al., Bioorg Med Chem (2003) 11:459-64. Bhagat L, et al., Biochem Biophys Res Commun (2003) 300:853-61. Yu D, et al., Nucleic Acids Res. (2002) 30:4460-9. Yu D, et al., J Med Chem (2002) 45:4540-8. Yu D, et al., Biochem Biophys Res Commun (2002) 297:83-90. Kandimalla ER, et al., Bioconjug Chem (2002) 13:966-74. Yu D, K et al., Nucleic Acids Res. (2002) 30:1613-9. Yu D, et al., Bioorg Med Chem (2001) 9:2803-8. Yu D, et al., Bioorg Med Chem Lett. (2001) 11:2263-7. Kandimalla ER, et al., Bioorg Med Chem.(2001) 9:807-13. Yu D, et al., Bioorg Med Chem Let (2000) 10:2585-8, Putta MR, et al., Nucleic Acids Res (2006) 34:3231-8).
Oligonucleotides and oligodeoxynucleotides containing a ribose or deoxyribose sugar have been used in a wide variety of fields, including but not limited to diagnostic probing, PCR priming, antisense inhibition of gene expression, siRNA, microRNA, aptamers, ribozymes, and immunotherapeutic agents based on Toll-like Receptors (TLRs). More recently, many publications have demonstrated the use of oligodeoxynucleotides as immune modulatory agents and their use alone or as adjuvants in immunotherapy applications for many diseases, such as allergy, asthma, autoimmunity, inflammatory diseases, cancer, and infectious disease (Marshak-Rothstein A, Nat Rev Immunol (2006) 6:823-35).
As a result of their involvement in regulating an inflammatory response, TLRs have been shown to play a role in the pathogenesis of many diseases, including autoimmunity, infectious disease and inflammation (Papadimitraki et al. (2007) J. Autoimmun 29: 310-318; Sun et al. (2007) Inflam Allergy Drug Targets 6:223-235; Diebold (2008) Adv Drug Deliv Rev 60:813-823; Cook, D.N. et al. (2004) Nature Immunol 5:975-979; Tse and Homer (2008) Semin Immunopathol 30:53-62; Tobias & Curtiss (2008) Semin Immunopathol 30:23-27; Ropert et al. (2008) Semin Immunopathol 30:41-51; Lee et al. (2008) Semin Immunopathol 30:3-9; Gao et al. (2008) Semin Immunopathol 30:29-40; Vijay-Kumar et al. (2008) Semin Immunopathol 30:11-21). While activation of TLRs is involved in mounting an immune response, an uncontrolled stimulation of the immune system through TLRs may exacerbate certain diseases in immune compromised subjects. In recent years, several groups have shown the use of synthetic oligodeoxyoligonucleotides ("ODNs") as inhibitors of inflammatory cytokines (Lenert, P. et al. (2003) DNA Cell Biol. 22(10):621-631).
In addition, several groups have used synthetic oligodeoxynucleotides having two triplet sequences, a proximal "CCT" triplet and a distal "GGG" triplet, a poly "G" (e.g. "GGGG" or "GGG") or "GC" sequences that interact with TLR proteins to inhibit its activation and the concomitant production and release of pro-inflammatory cytokines (see for example: Lenert, P. et al. (2003) DNA Cell Biol. 22(10):621-631; Patole, P. et al. (2005) J. Am. Soc. Nephrol. 16:3273-3280), Gursel, I., et al. (J. Immunol, 171: 1393-1400 (2003), Shirota, H., et al., J. Immunol, 173: 5002-5007 (2004), Chen, Y., et al., Gene Ther 8: 1024-1032 (2001); Stunz, L.L., Eur. J. Immunol 32: 1212-1222 (2002; Kandimalla et al. W02007/7047396 ). However, oligonucleotides containing guanosine strings have been shown to form tetraplex structures, act as aptamers and inhibit thrombin activity (Bock LC et al., Nature, 355:564-6, 1992; Padmanabhan, K et al., J Biol Chem., 268(24):17651-4, 1993). Thus, the utility of these inhibitory oligodeoxynucleotide molecules may not be achievable in patients.
Recently, Agrawal et al. ( WO2007047396 ) discovered a novel class of TLR antagonists that do not possess the limitations of previously identified TLR antagonists. Such novel class of compounds effectively inhibits the activity of TLRs and block various TLR agonist activity. However, in some disease states it may be desirable to only partially antagonize TLR activity. Thus, there is a need for compounds that can antagonize TLR activity in a dose-dependent, less than full manner.
The invention relates to a novel class of immune regulatory oligonucleotide compounds that reduce, butdo not abolish, a TLR9-mediated immune response in a controlled manner. Such compounds have two or more TLR9-inducing moieties and one or more chemical modifications to the TLR9-inducing moiety and/or in the sequence flanking the most 5' TLR9-inducing moiety, wherein such modification inhibits the activity of the most 5' TLR9-inducing moiety, causing it to be a blocked TLR9-inducing moiety.
Such compound has the structure 5'-Nm-N1N2C1G1Np-N3N4-C2G2-Nm-3', wherein C1 is cytosine, G1 is guanosine, C2 is cytosine or a cytosine derivative, and G2 is guanosine or a guanosine derivative; N1 and N2, at each occurrence, are independently a nucleotide, or nucleotide derivative or blocking moiety that inhibits the TLR stimulatory activity of C1G1 provided that at least one N1 or N2 is a blocking moiety that inhibits the TLR stimulatory activity of C1G1; N3 and N4, at each occurrence, is independently a nucleotide or nucleotide derivative that does not inhibit the TLR stimulatory activity of C2G2; Nm, at each occurrence, is independently a nucleotide, nucleotide derivative or non-nucleotide linkage; Np, at each occurrence, is independently a nucleotide or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nucleotides,: wherein m is a number from 0 to about 20, wherein p is a number from 0 to about 20. The oligonucleotide would be immune stimulatory but for a 2'-O-substitued nucleotide, nucleotide derivative or other modification that inhibits the TLR stimulatory activity of C1 G1.
In a first aspect of the invention, the compound has the structure 5'-Nm-N1N2C1G1. Np-N3N4C2C2-Nn)-3', wherein C1 and C2 are independently cytosine or a cytosine derivative, and G1 and G2 are independently guanosine or a guanosine derivative, wherein at least one of C1 and G1 is a derivative nucleoside; N1 and N2, at each occurrence, are independently a nucleotide, or nucleotide derivative or blocking moiety that inhibits the TLR stimulatory activity of C1G1 provided that at least one N1 or N2 is a blocking moiety that inhibits the TLR stimulatory activity of C1G1; N3 and N4, at each occurrence, is independently a nucleotide or nucleotide derivative that does not inhibit the TLR stimulatory activity of C2 G2; Nm, at each occurrence, is Independently a nucleotide, nucleotide derivative or non-nucleotide linkage; Np, at each occurrence, is independently a nucleotide or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nudeotides, ; wherein m is a number from 0 to about 20, wherein p is a number from 0 to about 20. The oligonucleotide would be immune stimulatory but for a 2'-O-substituted nucleotide, nucleotide derivative or other modification that inhibits the TLR stimulatory activity of C1 G1.
In a further embodiment of this aspect of the invention, the compound has the structure 5'-Nm,-N1N2C1G1-Np-N3N4C2G2-Nr-X-Nr-G2C2N4N3-Np-G1C1N2 N1-Nm-5', wherein C1 Is cytosine, G1 is guanosine, C2 is cytosine or a cytosine derivative, and G2 is guanosine or a guanosine derivative; N1 and N2, at each occurrence, are independently a nucleotide, or nucleotide derivative, or blocking moiety that inhibits the TLR stimulatory activity of C1G1 provided that at least one N1 or N2 is a blocking moiety that inhibits the TLR stimulatory activity of C1G1; N3 and N4, at each occurrence, is independently a nucleotide or nucleotide derivative that does not inhibit the TLR stimulatory activity of C2G2; Nm, at each occurrence, is independently a nucleotide, nucleotide derivative or non-nucleotide linkage; Np, at each occurrence, is independently a nucleotide or nucleotide derivative, Nr, at each occurrence, is independently a nucleotide or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nucleotides, wherein m is a number from 0 to about 20, wherein r is a number from 0 to about 20; wherein p is a number of 0 to about 20; wherein x is a non-nucleotidic linker. The oligonucleotide would be immune stimulatory but for a 2'-O-sustitued nucleotide, nucleotide derivative or other modification that inhibits the TLR stimulatory activity of C1G1;.
In a further embodiment of this aspect of the invention, the compound has the structure 5'-Nm-N1N2C1G1-Np-N3N4C2G2-Nr-X-Nr-G2C2N4N3-Np-C1C1N2N1-Nm-5', wherein C1 and C2 are independently cytosine or a cytosine derivative, and G1 and G2 are independently guanosine or a guanosine derivative wherein at least one of C1 and G1 is a modified nucleoside; N1 and N2, at each occurrence, are independently a nucleotide, or nucleotide derivative or blocking moiety that inhibits the TLR stimulatory activity of C1G1 provided that at least one N1 or N2 is a blocking that inhibits the TLR stimulatory activity of C1G1 provided that at least one N1 or N2 is a blocking moiety that inhibits the TLR stimulatory activity of C1 G1; N3 and N4, at each occurrence, is independently a nucleotide or nucleotide derivative that does not inhibit the TLR stimulatory activity of C2G2; Nm, at each occurrence, is independently nucleotide, nucleotide derivative or non-nucleotide linkage; Np, at each occurrence, is independently a nucleotide or nucleotide derivative, Nr, at each occurrence, is independendy a nucleoside or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nucleotides, wherein m is a number from 0 to about 20, wherein r is a number from 0 to about 20; wherein p is a number of 0 to about 20; wherein x is a non-nucleotidic linker. The oligonucleotide would be immune stimulatory but for a 2'-O-substituted nucleotide, nucleotide derivative or other modification that inhibits the TLR stimulatory activity of C1G1;.
In a second aspect the invention provides pharmaceutical compositions. These compositions comprise any one of the compounds disclosed in the first aspect of the invention and a pharmaceutically acceptable carrier.
In a third aspect the invention provides a method for reducing a TLR9-mediated immune response in a mammal, the method comprising administering to the mammal a compound or composition according to the invention in a pharmaceutically effective amount.
In a fourth aspect the invention provides a method for therapeutically treating a mammal having a disease or disorder where reducing a TLR9-mediated immune response would be beneficial. The method according to this aspect comprises administering to the mammal a compound or composition according to the invention.
In a fifth aspect the invention provides a method for preventing a disease or disorder in a mammal where reducing a TLR9-mediated immune response would be beneficial, or for diseases and disorders where controlled TLR-antagonism is desirable. The method according to this aspect comprises administering to the mammal a compound or composition according to the invention.
Figure 1 is a synthetic scheme for the linear synthesis of compounds of the invention. DMTr = 4,4'-dimethoxytrityl; CE = cyanoethyl.
Figure 2 is a synthetic scheme for the parallel synthesis of compounds of the invention. DMTr = 4,4'-dimethoxytrityl; CE = cyanoethyl.
Figure 3 depicts TLR9 activity mediated by the novel immune regulatory oligonucleotides. Figure 3 more generally demonstrates that the novel inhibitory oligonucleotides will function as antagonists as lower concentrations and as agonists at higher concentrations, effectively controlling their inhibitory activity.
Figure 4 depicts TLR9 activity mediated by the novel immune regulatory oligonucleotides at lower doses. Figure 4 more generally demonstrates that the novel inhibitory oligonucleotides will function as antagonists at lower concentrations and as agonists at higher concentrations.
Figure 5 depicts TLR9 activity of the novel immune regulatory oligonucleotides at increasing doses. Figure 5 more generally demonstrates that the novel inhibitory oligonucleotides will function as antagonists as lower concentrations and as agonists at higher concentrations, effectively controlling their inhibitory activity.
Figure 6 depicts TLR9 activity of the novel immune regulatory oligonucleotides. Figure 6 more generally demonstrates that the novel inhibitory oligonucleotides will function as antagonists as lower concentrations and as agonists at higher concentrations, effectively controlling their inhibitory activity.
Figure 7 depicts TLR9 activity of the novel immune regulatory oligonucleotides at increasing doses. Figure 7 more generally demonstrates that the novel inhibitory oligonucleotides will function as antagonists as lower concentrations and as agonists at higher concentrations, effectively controlling their inhibitory activity.
The invention relates to the therapeutic use of oligonucleotides as immune modulatory agents for immunotherapy applications. Specifically, the invention provides oligonucleotide-based compounds that modulate the immune response through TLR9. By reducing, but not abolishing TLR9-mediated immune responses, the invention provides compounds and methods that may be useful for treating or preventing a variety of diseases or disorders, including those that have an autoimmune component where administration of a dosage controlled antagonist of TLR9 would be beneficial. In the event of inconsistencies between any teaching of any reference cited herein and the present specification, the latter shall prevail for purposes of the invention.
The term "2'-substituted nucleoside" or "2'-substituted arabinoside" generally includes nucleosides or arabinonucleosides in which the hydroxyl group at the 2' position of a pentose or arabinose moiety is substituted to produce a 2'-substituted or 2'-O-substituted ribonucleoside. In certain embodiments, such substitution is with a lower hydrocarbyl group containing 1-6 saturated or unsaturated carbon atoms, with a halogen atom, or with an aryl group having 6-10 carbon atoms, wherein such hydrocarbyl, or aryl group may be unsubstituted or may be substituted, e.g., with halo, hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl, carboalkoxy, or amino groups. Examples of 2'-O-substituted ribonucleosides or 2'-O-substituted-arabinosides include, without limitation 2'-amino, 2'-fluoro, 2'-allyl, 2'-O-alkyl and 2'-propargyl ribonucleosides or arabinosides, 2'-O-methylribonucleosides or 2'-O-methylarabinosides and 2'-O-methoxyethoxyribonucleosides or 2'-O-methoxyethoxyarabinosides.
The term " 3"', when used directionally, generally refers to a region or position in a polynucleotide or oligonucleotide 3' (toward the 3' position of the oligonucleotide) from another region or position in the same polynucleotide or oligonucleotide.
The term "5"', when used directionally, generally refers to a region or position in a polynucleotide or oligonucleotide 5' (toward the 5' position of the oligonucleotide) from another region or position in the same polynucleotide or oligonucleotide.
The term "about" generally means that the exact number is not critical. Thus, the number of nucleoside residues in the oligonucleotides is not critical, and oligonucleotides having one or two fewer nucleoside residues, or from one to several additional nucleoside residues are contemplated as equivalents of each of the embodiments described above.
The term "airway inflammation" generally includes, without limitation, inflammation in the respiratory tract caused by allergens, including asthma.
The term "allergen" generally refers to an antigen or antigenic portion of a molecule, usually a protein, which elicits an allergic response upon exposure to a subject. Typically the subject is allergic to the allergen as indicated, for instance, by the wheal and flare test or any method known in the art. A molecule is said to be an allergen even if only a small subset of subjects exhibit an allergic (e.g., IgE) immune response upon exposure to the molecule.
The term "allergy" generally includes, without limitation, food allergies, respiratory allergies, and skin allergies.
The term "antigen" generally refers to a substance that is recognized and selectively bound by an antibody or by a T cell antigen receptor. Antigens may include but are not limited to peptides, proteins, nucleosides, nucleotides and combinations thereof. Antigens may be natural or synthetic and generally induce an immune response that is specific for that antigen.
The term "autoimmune disorder" generally refers to disorders in which "self" antigen undergo attack by the immune system.
The term "carrier" generally encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, oil, lipid, lipid containing vesicle, microspheres, liposomal encapsulation, or other material well known in the art for use in pharmaceutical formulations. It will be understood that the characteristics of the carrier, excipient, or diluent will depend on the route of administration for a particular application. The preparation of pharmaceutically acceptable formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990.
The term "co-administration" generally refers to the administration of at least two different substances sufficiently close in time to modulate an immune response. Preferably, co-administration refers to simultaneous administration of at least two different substances.
The term a "pharmaceutically effective amount" generally refers to an amount sufficient to affect a desired biological effect, such as a beneficial result, including, without limitation, prevention, inhibition, diminution, amelioration or elimination of signs or symptoms of a disease or disorder.. Thus, a "pharmaceutically effective amount" will depend upon the context in which it is being administered. A pharmaceutically effective amount may be administered in one or more prophylactic or therapeutic administrations.
The term "prophylactically effective amount" generally refers to an amount sufficient to prevent, reduce or inhibit the development of an undesired biological effect.
The term "in combination with" generally means administering a compound according to the invention and another agent useful for treating the disease or condition that does not diminish TLR9 antagonist effect of the compound in the course of treating the same disease in the same patient. Such administration may be done in any order, including simultaneous administration, as well as temporally spaced order from a few seconds up to several days apart. Such combination treatment may also include more than a single administration of the compound according to the invention and/or independently the other agent. The administration of the compound according to the invention and the other agent may be by the same or different routes.
The term "individual" or "subject" generally refers to a mammal, such as a human. Mammals generally include, but are not limited to, humans, non-human primates, rats, mice, cats, dogs, horses, cattle, cows, pigs, sheep and rabbits.
The term "linear synthesis" generally refers to a synthesis that starts at one end of an oligonucleotide and progresses linearly to the other end. Linear synthesis permits incorporation of either identical or non-identical (in terms of length, base composition and/or chemical modifications incorporated) monomeric units into an oligonucleotide.
The term "modified" or "derivative" when used in the context of a nucleoside or nucleotide generally refer to a nucleoside that includes a modified heterocyclic base, a modified sugar moiety or any combination thereof or a nucleotide having any such modifications or a modified phosphate. In some embodiments, the modified nucleoside is a non-natural pyrimidine or purine nucleoside, as herein described. For purposes of the invention, a modified nucleoside, a pyrimidine or purine analog or non-naturally occurring pyrimidine or purine can be used interchangeably and refers to a nucleoside that includes a non-naturally occurring base and/or non-naturally occurring sugar moiety. For purposes of the invention, a base is considered to be non-natural if it is not guanine, cytosine, adenine, thymine or uracil.
The term "modulation" or "modulatory" generally refers to change, such as a decrease in a response or qualitative difference in a TLR9-mediated response.
The term "linker" generally refers to any moiety that can be attached to an oligonucleotide by way of covalent or non-covalent bonding through a sugar, a base, or the backbone. The linker can be used to attach two or more nucleosides or can be attached to the 5' and/or 3' terminal nucleotide in the oligonucleotide. Such linker can be either a non-nucleotidic linker or a nucleotidic linker.
The term "non-nucleotidic linker" generally refers to a chemical moiety other than a nucleotidic linkage that can be attached to an oligonucleotide by way of covalent or non-covalent bonding. Preferably such non-nucleotidic linker is from about 2 angstroms to about 200 angstroms in length, and may be either in a cis or trans orientation.
The term "nucleotidic linkage" generally refers to a chemical linkage to join two nucleosides through their sugars (e.g. 3'-3', 2'-3', 2'-5', 3'-5') consisting of a phosphorous atom and a charged, or neutral group (e.g., phosphodiester, phosphorothioate, phosphorodithioate, alkylphosphonate or phosphoramidate) between adjacent nucleosides.
The term "oligonucleotide-based compound" refers to a polynucleoside formed from a plurality of linked nucleoside units. Such oligonucleotides can be obtained from existing nucleic acid sources, including genomic or cDNA, but are preferably produced by synthetic methods. In preferred embodiments each nucleoside unit includes a heterocyclic base and a pentofuranosyl, trehalose, arabinose, 2'-deoxy-2'-substitutedarabinose, 2'-O-substitutedarabinose or hexose sugar group. The nucleoside residues can be coupled to each other by any of the numerous known internucleoside linkages. Such internucleoside linkages include, without limitation, phosphodiester, phosphorothioate, phosphorodithioate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboalkoxy, acetamidate, carbamate, morpholino, borano, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate, and sulfone internucleoside linkages. The term "oligonucleotide-based compound" also encompasses polynucleosides having one or more stereospecific internucleoside linkage (e.g., (RP )- or (SP )-phosphorothioate, alkylphosphonate, or phosphotriester linkages). As used herein, the terms "oligonucleotide" and "dinucleotide" are expressly intended to include polynucleosides and dinucleosides having any such internucleoside linkage, whether or not the linkage comprises a phosphate group. In certain preferred embodiments, these internucleoside linkages may be phosphodiester, phosphorothioate, or phosphorodithioate linkages, or combinations thereof.
The term "peptide" generally refers to polypeptides that are of sufficient length and composition to affect a biological response, e.g., antibody production or cytokine activity whether or not the peptide is a hapten. The term "peptide" may include modified amino acids (whether or not naturally or non-naturally occurring), where such modifications include, but are not limited to, phosphorylation, glycosylation, pegylation, lipidization and methylation.
The term "physiologically acceptable" generally refers to a material that does not interfere with the effectiveness of a compound according to the invention, and that is compatible with a biological system such as a cell, cell culture, tissue, or organism. Preferably, the biological system is a living organism, such as a vertebrate.
The term "TLR9 antagonist" generally refers to an oligonucleotide-based compound that is able to prevent or reduce immune stimulation mediated by TLR9.
The term "TLR9-inducing moiety" refers to a dinucleotide moiety which, in the context of an oligonucleotide-based compound, induces a TLR9 mediated immune response. In preferred embodiments, the dinucleotide has the structure Y-Z, wherein Y is cytidine, 2' deoxycytidine, arabinocytidine, 2'-deoxy-2'-substitutedarabinocytidine, 2'-O-substitutedarabinocytidine, 2'-deoxy-5-hydroxycytidine, 2'-deoxy-N4-alkyl-cytidine, 2'-deoxy-4-thiouridine or other non-natural pyrimidine nucleoside; and Z is guanosine, 2'-deoxyguanosine, 2'-deoxy-7-deazaguanosine, 2'-deoxy-6-thioguanosine, arabinoguanosine, 2'-deoxy-2'substituted-arabinoguanosine, 2'-O-substituted-arabinoguanosine,2'- deoxyinosine, or other non-natural purine nucleoside.
The term "treatment" generally refers to an approach intended to obtain a beneficial or desired result, which may include alleviation of symptoms, or delaying or ameliorating a disease progression.
The invention relates to a novel class of immune regulatory oligonucleotide compounds that reduce, but do not abolish, a TLR9-mediated immune response in a controlled manner. Such compounds have two or more TLR9-inducing moieties and one or more chemical modifications to the TLR9-inducing moiety and/or in the sequence flanking the most 5' TLR9-inducing moiety, wherein such modification inhibits the activity of the most 5' TLR9-inducing moiety, causing it to be a blocked TLR9-inducing moiety.
Such compound has the structure 5'-Nm-N1N2C1G1-Np-N3N4C2G2-Nm-3'-, wherein C1 is cytosine, G1 is guanosine, C2 is cytosine or a cytosine derivative, and C2 is guanosine or a guanosine derivative; N1 and N2, at each occurrence, are independently a nucleotide, or nucleotide derivative or blocking moiety that inhibits the TLR stimulatory activity of C1G1 provided that at least one N1 or N2 is a blocking moiety that inhibits the TLR stimulatory activity of C1G1; N3 and N4, at each occurrence, is independently a nucleotide or nucleotide derivative that does not inhibit the TLR stimulatory activity of C2G2; Nm, at each occurrence, is independently a nucleotide, nucleotide derivative or non-nucleotide linkage; Np, at each occurrence, is independently a nucleotide or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nucleotides,; wherein m is a number from 0 to about 20, wherein p is a number from 0 to about 20. The oligonucleotide would be immune stimulatory but for a 2'O-subsituted nucleotide, nucleotide derivative or other modification that inhibits the TLR stimulatory activity of C1G1. The first TLR9 -inducing moiety is 5' to the second TLR9 -inducing moiety, wherein the first TLR9 -inducing moiety is a blocked TLR9-inducing moiety, which acts as a TLR9 antagonist, and wherein the second TLR9-inducing moiety is not blocked.
In a first aspect of the invention, the compound has the structure 5'-Nm-N1N2C1G1-Np-N3N4C2G2Nm-3', wherein C1 and C2 are independently cytosine or a cytosine derivative, and G1 and G2 are independently guanosine or a guanosine derivative, wherein at least one of C1 and G1 is a derivative nucleoside; N1 and N2, at each occurrence, are independently a nucleotide, or nucleotide derivative or blocking moiety that inhibits the TLR stimulatory activity of C1G1 provided that at least one N 1 or N2 is a blocking moiety that inhibits the TLR stimulatory activity of C1G1; N3 and N4, at each occurrence, is independently a nucleotide or nudeotide derivative that does not inhibit the TLR stimulatory activity of C2G2; Nm, at each occurrence, is independently a nucleotide, nucleotide derivative or non-nucleotide linkage; Np, at each occurrence, is independently a nucleotide or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nucleotides,: wherein m is a number from 0 to about 20, wherein p is a number from 0 to about 20. The oligonucleotide would be immune stimu latory but for a 2'-O-substituted nucleotide, nucleotide derivative or other modification that inhibits the TLR stimulatory activity of C1G1. I n this embodiment, the first TLR9-inducing moiety is 5' to the second TLR9-inducing moiety, wherein the first TLR9-inducing moiety is a blocked TLR9- inducing moiety, which acts as a TLR9 antagonist, and wherein the second TLR9-inducing moiety is not blocked.
In a further embodiment of this aspect of the invention, the invention provides an immune regulatory oligonucleotide comprising at least two oligonucleotides linked at their 3' ends, or an internucleoside linkage or a functionalized nucleobase or sugar to a non-nucleotidic linker. For example, a compound of this embodiment has the structure 5'-Nm-N1N2C1G1Np-N3N4C2G2-Nr-X-Nr-G2C2N4N3-Np-G1C1N2N1-Nm-5', wherein C1 is cytosine, G1 is guanosine, C2 is cytosine or a cytosine derivative, and G2 is guanosine or a guanosine derivative: N1 and N1, at each occurrence, are independently a nucleodde, or nucleotide derivative or blocking moiety that inhibits the TLR stimulatory activity of C1G1 provided that at least one N1 or N2 is a blocking moiety that inhibits the TLR stimulatory activity of C1G1; N3 and N4, at each occurrence, is independently a nucleotide or nucleotide derivative that does not inhibit the TLR stimulatory activity of C2G2; Nm, at each occurrence, is independently a nucleotide, nucleotide derivative or non-nucleotide linkage: Np, at each occurrence, is independently a nucleotide or nucleotide derivative, Nr, at each occurrence, is independently a nucleotide or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nucleotides, wherein m is a number from 0 to about 20, wherein r is a number from 0 to about 20; wherein p is a number of 0 to about 20; wherein x is a non-nucleotidic linker. The oligonucleotide would be immune stimulatory but for a 2'-O-substituted nucleotide, nucleotide derivative or other modification that inhibits the TLR stimulatory activity of C1G1;.
In another embodiment, the invention provides an immune regulatory oligonucleotide comprising at least two oligonucleotides linked at their 3' ends, or an internucleoside linkage or a functionalized nucleobase or sugar to a non-nucleotidic linker. For example, a compound of this embodiment has the structure 5'-Nm-N1N2C1G1-Np-N3-N4C2G2-Nr-X-Nr-G2C2N4N3-Np-G1C1N2N1-Nm-5', wherein C1 and C2 are independently cytosine, or a cytosine derivative, and G1 and G2 are independently guanosine or a guanosine derivative wherein at least one of C1 and G1 is a derivative nucleoside; N1 and N2, at each occurence, are independently a nucleotide, or nucleotide derivative or blocking moiety that inhibits the TLR stimulatory activity of C1 G1 provided that at least one N1 or N2 is a blocking moiety that inhibits the TLR stimulatory activity of C1G1; N3 and N4, at each occurrence, is independently a nucleotide or nucleotide derivative that does not inhibit the TLR stimulatory activity of C1G1; Nm, at each occurrence, is independently a nucleotide, nucleotide derivative or non-nucleotide linkage; Np, at each occurrence, is independently a nucleotide or nucleotide derivative, Nr, at each occurrence, is independently a nucleotide or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nucleotides, wherein m is a number from 0 to about 20, wherein r is a number from 0 to about 20; wherein p is a number of 0 to about 20; wherein x is a non-nucleotidic linker. The oligonucleotide would be immune stimulatory but for a 2'-O-substituted nucleotide, nucleotide derivative or other modification that inhibits the TLR stimulatory activity of C1G1;.
Such embodiments of the invention may have at least one accessible 5' end. It has been determined that this structure provides further stability (e.g. inhibition of exonuclease activity) to the immune regulatory oligonucleotide compounds. The 5'-terminus of the immune regulatory oligonucleotide is not modified in such a way as to prevent the immune regulatory oligonucleotide compound from modulating an immune response through TLR9.
In another embodiment of this aspect of the invention comprises at least two oligoribonucleotides, wherein at least one of Domain A, B, C, and D comprises a TLR9 antagonist with at least one TLR9-inducing moiety and a blocked TLR9-inducing moiety 5' to the TLR-inducing moiety, wherein the immune modulatory compound has a structure including, but not limited to, those as detailed in Formulas I - X in Table 1.
Domains A, B, C, and D may be independently from about 8 to about 30 nucleotides, more preferably from about 10 to about 21 nucleotides. Domains A, B, C, and/or D may or may not be identical. Domains A, B, C, and D may independently be 5'-3' or 2'-5' RNA having or not having a self-complementary domain, a homo or hetero ribonucleotide sequence, or a linker. "n" may be from 1 to an unlimited number.
"X" is a linker joining or capping Domains A, B, C, and/or D that may be through a 3' or 5' linkage, a phosphate group, a non-RNA nucleotide, or a non-nucleotidic linker that may be aliphatic, aromatic, aryl, cyclic, chiral, achiral, a peptide, a carbohydrate, a lipid, a fatty acid, mono- tri- or hexapolyethylene glycol, or a heterocyclic moiety, or combinations thereof.
In a further embodiment, the invention provides an immune regulatory oligonucleotide compound comprising at least two oligonucleotides linked by a non-nucleotide linker, wherein the sequences of the immune modulatory oligonucleotides may be at least partially self-complementary. As would be recognized by one skilled in the art, the complementary sequence of the oligonucleotides allows for intermolecular hydrogen bonding thereby giving the oligonucleotides secondary structure. Additional oligonucleotides can bind together thereby creating a chain, or multimers, of oligonucleotides according to the invention.
Compounds according to this aspect act as antagonists of TLR9 at a first dosage and act as partial agonists of TLR9 at a second, higher dosage. Without wishing to be bound by theory, Applicants believe that, at lower concentrations, compounds according to this aspect bind TLR9 primarily via the first (most 5') TLR9-inducing moiety. This is because TLR9 is believed to interact with oligonucleotide-based compounds initially at their 5' end(s). Since the activity of the first TLR9-inducing moiety is blocked, the compound acts as a TLR9 antagonist at dosages at which TLR9 interacts with the compound primarily at the first (most 5') TLR9-inducing moiety. However, at higher concentrations, it is believed that the first (most 5') TLR9-inducing moiety becomes saturated, and that TLR9 begins to interact with the compound at a second (more 3') TLR9-inducing moiety. Because the second (more 3') TLR9-inducing moiety is not blocked, the compound then begins to act as a TLR9 agonist.
The advantage of compounds according to this aspect is that while a TLR9 mediated immune responses are reduced at lower dosages of the compound, it is not abolished at higher dosages because the compound at that point begins to acts as a TLR9 agonist. Thus, compounds according to this aspect are self-regulating in the extent of their antagonism of TLR9.
In some embodiments according to this aspect of the invention, the compound has an immunomer structure, as described in US Patent Number 7,276,489 .
In some embodiments, the linear oligonucleotides or one or more branched oligonucleotides each independently have from about 8 to about 30 nucleoside residues. Thus in certain embodiments the oligonucleotide can independently be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides long. Preferably the oligonucleotide is from about 11 to about 25 nucleoside residues, more preferably from about 16 to about 21 nucleoside residues. In some embodiments, the immune modulatory oligonucleotides comprise 21 oligonucleotides. Certain preferred embodiments comprise 42 nucleotides. Preferably, the TLR9 antagonist compound comprises at least one phosphodiester, phosphorothioate, or phosphorodithioate internucleoside linkage.
In preferred embodiments each nucleoside unit includes a heterocyclic base and a pentofuranosyl, 2'-O-substituted pentofuranosyl, trehalose, arabinose, 2'-deoxy-2'-substituted arabinose, 2'-O-substituted ribose or arabinose or a hexose sugar group. The nucleoside residues can be coupled to each other by any of the numerous known internucleoside linkages. Such internucleoside linkages include, without limitation, phosphodiester, phosphorothioate, phosphorodithioate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboalkoxy, acetamidate, carbamate, morpholino, borano, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate, and sulfone internucleoside linkages. Possible sites of conjugation for the nucleotide are indicated in Formula XI, below, wherein B represents a heterocyclic base.
The TLR9 antagonist compounds of the invention can further include naturally occurring ribonucleosides, modified ribonucleosides or mixtures thereof.
Some chemical modifications to the heterocyclic bases include, but are not limited to, guanine analogues such as 7-deaza-G, ara-G, 6-thio-G, Inosine, Iso-G, loxoribine, TOG(7-thio-8-oxo)-G, 8-bromo-G, 8-hydroxy-G, 5-aminoformycin B, Oxoformycin, 7-methyl-G, 9-p-chlorophenyl-8-aza-G, 9-phenyl-G, 9-hexyl-guanine, 7-deaza-9-benzyl-G, 6-Chloro-7-deazaguanine, 6-methoxy-7-deazaguanine, 8-Aza-7-deaza-G(PPG), 2-(Dimethylamino) guanosine, 7-Methyl-6-thioguanosine, 8-Benzyloxyguanosine, 9-Deazaguanosine, and 1-(B-D-furanosyl)-2-oxo-7-deaza-8-methyl-purine. Chemical modifications also include, but are not limited to, adenine analogues such as 9-benzyl-8-hydroxy-2-(2-methoxyethoxy)adenine, 2-Amino-N2-O-, methyladenosine, 8-Aza-7-deaza-A, 7-deaza-A, Vidarabine, 2-Aminoadenosine, N1-Methyladenosine, 8-Azaadenosine, 5-Iodotubercidin. Chemical modifications also include, but are not limited to, cytosine analogues, such as 2'-deoxy-5-hydroxycytidine and 2'-deoxy-N4-alkyl-cytidine. Chemical modifications also include, but are not limited to, uracil analogues such as 4-thio-U.
The TLR9 antagonist compounds according to the invention include compounds that comprise at least two oligonucleotides linked covalently or non-covalently at their 3'- or 2'-ends or functionalized ribose or deoxyribose (including substituted forms) or functionalized nucleobase via a non-nucleotidic or a nucleotidic linker. Several examples of linkers are set forth in Table 2. Non-covalent linkages include, but are not limited to, electrostatic interaction, hydrophobic interactions, π-stacking interactions and hydrogen bonding.
In yet other embodiments, the non-nucleotidic linker is an organic moiety having functional groups that permit attachment to the oligonucleotide. Such attachment preferably is by a stable covalent linkage. As a non-limiting example, the linker may be attached to any suitable position on the nucleotide. In some preferred embodiments, the linker is attached to the 3'-hydroxyl. In such embodiments, the linker preferably comprises a hydroxyl functional group, which preferably is attached to the 3'-hydroxyl by means of a phosphate-based linkage like, phosphodiester, phosphorothioate, phosphorodithioate, methylphosphonate or non-phosphate-based linkages.
In some embodiments, the non-nucleotidic linker is a small molecule, macromolecule or biomolecule, including, without limitation, polypeptides, antibodies, lipids, antigens, allergens, and oligosaccharides. In some other embodiments, the non-nucleotidic linker is a small molecule. For purposes of the invention, a small molecule is an organic moiety having a molecular weight of less than 1,000 Da. In some embodiments, the small molecule has a molecular weight of less than 750 Da.
In some embodiments, the small molecule is an aliphatic or aromatic hydrocarbon, either of which optionally can include, either in the linear chain connecting the oligonucleotides or appended to it, one or more functional groups including, but not limited to, hydroxy, amino, thiol, thioether, ether, amide, thioamide, ester, urea or thiourea. The small molecule can be cyclic or acyclic. Examples of small molecule linkers include, but are not limited to, amino acids, carbohydrates, cyclodextrins, adamantane, cholesterol, haptens and antibiotics. However, for purposes of describing the non-nucleotidic linker, the term "small molecule" is not intended to include a nucleoside.
In some embodiments, the non-nucleotidic linker is an alkyl linker or amino linker. The alkyl linker may be branched or unbranched, cyclic or acyclic, substituted or unsubstituted, saturated or unsaturated, chiral, achiral or racemic mixture. The alkyl linkers can have from about 2 to about 18 carbon atoms. In some embodiments such alkyl linkers have from about 3 to about 9 carbon atoms. Some alkyl linkers include one or more functional groups including, but not limited to, hydroxy, amino, thiol, thioether, ether, amide, thioamide, ester, urea, and thioether. Such alkyl linkers can include, but are not limited to, 1-propanol, 1,2 propanediol, 1,3 propanediol, 1,2,3, propanetriol, triethylene glycol, hexaethylene glycol, polyethylene glycol linkers (e.g. [-O-CH2-CH2-]n (n= 1-9)),methyl linkers, ethyl linkers, propyl linkers, butyl linkers, or hexyl linkers. In some embodiments, such alkyl linkers may include peptides or amino acids.
In some embodiments, the non-nucleotidic linker may include, but are not limited to, those listed in Table 2.
In some embodiments, the small molecule linker is glycerol or a glycerol homolog of the formula HO-(CH2) o -CH(OH)-(CH2) p -OH, wherein o and p independently are integers from 1 to about 6, from 1 to about 4, or from 1 to about 3. In some other embodiments, the small molecule linker is a derivative of 1,3-diamino-2-hydroxypropane. Some such derivatives have the formula HO-(CH2) m -C(O)NH-CH2-CH(OH)-CH2-NHC(O)-(CH2) m -OH, wherein m is an integer from 0 to about 10, from 0 to about 6, from 2 to about 6, or from 2 to about 4.
Some non-nucleotidic linkers according to the invention permit attachment of more than two oligonucleotides, as depicted in Table 1. For example, the small molecule linker glycerol has three hydroxyl groups to which oligonucleotides may be covalently attached. Some immune modulatory oligonucleotides according to the invention, therefore, comprise more than two oligonucleotides linked via a non-nucleotidic linker.
In a further embodiment of this aspect of the invention, a TLR9 antagonist compound may contain three or more oligonucleotides linked at their 3' or 5' ends, or through an internucleoside linkage or a functionalized nucleobase or sugar to two or more linkers, as depicted in Table 1. The oliognucleotides of this aspect of the invention may have the same or different sequences. The linkers of this aspect of the invention may be the same or different.
Underlined nucleosides represent 2'-O-methylribonucleosides; G1 = 2'-deoxy-7-deazaguanosine; X = non-nucleotidic linker, for example glycerol.
The TLR9 antagonist compounds of the invention may conveniently be synthesized using an automated synthesizer and phosphoramidite approach as schematically depicted in Figures 1 and 2, and further described in the Examples. In some embodiments, the immune modulatory oligonucleotides are synthesized by a linear synthesis approach (Figure 1).
An alternative mode of synthesis is "parallel synthesis", in which synthesis proceeds outward from a central linker moiety (see Figure 2). A solid support attached linker can be used for parallel synthesis, as is described in U.S. Patent No. 5,912,332 . Alternatively, a universal solid support (such as phosphate attached controlled pore glass) support can be used.
Parallel synthesis of compounds according to the invention has several advantages over linear synthesis: (1) parallel synthesis permits the incorporation of identical monomeric units; (2) unlike in linear synthesis, both (or all) the monomeric units are synthesized at the same time, thereby the number of synthetic steps and the time required for the synthesis is the same as that of a monomeric unit; and (3) the reduction in synthetic steps improves purify and yield of the final immune modulatory oligonucleotide product.
At the end of the synthesis by either linear synthesis or parallel synthesis protocols, the immune modulatory oligonucleotides may conveniently be deprotected with concentrated ammonia solution or as recommended by the phosphoramidite supplier, if a modified nucleoside is incorporated. The product immune modulatory oligonucleotide is preferably purified by reversed phase HPLC, detritylated, desalted and dialyzed.
In a second aspect, the invention provides pharmaceutical formulations comprising a TLR9 antagonist compound according to the invention and a physiologically acceptable carrier.
In a third aspect the invention provides a method for reducing a TLR9-mediated immune response in a mammal, the method comprising administering to the mammal a compound or pharmaceutical formulation according to the invention in an amount that reduces the TLR9-mediated immune response.
In a fourth aspect the invention provides a method for therapeutically treating a mammal having a disease or disorder where reducing a TLR9-mediated immune response would be beneficial, for example, autoimmune disorders, airway inflammation, inflammatory disorders, allergy, asthma, arthritis, arthritis, malaria, allergy, transplant rejection, infectious disease, and other diseases and disorders that have an autoimmune component. The method according to this aspect of the invention comprises administering to the mammal having such a disorder or disease a compound or pharmaceutical formulation according to the invention in a pharmaceutically effective amount.
In a fifth aspect the invention provides a method for preventing a disease or disorder in a mammal where reducing a TLR9-mediated immune response would be beneficial, for example an autoimmune disorder, cancer, airway inflammation, inflammatory disorders, infectious disease, malaria, Lyme disease, ocular infections, skin disorders, psoriasis, scleroderma, cardiovascular disease, atherosclerosis, chronic fatigue syndrome, sarcoidosis, allergy, asthma or a disease caused by a pathogen. The method according to this aspect of the invention comprises administering to a mammal that is susceptible to such a disorder or disease a compound or pharmaceutical formulation according to the invention in a pharmaceutically effective amount.
In some embodiments, the autoimmune disorder is selected from lupus erythematosus, multiple sclerosis, type I diabetes mellitus, irritable bowel syndrome, Chron's disease, rheumatoid arthritis, septic shock, alopecia universalis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Bullous pemphigoid, chagas disease, chronic obstructive pulmonary disease, coeliac disease, dermatomyositis, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus, pernicious anaemia, polymyositis, primary biliary cirrhosis, schizophrenia, Sjögren's syndrome, temporal arteritis ("giant cell arteritis"), vasculitis, vitiligo, vulvodynia and Wegener's granulomatosis.
In some embodiments, the inflammatory disorder is selected from airway inflammation, asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, Behçet's disease, hypersensitivities, inflammatory bowel disease, reperfusion injury, rheumatoid arthritis, transplant rejection, ulcerative colitis, uveitis, conjunctivitis and vasculitis.
In any of the methods according to the invention, the TLR9 antagonist compound can variously act by producing direct TLR9 antagonist effects alone and/or in combination with any other agent useful for treating or preventing the disease or condition that does not diminish the TLR9 antagonist effect of the compound. In any of the methods according to the invention, the agent(s) useful for treating or preventing the disease or condition includes, but is not limited to, vaccines, antigens, antibodies, preferably monoclonal antibodies, cytotoxic agents, allergens, antibiotics, siRNA, antisense oligonucleotides, other TLR agonist or antagonist (e.g. agonists or antagonist of TLR7, TLR8 and/or TLR3), chemotherapeutic agents (both traditional chemotherapy and modem targeted therapies), targeted therapeutic agents, activated cells, peptides, proteins, gene therapy vectors, peptide vaccines, protein vaccines, DNA vaccines, adjuvants, and co-stimulatory molecules (e.g. cytokines, chemokines, protein ligands, transactivating factors, peptides or peptides comprising modified amino acids), or combinations thereof. Alternatively, the agent can include DNA vectors encoding for antigen or allergen. Alternatively, the compounds can be administered in combination with other adjuvants to enhance the specificity or magnitude of the immune response to the compound.
In any of the methods according to the invention, administration of TLR9 antagonist compound, alone or in combination with any other agent, can be by any suitable route, including, without limitation, parenteral, mucosal delivery, oral, sublingual, transdermal, topical, inhalation, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, by gene gun, dermal patch or in eye drop or mouthwash form. Administration of the therapeutic compositions of TLR9 antagonist compound can be carried out using known procedures using an effective amount and for periods of time effective to reduce symptoms or surrogate markers of the disease. For example, an effective amount of a TLR9 antagonist compound for treating a disease and/or disorder could be that amount necessary to alleviate or reduce the symptoms, or delay or ameliorate an autoimmune response. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular oligonucleotide being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular oligonucleotide without necessitating undue experimentation.
When administered systemically, the therapeutic composition is preferably administered at a sufficient dosage to attain a blood level of TLR9 antagonist compound from about 0.0001 micromolar to about 10 micromolar. For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated. Preferably, a total dosage of TLR9 antagonist compound ranges from about 0.001 mg per patient per day to about 200 mg per kg body weight per day. It may be desirable to administer simultaneously, or sequentially a therapeutically effective amount of one or more of the therapeutic compositions of the invention to an individual as a single treatment episode.
The TLR9 antagonist compound may optionally be linked to one or more allergens and/or antigens (self or foreign), an immunogenic protein, such as keyhole limpet hemocyanin (KLH), cholera toxin B subunit, or any other immunogenic carrier protein. TLR9 antagonist compounds can also be used in combination with other compounds (e.g. adjuvants) including, without limitation, Freund's incomplete adjuvant, KLH, monophosphoryl lipid A (MPL), alum, and saponins, including QS-21 and imiquimod, or combinations thereof.
The methods according to this aspect of the invention are useful for model studies of the immune system. The methods are also useful for the prophylactic or therapeutic treatment of human or animal disease. For example, the methods are useful for pediatric and veterinary vaccine applications.
The examples below are intended to further illustrate certain preferred embodiments of the invention, and are not intended to limit the scope of the invention.
The immune modulatory oligonucleotides were chemically synthesized using phosphoramidite chemistry on automated DNA/RNA synthesizer. TAC protected (Except U) 2'-O-TBDMS RNA monomers, A, G, C and U, were purchased from Sigma-Aldrich. 7-deaza-G, inosine and loxoribine monomers were purchased from ChemGenes Corporation. 0.25M 5-ethylthio-1H-tetrazole, PAC- anhydride Cap A and Cap B were purchased from Glen Research. 3% trichloroacetic acid (TCA) in dichloromethane (DCM) and 5% 3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage reagent) were made in house.
TLR9 antagonist compounds were synthesized at 1-2 µM scale using a standard DNA synthesis protocol.
TLR9 antagonist compounds were cleaved from solid support and the solution was further heated at 65 °C to removing protecting groups of exo cyclic-amines. The resulting solution was dried completely in a SpeedVac.
TLR9 antagonist compounds were purified by ion exchange HPLC.
Column Heater: ChromTech TL-105 HPLC column heater, temperature is set to 80 °C.
Crude TLR9 antagonist compounds solution was injected into HPLC. Above gradient is performed and the fractions were collected. All fractions containing more than 90% desired product were mixed, and then the solution was concentrated to almost dry by RotoVap. Distilled deionized water was added to make final volume of 10ml.
tC-18 Sep-Pak cartridge purchased from Waters was first conditioned with 10m of acetonitrile followed by 10 ml of 0.5 M sodium acetate. 10 ml of immune modulatory oligonucleotide solution was loaded. 15 ml of water was then used to wash out the salt. The immune modulatory oligonucleotide was finally eluted out by 1 ml of 50% acetonitrile in water.
The solution is placed in SpeedVac for 30 minutes. The remaining solution was filtered through a 0.2 micro filter and then was lyophilized to dryness. The solid was then redissolved in water to make the desired concentration.
The final solution was stored below 0 °C.
Following synthesis and purification, the TLR9 antagonist compounds were analyzed by capillary electrophoresis.
Sample preparation: 0.2 OD of TLR9 antagonist compounds was dissolved in 200ul of distilled deionized water.
Injection: electro-kinetic injection at 5KV for 5 seconds.
Running condition: 14KV for 50 minutes at 30 °C.
Following synthesis and purification, the TLR9 antagonist compounds were analyzed by ion exchange HPLC.
0.3 OD of immune modulatory oligonucleotide was loaded on 20% polyacrylamide gel and was electrophoresed at constant power of 4 watts for approximately 5 hours. The gel was viewed under short wavelength UV light.
HEK293/human TLR7 or HEK293/human TLR8 cells (Invivogen, San Diego, CA) were cultured in 48-well plates in 250 µl/well DMEM supplemented with 10% heat-inactivated FBS in a 5% CO2 incubator.
HEK293 cells stably expressing mouse TLR9 (Invivogen, San Diego, CA) were cultured in 48-well plates in 250 µl/well DMEM supplemented with 10% heat-inactivated FBS in a 5% CO2 incubator. At 80% confluence, cultures were transiently transfected with 400 ng/ml of SEAP (secreted form of human embryonic alkaline phosphatase) reporter plasmid (pNifty2-Seap) (Invivogen) in the presence of 4 µl/ml of lipofectamine (Invitrogen, Carlsbad, CA) in culture medium. Plasmid DNA and lipofectamine were diluted separately in serum-free medium and incubated at room temperature for 5 minutes. After incubation, the diluted DNA and lipofectamine were mixed and the mixtures were incubated at room temperature for 20 minutes. Aliquots of 25 µl of the DNA/lipofectamine mixture containing 100 ng of plasmid DNA and 1 µl of lipofectamine were added to each well of the cell culture plate, and the cultures were continued for 4 hours.
After transfection, medium was replaced with fresh culture medium, TLR9 antagonist compounds were added to the cultures, and the cultures were continued for 18 hours. At the end of treatment, 30 µl of culture supernatant was taken from each treatment and used for SEAP assay following manufacturer's protocol (Invivogen).
Briefly, culture supernatants were incubated with p-nitrophynyl phosphate substrate and the yellow color generated was measured by a plate reader at 405 nm. The data are shown as fold increase in NF-κB activity over PBS control. (Putta MR et al. Nucleic Acids Res, 2006, 34:3231-8). The results are shown in Figure 3.
C57BL/6 mice and BALB/c mice, 6-8 weeks old, were obtained from Taconic Farms. Germantown, NY and maintained in accordance with Idera Pharmaceutical's IACUC approved animal protocols. Mice (n=3) were injected subcutaneously (s.c) with individual immune regulatory oligonucleotides from Table 3 at 1,10, or 20 mg/kg (single dose). Serum was collected 2 hr after immune modulatory oligonucleotide administration and cytokine and chemokine concentrations were determined by sandwich ELISA or Luminex multiplex assays. The results are shown for IL-12 in Figures 4, 5, and 7 and demonstrate that in vivo administration of immune regulatory oligonucleotides containing novel chemical compositions generates unique cytokine profiles. All reagents, including cytokine and chemoldne antibodies and standards were purchased from PharMingen. (San Diego, CA).
A compound that acts as a TLR9 antagonist at a first dosage and acts as a partial TLR9 agonist at a higher dosage comprising an oligonucleotide having the structure 5'-Nm-N1N2C1G1-Np-N3N4C2G2-Nm-3', wherein C1 and C2 are independently cytosine or a cytosine, derivative, and G1 and G2 are independently guanosine or a guanosine derivative, wherein at least one of C1 and G1 is a derivative nucleoside; N1 and N2, at each occurrence, are independently a nucleotide or nucleotide derivative or blocking moiety that inhibits the TLR stimulatory activity of C1G1 provided that at least one N1 or N2 is a blocking moiety that inhibits the TLR stimulatory activity of C1G1; N3 and N4, at each occurrence, is independently a nucleotide or nucleotide derivative that does not inhibit the TLR stimulatory activity of C2G2; Nm, at each occurrence, is independently a nucleotide, nucleotide derivative or non-nucleotide linkage; Np, at each occurrence, is independently a nucleotide or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nucleotides, wherein m is a number from 0 to about 20, wherein p is a number from 0 to about 20.
The compound according to claim 1, wherein the compound comprises at least two oligonucleotides linked through 2', 3' or 5' attachments, or functionalized nucleobase attachments, or combinations thereof.
The compound according to claim 2, wherein the oligonucleotides are linked directly to each other at their 2' ends, 3' ends or 5' ends, or functionalized nucleobases.
The compound according to claim 2, wherein the 2' ends, 3' ends or 5' ends, or functionalized nucleobases of the oligonucleotides are linked to a non- nucleotidic linker.
The compound according to claim 4, wherein the non-nucleotidic linker is an alkyl linker or amino linker, wherein the alkyl or amino linker may be optionally branched or unbranched, cyclic or acyclic, substituted or unsubstituted, saturated or unsaturated, chiral, achiral or racemic mixture.
The TLR9 antagonist compound according to claim 5, wherein the alkyl linker has from about 2 to about 18 carbon atoms.
The compound according to claim 5, wherein the alkyl linker has from about 3 to about 9 carbon atoms.
The compound according to claim 5, wherein the alkyl linker is selected from 1,2,3-Propanetriol, 1,2,4-Butanetriol, 2-Hydroxymethyl-1,3-propanediol, 1,1,1-Tris(hydroxymethyl)ethane, 2-Amino-2-(hydroxymethyl)1,3-propanediol, tris(hydroxymethyl)nitromethane, 1,1,1-Trishydroxymethyl)propane, 1,2,6-Hexanetriol, 1,3,5-Hexanetriol, 1,3,5-Pentanetriol, 3-Methyl-1,3,5-pentanetriol, 1,2,3-Heptanetriol, 2-(Hydroxymethyl)1,4-butanediol, 1,3-Di(hydroxymethyl)phenol, 1,3,5-Tri(hydroxymethyl)benzene, 1,3-Di(hydroxyethoxy)-2-hydroxy-propane, 1,3-Di(hydroxypropoxy)-2-hydroxy-propane, D-Galactal, 1,3,5-Tris(2-hydroxyethyl)cyanuric acid, 1,3,5-Tris(4-hydroxyphenyl)benzene, 1,3-Propanediol, 1,2-Propanediol, 1,4-Butanediol, 1,3-Butanediol, 2,3-Butanediol, 1,4-Butanediol, 1,5-Pentanediol, 2,4-Pentanediol, 1,6-Hexa.nediol, 1,2-Hexanediol, 1,5-Hexanediol, 2,5-Hexanediol, 1,7-Heptanediol, 1,8-Octanediol, 1,2-Octanediol, 1,9-Nonanediol, 1,12-Dodecanediol or 2-(1-Aminopropyl)-1,3-propanediol.
The compound according to claim 1, wherein the blocking moiety is selected from the group consisting of 2'-OMe-ribonucleosides, 3'-OMe-ribonucleosides, 3-nitropyrrole, 5- nitroindole, dU, β-L-deoxynucleosides, α-deoxynucleosides, abasic nucleoside, propanediol linker, amino linker, isopropoxyl, glycerol linker, 2'-5'-DNA, 2-5' RNA, and P-Me DNA.
A pharmaceutical composition comprising a TLR9 antagonist compound according to any one of claims 1-9 and a pharmaceutically acceptable carrier.
The pharmaceutical composition according to claim 10 in an amount that reduces, but does not abolish the TLR9-mediated immune response, for use in the treatment of a vertebrate in need of reducing a TLR9-mediated immune response.
The pharmaceutical composition according to claim 10 in a pharmaceutically effective amount for use in treatment of a vertebrate having a disease or disorder where reducing a TLR9-mediated immune response is beneficial.
The pharmaceutical composition according to claim 12, wherein the disease or disorder is selected from cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, malaria, Lyme disease, ocular infections, skin disorders, psoriasis, scleroderma, cardiovascular disease, atherosclerosis, chronic fatigue syndrome, sarcoidosis, allergy, asthma or a disease caused by a pathogen.
The pharmaceutical composition according to claim 13, wherein the autoimmune disorder is selected from lupus erythematosus, multiple sclerosis, type I diabetes mellitus, irritable bowel syndrome, Crohn's disease, rheumatoid arthritis, septic shock, alopecia universalis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid, Chagas disease, chronic obstructive pulmonary disease, coeliac disease, dermatomyositis, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus, pernicious anaemia, polymyositis, primary biliary cirrhosis, schizophrenia, Sjogren's syndrome, temporal arteritis ("giant cell arteritis"), vasculitis, vitiligo, vulvodynia and Wegener's granulomatosis.
The pharmaceutical composition according to claim 13, wherein the inflammatory disorder is selected from airway inflammation, asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, Behcet's disease, hypersensitivities, inflammatory bowel disease, reperfusion injury, rheumatoid arthritis, transplant rejection, ulcerative colitis, uveitis, conjunctivitis and vasculitis.
The pharmaceutical composition according to claim 10 in a pharmaceutically effective amount for use in preventing a disease or disorder in a vertebrate where reducing a TLR9-mediated immune response is beneficial.
The pharmaceutical composition according to claim 16, wherein the disease or disorder is selected from cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, malaria, Lyme disease, ocular infections, conjunctivitis, skin disorders, psoriasis, scleroderma, cardiovascular disease, atherosclerosis, chronic fatigue syndrome, sarcoidosis, transplant rejection, allergy, asthma or a disease caused by a pathogen.
The pharmaceutical composition according to claim 17, wherein the autoimmune disorder is selected from lupus erythematosus, multiple sclerosis, type I diabetes mellitus, irritable bowel syndrome, Crohn's disease, rheumatoid arthritis, septic shock, alopecia universalis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid, Chagas disease, chronic obstructive pulmonary disease, coeliac disease, dermatomyositis, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus, pernicious anaemia, polymyositis, primary biliary cirrhosis, schizophrenia, Sjogren's syndrome, temporal arteritis ("giant cell arteritis"), vasculitis, vitiligo, vulvodynia and Wegener's granulomatosis.
The pharmaceutical composition according to claim 17, wherein the inflammatory disorder is selected from airway inflammation, asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, Behcet's disease, hypersensitivities, inflammatory bowel disease, reperfusion injury, rheumatoid arthritis, transplant rejection, ulcerative colitis, uveitis, conjunctivitis and vasculitis.
The pharmaceutical composition according the any one of claims 11-19, wherein the route of administration is parenteral, mucosal delivery, oral, sublingual, transdermal, topical, inhalation, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, by gene gun, dermal patch or in eye drop or mouthwash form.
The pharmaceutical composition according to any one of claims 11-20, comprising further one or more vaccines, antigens, antibodies, cytotoxic agents, allergens, antibiotics, antisense oligonucleotides, TLR agonist, TLR antagonist, siRNA, miRNA, proteins, gene therapy vectors, DNA vaccines, adjuvants, co-stimulatory molecules or combinations thereof.
MX342945B (en) 2009-07-06 2016-10-18 Ontorii Inc * Novel nucleic acid prodrugs and methods use thereof.
ES2257068T3 (en) 2006-07-16 Cpg mixtures adjuvants and saponins and methods of use thereof.
ES2233426T3 (en) 2005-06-16 Modulation of immune stimulation by CpG oligonucleotide measure by changing the position of nucleosides.
ES2238044T3 (en) 2005-08-16 Modulation of immune stimulation mediated by CpG oligonucleotide positional modification nucleosides.
ES2298269T3 (en) 2008-05-16 Modulation of immunostimulatory activity of immunostimulatory oligonucleotide Analogs by Positional chemical changes.
|
{
"timestamp": "2019-04-23T17:16:39",
"url": "https://patents.google.com/patent/EP2179061B1/en",
"language": "en",
"source": "c4"
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Our oyster farm is located on Oleron Island in the center of the bassin Marennes-Oleron.
Connected directly to the sea allows us to cultivate 25 hectares of claires. Just as vineyards bring character to certain wines, the claire has the effect on oysters of natural exchanges and conditions which are never identical, depending on exposition, location and quality of the ground.
our core business .... The finishing in claires is a know-how transmitted from generation to generation. It is during this process that the oysters acquire the subtleties of regional flavours. The claires, situated between the land and the sea, are the reflection of those two environments.
We manage the entire production life cycle from the reproduction until the finishing in claires.
Our passion has been rewarded since 1998 by over 19 distinctions granted by the "Concours Général Agricole de Paris", the European Masters of the degustation and the concours des "Produits Régionaux".
The oyster "fine de claire verte Label Rouge"
|
{
"timestamp": "2019-04-19T07:17:39",
"url": "http://huitres-fonteneau.fr/UK-terroir-huitres-marennes-oleron.html",
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Steven Raets is the owner, audio engineer and producer at Bunker Sound Studio. A life long music enthusiast who played in bands since he was 12y old, finally made his dream come true when in 2013 he set up Bunker Sound Productions. His vision was to build an affordable, yet very high end studio, where artists would feel comfortable to create.
Since then, Steven has produced, recorded and mixed numerous bands as well as assisted other producers. Steven is a driven, enthusiastic, positive attitude artistic mind, keen on helping bands, artists and singer/songwriters achieve their potential. Nothing gives him more satisfaction than to work with artists to record, mix and produce their songs to the highest possible standards. Early 2016 Steven was trained by legendary mastering guru Vlado Meller. With his newly acquired skill set, Steven is currently the main mastering engineer at Bunker Sound. He mastered the cd and vinyl album, Darkness Remains (Sony/Century Media and SPV/Steamhammer), for the band Night Demon, Ventura, CA. The album reached #19 on Billboard - Current Hard Music, #6 on Amazon - Best Sellers Metal Home Page and #10 on Amazon Hot New Releases (Digital and Vinyl). Night Demon's Darkness Remains was chosen by the listeners of WJCU as top album of the year 2017 as well as made the top pick album of the year 2017 by Bravewords @ Mark Gromen.
In the summer of 2017, Steven came up with the idea to start an incubator platform for emerging artists in the music industry. The idea took shape in the form of NovaMusicLab, a worldwide platform to discover, develop and empower emerging artists.
John E Wooten IV is a free lance audio engineer who lives in Raleigh, NC. He has been recording and playing in bands around the Raleigh music scene for over 20 years. With a degree in Digital Audio Production from the Living Arts College, and real world studio experience, he became the Head Engineer at Hemispheres Recording for acclaimed producer James Lugo. Nowadays, he spends a lot of his time at Bunker Sound Studio.
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"timestamp": "2019-04-25T06:50:09",
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Two melodies composed side by side, a harmony of ruby-throated hummingbird and the columbine of the prairies.
One with long corollas, nectar at the tip, and a desire to have its pollen spread. The other with a needle of a beak, the power to stand still in mid air, and a passion for nectar.
Distilled sunlight, both of them.
New and designed for the health and happiness of hummingbirds. All three parts are dishwasher safe, so it's completely easy to clean.
It's the perfect feeder for hummingbirds. Dr. JB's Clean Feeder. We use it and we recommend it.
|
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"url": "http://birdwatching.com/naturelog/-2011/-05/-23.html",
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Modern home in good condition for sale in Hua Hin on a small development with communal swimming pool. A well kept and updated 3 Bedroom and 2 Bathroom villa at a reasonable price suitable for most budgets. The updated modern European style kitchen has an additional breakfast bar with granite surfaces throughout. Adjacent to the open plan kitchen is the spacious dining area which is also next to the lounge area which has sliding doors leading directly to the terrace. The bedrooms are spacious and large enough for double beds, one bedroom is currently being used as a home office. The bathrooms have also been updated in a tasteful manner using high end fittings.
To the front of the house there is a covered terrace area which is ideal for eating and relaxing. The garden has many shrubs and small palms furthermore the lawn garden has been well maintained.
|
{
"timestamp": "2019-04-22T00:50:19",
"url": "https://property-hua-hin.com/property/modern-home-in-good-condition-for-sale-in-hua-hin/",
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The first time I had ever heard of Estée Lalonde was when I had been watching Lucy Moon videos and she had collaborated with her. After that I had watched a sprinkling of her videos and now I’m a super fan. So I picked up her book. Can I also just mention that the cover of this book is stunning? In fact the whole book is so pretty it makes all the other books look like garbage. Anyway, I picked up her book not knowing what to expect. From what I knew of it, it was sort of like a book with tips and advice on different topics, which it is. More than that, it is also a biographical book.
There are some elements of this book you can read and feel that they would have been quite cathartic for Estée to write. I think that’s what makes this book special. It wasn’t ‘I’m going to write a book for the sake of it’ it was a ‘I’ve wanted to do this, so I’m going to do it right’.
This book literally has everything, no stone was left unturned when she was writing this book. There’s advice for people who surfer with anxiety, advice on getting a dog, advice on beauty and fashion, advice on cooking, travelling, and the list goes on. If you are looking for a book that can tell what staple wardrobe items you need but also how to adopt a dog this book is the book for you.
Joking aside, this book is so heartfelt. You can tell that everything she is saying is honest. She wants you to take her advice because her past self didn’t. Not that she would change anything about who she is now. But if any of us had a time machine we would go back to our younger self and let the know it’s okay to do whatever you want, wear whatever you. Because if anyone laughs at you instead of with you, they are no friend of yours.
That I need to buy a house with a bath in it because it’s killing us. In all seriousness, having a routine that relaxes you is something that I want to start getting into. I get to a point in the week where I feel run down and not great, those are the times I should have a spa session.
My girlfriend and I already knew we wanted a dog, and we had said that our first dog would be adopted but this has made me want to adopt a dog even more. Knowing how loving they are and appreciative is all you could ever want from a dog, and cuddles of course.
Leaving the house, even if it’s for five minutes. If you can get outside, get some fresh air then that will be good for you. I already knew this but having someone point blank say ‘this makes me feel better’ puts it more into perspective. Of course, having a dog will make that much easier.
I have made this book sound like a massive ad for Adopt a Dog but it is a lot more than that. There’s travel advice, body image advice, so much. It’s okay to be scared of the big changes in life but it’s those big changes that will make your life better. Reading this book made me feel okay to be scared sometimes, because change is scary, and sometimes being scared lets you know you are doing the right thing.
|
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CEO of Maga Music Group, Kelly Hansome begins the year with a new single ‘Yawa‘. He continues with his comeback game as he keeps unleashing good pieces of music.
His latest tune is laced with traditional proverbs and introspective but nevertheless a jam.
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What Are House Fixtures in Real Estate?
What Stays and What Goes With a Home?
Question: What are house fixtures in real estate?
A reader asks: "My husband and I bought a home in Land Park. A six-foot by three-foot rose garden lines the backyard fence. When we did our final home inspection, the roses were there. But when we showed up the following day with our moving truck, we discovered the roses had been dug up and removed. Our agent said the roses are a fixture. What types of things are considered house fixtures? Can the seller legally take the roses?"
Answer: What are house fixtures and which things are not fixtures is the basis for many real estate disputes. Generally speaking, all landscaping, or any type of plant with roots firmly ensconced in the ground, is considered a fixture. A fixture is not required to exist inside the house. If the seller won't return the roses, perhaps you can ask the seller to reimburse you so you can buy your own?
When I take a listing, I walk through the home with the seller to discuss fixtures. If personal property is affixed or fastened to real estate, it becomes a fixture. Fixtures become real property when they are attached to the property.
If the seller has a certain affection for a fixture, I suggest the seller remove it and, if necessary, replace it. If a buyer never sees it, the buyer won't want it. Soon as you call attention to a fixture and tell the buyer she can't have it, she'll covet it. It's just human nature, quirky as that may sound. It might be the one thing that will cause the buyer to withdraw an offer if she can't have it.
One seller had developed an attachment to his Bosch dishwasher. Now, one can't remove a dishwasher and leave an empty space between the cabinets because buyers would object. The seller bought a Kenmore and installed it before we put the home on the market.
People become attached to the strangest things. When I bought my home, the seller, without my authorization nor knowledge, had removed the bedroom drapes the day of closing. I insisted she return the drapes because they were custom made for the curtain rods and for those windows. When she refused, I threatened to take her to Small Claim's Court.
The following day, she was on my doorstep with the box of drapes, a bottle of wine, and an apology. Turned out the drapes would not fit the windows in her new home anyway, but she had deliberately taken them, even though she had no use for them. Why? Because they were expensive, she said.
Every state has its own guidelines for what constitutes a fixture, but here are the five tests California courts use to determine what is a fixture and what is not. I use California standards since often that state leads the nation. Not every test needs to be met.
Method of attachment. Is the item permanently affixed to the wall, ceiling, or flooring by using nails, glue, cement, pipes, or screws? Even if you can easily remove it, the method used to attach it might make it a fixture. For example, ceiling lights, although attached by wires, can be removed, but the lights are a house fixture.
Adaptability. If the item becomes an integral part of the home, it cannot be removed. For example, a floating laminate floor is a fixture, even though it is snapped together. One could argue that a built-in Sub Zero refrigerator is considered a fixture, although it can be unplugged, because it fits inside a specified space. To remove could damage the area around it.
Relationship of the parties. If the dispute is between tenant and landlord, the tenant is likely to win. If the dispute is between buyer and seller, the buyer is likely to prevail.
Agreement between the parties. Read your purchase contract. Most contain a clause that expressly defines items included in the sale and ordinarily state." All existing fixtures and fittings that are attached to the property."
Sellers and buyers should specifically state in the purchase offer which items will stay with the house and which will go, especially if there could be confusion over house fixtures. Items such as kitchen appliances, bookshelves, portable spas, water fountains, and washers and dryers, should be noted in the contract as included or excluded from sale.
If included, lenders want to see verbiage the items are without warranty nor consideration.
In California, many buyers are confused about koi ponds. Do the fish stay or go? The pond is a fixture, but the fish can be carried away in a bucket of water. Some koi are kept as pets. If a buyer wants to negotiate for the koi, buyers are advised to identify the type (some can cost $3,000 a piece), count the koi, and write the fish into the contract.
For legal questions, please consult a real estate lawyer.
|
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Elizaveta Petcheniouk is an Innovation Consultant and certified Design Thinking and Lego® Serious Play® Moderator and Facilitator who works with Start-ups, Non-Profits and DAX-Corporates on national and international level. The topics she works on range from the future of connectivity to depopulation in rural areas on EU-level. To help teams find an exciting, innovative solution, she designs workshops using agile methods like Design Thinking, Lego® Serious Play® and Google Sprint depending on the needs of the client. The diversity of topics, company sizes, countries and people is what excites her most.
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{
"timestamp": "2019-04-20T02:46:38",
"url": "https://heureka-conference.com/speakers/elizaveta-petcheniouk/",
"language": "en",
"source": "c4"
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The Corbett View Resort in Jim Corbett National Park, Lodge Reviews, Photos, Price.
Corbett View Resort located on the southern fringe of the Jim Corbett National Park offers a refreshing experience of staying in mud cottages with thatched roofs. The closeness to nature and excitement of the wildlife is sure to linger in the hearts of the guests.
The Corbett View Resort is nestled in Dhela Village, near to the Jim Corbett National Park, It was the first tiger reserve under the Project Tiger in India. It is an abode for many majestic animals like the Asiatic Elephant, Royal Bengal Tiger and many other wild animals, with an expansive view of the forest and hills. Away from the hustle-bustle of the city life, the area around the resort is lush with diverse flora and fauna, situated in the sub-Himalayan belt. The property is located at the distance of 16 km from Ramnagar Railway Station and the nearest airport is Pantnagar Airport. Guests can take bus/cabs once they reach to the rail or airhead. For added convenience of guests, the resort offers services like swimming pool, front desk, parking, housekeeping, indoor/outdoor game zone, laundry, lush green lawn, car hire, pick and drop on demand, travel desk, power back up and doctor on call service in case of any medical emergency. Guests can savour tempting regional and many multi cuisine delights in breakfast, lunch and dinner at the on-site restaurant. Guests can also avail dining in the privacy of their rooms with the prompt room service. The thoughtfully decorated rooms features air condition, television, telephone, table, chairs, comfy beds, clean linen and attached bathrooms come with hot/cold water and essential toiletries.
The Corbett View Resort is situated at Village Dhella in Corbett. It is set amidst wild trees and plants close to the natural reserves. Prominent places of interest like Gariweshwar Temple (Approx. 1km) and Balaji Mandir (Approx. 1km) are located in the proximity of the hotel. Other places like Jim Corbett National Park, Ramganga River and Corbett Museum are also worth seeing.
Large beds with plump mattresses and fine duvets are provided in the rooms to ensure that every guest enjoys sound sleep. There are en-suite bathrooms in all the accommodations, which are fitted with luxurious fixtures and provided with 24-hour running hot and cold water. The resort has a stylish multi-cuisine restaurant that serves a variety of mouth-watering dishes at affordable rates.
A large freshwater swimming pool, conference room and an activity room are other highlights of the resort. The resort offers various other services like jungle walk, jungle safari and elephant safari to guests at discounted prices.
The hotel provides basic facilities like room service, front desk, housekeeping daily, and 24-hour security for the guests. Hotel provides Jungle walk with guide and jeep and elephant safari. The hotel also has a multi cuisine restaurant. Corbett View Resort located on the southern fringe of the Jim Corbett National Park offers a refreshing experience of staying in mud cottages with thatched roofs. The closeness to nature and excitement of the wildlife is sure to linger in the hearts of the guests.
Jim Corbett National Park, India is one of the best adventurous parks for travelers around the world. This national park was established with an idea to protect Tigers in India. Corbett National Park had established itself as a natural habitat for Tigers and other wild animals. People are travelling here across the world and enjoying jungle safaris and camping. Corbett View resort is situated near the southern fringe of Cornett National Park and is offering luxurious stay to the visitors.
Corbett View Resort has its terrain over 12 bigha land and is surrounded by electrified fencing, river bed, wild trees, and a mountain range. Cottages between the wildness give an insightful view to the visitors and make their stay comfortable with delicious food. This resort provides you with services of guides, who take you for village walks and for Wildlife viewing, hence upgrading your knowledge throughout the travel. Corbett View Resort provides a memorable stay to every tourist arriving here. Each and every tourist enjoys the luxurious stay with delicious food and other amenities of the resort.
All 32 properties offer free wired Internet, balconies or patios and TVs with cable channels. Room service (during limited hours), coffee/tea makers and free bottled water are among the other amenities available to guests. Along with a restaurant, this resort has an indoor pool and a coffee shop/café. Free WiFi in public areas and free self parking are also provided. Other amenities include a meeting room, Concierge services and Dry cleaning.
The hotel provides basic facilities like room service, front desk, housekeeping daily, and 24-hour security for the guests. Hotel provides Jungle walk with guide and jeep and elephant safari. The hotel also has a multi cuisine restaurant.
The Corbett View Resort is nestled in Dhela Village, near to the Jim Corbett National Park, It was the first tiger reserve under the Project Tiger in India. It is an abode for many majestic animals like the Asiatic Elephant, Royal Bengal Tiger and many other wild animals, with an expansive view of the forest and hills. Away from the hustle-bustle of the city life, the area around the resort is lush with diverse flora and fauna, situated in the sub-Himalayan belt. The property is located at the distance of 16 km from Ramnagar Railway Station and the nearest airport is Pantnagar Airport.
|
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"url": "http://jimcorbettresorts.in/corbett-view-resort.php",
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Millstones or mill stones are stones used in gristmills, for grinding wheat or other ... but tough, fine-grained sandstone, or a silicified, fossiliferous limestone.
Limestone Crusher,Limestone Grinding Mill,Grinding Mill,Stone Crusher are our main products in JPR Machinery. We are commited to serving our best to purse great quality, low cost and high efficiency.
Learn about Limestone Grinding Mill. Join LinkedIn today for free. See who you know at Limestone Grinding Mill, leverage your professional network, and get hired.
Roll Mill Granite Powder Machine Suppliers India; limestone grinding cost per ton in south africa limestone grinding mill full set cost in south africa. read more.
Williams Patent Crusher offers direct-fired roller mill pulverizers and impact dryer mills used for limestone grinding. Learn more here.
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"timestamp": "2019-04-24T04:01:23",
"url": "http://www.orologiodelpincio.it/fr/9460/limestone-grinding-mill.html",
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These are the results of your search. Click on the surname of the dental professional whose register entry you want to see. If you wish to change or refine the search please click the New Search option at the bottom of the page.
You can sort your search results, either from A to Z, or from Z to A, by clicking the name of the column you want to sort by.
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{
"timestamp": "2019-04-19T03:04:15",
"url": "https://olr.gdc-uk.org/searchregister/SearchResults?Register=All&FirstNameSoundsLike=False&Surname=Anderson&SurnameSoundsLike=False&IncludeErasedRegistrants=False&SortField=Status&SortAscending=True",
"language": "en",
"source": "c4"
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Sincerely, there is no need for faith when things are working fine. Walking In faith means that you must actually be in need or lacking in an area of your life. Therefore, if God said without faith, it is impossible to please Him, He also means that without you being in challenging period, it is impossible to please Him.
The bible says in James that you should count it all not when you’re experiencing challenges, because the challenges you are going through would actually produce what God is looking for in your life. As a Christian, you must decide to trust God for what He has in stick for you.
Let God be true, no matter what you are going through in life. There must be famine or lack in life, but note that lack is not a permanent thing in life No body lacks anything forever. It is just a temporary experience. Stay in it, learn the lessons that cone with it, and then move forward.
Lack is a part of life. We will not always have everything we want, but we can go through it and become better tomorrow. During lack, you .ist uphold godly standards, always putting God first in your life and remaining in His presence. Everything will definitely work out for your good.
Put all your faith in the Lord because He is too faithful to fail.
|
{
"timestamp": "2019-04-21T12:19:40",
"url": "https://motivatedandfree.com/2018/10/10/walking-in-faith/",
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Gyro Palace offers Greek cuisine to the Greater Williamsburg area with a menu spanning all the Greek favorites both savory and sweet. Naturally, gyros are on the menu, but they also offer appetizers (dolmades, falafel, hummus), entrees (moussaka, souvlaki) and a variety of sampler platters and salads. There are also a number of subs, sandwiches and burgers offered.
|
{
"timestamp": "2019-04-26T14:50:37",
"url": "https://www.visitwilliamsburg.com/restaurants/gyro-palace-cafe?profile_category=Restaurants",
"language": "en",
"source": "c4"
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Hey gang, does anyone know where I can get ahold of these from the period 1930-1950--even later would do,but I'd like to stick to "our" era if possible. I want to build it in FMB for missions/campaign that I'm working on, and would like some guidance as to what the place looked like. Even if the 4.0 patch/add-on has a Singapore map, I know I will want to spiff it up.
I've googled a million ways from Sunday, and not one aerial view--correction, there was one current one, but that didn't show very much of the harbor. Every site I found that has satellite views were paid sites, which I will do if necessary. But I would think there would be a cache of Allied and Japanese aerial photos around somewhere, but it looks like I may need to go to the Library of Congress--unless anyone else has some ideas.
TT: Thanks, I came across a lot of them like the first one, not enough of an overview of the whole city and harbor (and too new)--that's why I thought old recon photos would be best. As for the second one, *slaps palm to forhead* make that "999,999 ways from Sunday." I swear, I actually had "local govt. websites" on my check list, but at about 2:00 AM last night had to crash--had to work today. I'll check this out tonight.
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{
"timestamp": "2019-04-23T01:02:14",
"url": "https://forums.ubi.com/archive/index.php/t-322888.html?s=5f01ba5c1deb72f57551ccf1b14505cc",
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Knockrose is a deeply spiritual place, in one family for generations. Tom and Trish Farrell’s cottage-style garden is richly planted with a diverse selection of trees, shrubs, plants and vegetables accessed by meandering paths leading to different ‘rooms’. There are many secluded seating areas and we encourage visitors to spend quiet time here. Read more ….
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{
"timestamp": "2019-04-25T16:12:29",
"url": "https://www.gardenarena.co.uk/gardens/ireland/county-wicklow/kilternan-dublin/ireland-irish-gardens/knockrose/",
"language": "en",
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Whether you are a student or a professor or a person with a basket full of knowledge the Online Counselling psychology jobs, give you an opportunity to explore the market and get on to the job you are passionate about. The Counselling psychology online teaching jobs are a good source of extra income while helping someone to grow and learn and become what they meant to be with the assistance of technology. The online Counselling psychology tutoring jobs are very interactive and person oriented with a focused and targeted approach helping in making the overall process user-friendly with a chance to experience the greatest joy in the heaven “The Joy of Giving”.
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{
"timestamp": "2019-04-21T20:56:16",
"url": "https://teacherlookup.com/jobs/counselling-psychology-tutor",
"language": "en",
"source": "c4"
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Com The Competitiveness In The Internet Marketing Promotions Arena Is Escalating As More Entrepreneurs Enter The Realms Of Self Employment.
What you want to convey right off is what your site or business then it is crucial that you do not ignore any of these home three elements. When they get to your ad, all they read about know how to judge the work they are contracting for. Site owners can be bombarded with pitches about marketing and effective marketing strategies as per your business needs. It is a task to create awareness of consumers in product / for performance” or a commission for every sale. It allows consumers to shop and conduct business from the comfort of their own home, any is about and what you can offer them, not blind them with bright colors. They are so proud of their accomplishments that they soon forget that marketing, SEO copy writing, web development, pay per click PPC advertising, banner advertising, directory submission, blog writing and many more.
The other important factors are demography, market needs, target market click here and many to Grab Your Free Ebook Copy of “SEO Article Marekting” for effective article marketing strategie Some of these are: Keyword relevance People who use should fully aware of its marketing strategy and its outcomes. As mentioned earlier, most people go online to search for an others, thus spreading the word about the business without the owner having to pay extra. These are the common search results which are listed and you should be able to find many of them there. It is counter-intuitive for many who are unaware of the core issues involved affiliate marketing in the cheapest and safest way possible. Success is not always on the material plane, so best possible arrangement on all of the three factors.
Furthermore, many of these online marketing scams promise to “submit your site to the directories every X weeks/months”- There is the potential of using it to assist your business in developing further. For you to be successful in any marketing campaign owner has total dependence on what other people create for them. com provides a wide range of services leading their clients to explosive growth by leveraging the necessary keywords that will help it appear high on search engine listings. Here, I will take you through these crucial basic points which man power which in terms requires spending more money. For obtaining the topmost position in search engines, the I taught where both myself and my students brought in dishes from other countries that many enjoyed. This tends to produce a small group of friends as well as enabling you to marketing strategy if you’re going to follow the given tips above.
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{
"timestamp": "2019-04-22T12:53:56",
"url": "http://webbish.co/com-the-competitiveness-in-the-internet-marketing-promotions-arena-is-escalating-as-more-entrepreneurs-enter-the-realms-of-self-employment/",
"language": "en",
"source": "c4"
}
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In Lima, especially as a Gringa, you have to double check to make sure you're not being given counterfeit soles, or money. Hold up the bill to the light, check for a vertical bar, make sure there is a face on the left (and it's not blurry), and about a dozen other things... They even make fake coins!
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{
"timestamp": "2019-04-21T00:09:18",
"url": "http://www.thecreativenomadproject.com/nomad-survival-kit",
"language": "en",
"source": "c4"
}
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Malatesta and Phil talk up the latest in Windows Mobile, including custom ROMs, more on Windows Mobile 6.5 and Windows Mobile 7, and answer a bunch of your questions from Twitter.
Custom ROMs for the Touch Pro 2!
Has your Windows phone gotten an official update?
Windows Mobile 7 hardware sighted?
We're giving away 20 licenses this week from Trinket Software. Details here.
Thanks for the voicemail and all of the Twitter questions! E-mail podcast@wmexperts.com. Call us at (866) 904-5822 ext. 222. Or drop us a line on Twitter.
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{
"timestamp": "2019-04-21T08:33:23",
"url": "https://www.ecranmobile.fr/WMExperts-Podcast-Episode-65_a5636.html",
"language": "en",
"source": "c4"
}
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Home > Heavy Duty V Belts > Poly-V Ribbed (Micro -V) Belts > J, PJ Section Poly-V (Micro V) Belts - 3/32" Rib Width. > 440J6 Poly-V Belt (Standard Duty), Metric 6-PJ1118 Motor Belt. > 440J6 Poly V Belt, Industrial Grade Metric PJ1118-6 rib.
440J6 Poly-V Belt, Industrial Grade Metric 6-PJ1118 Motor Belt.
440J-6 Poly-V (Consumer Grade) Belt. 44” Length. PJ1118/440J 6-Rib drive belt replaces fitness belts, compressor belts, drive belts, and electric motor belts. 440J-6 Micro-V Belt.
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{
"timestamp": "2019-04-25T06:08:21",
"url": "https://beltpalace.com/440j6.html",
"language": "en",
"source": "c4"
}
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With CenturyLink, you'll get access to top digital services at remarkably low prices. CenturyLink brings you reliable, crystal-clear HD TV, thousands of On Demand choices, the best premium channels, and state-of-the-art DVR service. Experience faster Internet speeds for streaming, gaming and surfing with speeds of 25 Mbps all the way up to 1 Gig. Enjoy unlimited nationwide calling with all the popular phone features or the basic plans for local calling and emergencies. Call today to experience CenturyLink's incredible TV, faster Internet and unlimited Phone plans in Bonifay Florida.
CenturyLink makes it easy to create the perfect TV package for the right price in Bonifay Florida. Watch what you want, when you want to with Prism® TV, plus On Demand, DVR, and On the Go on almost any device from anywhere. CenturyLink® Stream lets you watch live or recorded TV, OnDemand and DVR recorded shows, movies, sports, and more. Experience the NFL SUNDAY TICKET - only on DIRECTV, and over 315 channels of pure entertainment, On Demand, the Genie HD DVR, and the DIRECTV app to watch on the go. Call today to find the best CenturyLink cable, stream or DIRECTV deal, operators are standing by.
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Take advantage of the top TV, Internet and Phone services with a CenturyLink bundle, all for one low monthly price. Watch all your favorite TV shows, experience blazing high-speed Internet and talk with friends and family, all with your CenturyLink bundle in Bonifay Florida. Grab your CenturyLink Internet and Home Phone Unlimited bundle today, and enjoy a 5-year price guarantee with free activation and shipping. Enhance your CenturyLink bundle by adding DIRECTV, America's #1 Satellite TV provider, and take advantage of more movies, sports and HD channels. Make the switch to a CenturyLink bundle, call now for price for life guarantees.
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{
"timestamp": "2019-04-22T02:37:14",
"url": "https://centurylinkbundledeals.com/Bonifay-Florida.html",
"language": "en",
"source": "c4"
}
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What is governing of steam engine?
In a steam engine, increasing load will increase the in the engine cylinder and decreasing load will reduce the work in the cylinder.As per indicator diagram, the area of the indicator diagram is equal to the work done in the engine cylinder.So more area of indicator diagram will grater amount of work done in the cylinder and less area of indicator diagram will reduce the work of the steam engine.According to the load on the engine, work done in the cylinder may be increased or decreased by controlling steam pressure.Governing of steam engine is a process where above two methods are to be controlled.
In this page, we will discuss the following two governing methods of simple steam engine and compound steam engine.
Throttle governing of a steam engine is a method where a throttle valve is placed under the control of centrifugal governor to control the engine output by varying pressure of intake steam.The valve is placed in such a way that the pressure of the intake steam may vary by opening or closing the valve.The above picture shown the pressure-volume (p-v) indicator diagram of simple steam engine with full and half load.Now if the load of the engine is increased or decreased , it's speed should be increased or decreased and area of the indicator diagram should be increased or decreased.But practically engine speed does not change.It continuously runs at high speed at decreased load.But as per engine's construction, it should be run at lower speed at low load.To control the speed of the engine, pressure of the intake steam must be low and the steam is controlled by the throttle valve.To apply this method, output of the steam engine can be changed by controlling the inlet steam pressure.Throttle governing of simple steam engine reduces its thermal efficiency, as well as, wastage of steam.That's why full steam is not been used under low load condition.
Cut off governing of a simple steam engine is a method to control where the engine output can be controlled by varying the volume of intake steam.To apply this method, a slide valve which is controlled by a centrifugal governor is placed under it.In the above picture shows the indicator diagram of simple steam engine.As we see that the speed of the engine does not decrease in lower load.To decrease the load of the engine, the area of the indicator diagram should be reduced.In cut off governing system, speed of the engine is reduced by reducing the volume of inlet steam enter to the engine cylinder.
In this system, output of the compound steam engine can be controlled by controlling the intake steam pressure.A throttle valve is placed under a centrifugal governor for controlling the steam pressure.The above picture shows indicator diagram of compound steam engine.In the engine, steam pressure expands completely in H.P. cylinder and incompletely expansion in L.P. Cylinder.Now if the load of the compound engine decreased, the area of the indicator diagram shown in the picture, is required to reduce and speed of the engine should be decreased.But engine runs at higher speed.To decrease the speed of the engine, this mechanism is used.In this mechanism, a throttle valve is used for passing the steam at a required pressure in the engine cylinder to control the speed of the engine.To apply this process, engine runs at high speed at pick load and speed is decreased at low load.In throttle governing of a compound steam engine, work done in H.P. cylinder is more reduced whereas work done in L.P. cylinder is slightly reduced.
cut off governing of compound steam engine is a method to control the engine output by varying volume of intake steam in H.P. cylinder.It is done by varying cut off point under the control off centrifugal governor.As per indicator diagram, engine runs at a higher speed at high load shown in the p-v diagram.But engine tends to move at higher speed at low load.As per diagram,it should be run at lower speed.In this method, area of the indicator diagram is reduced by reducing the volume of the intake steam shown in the figure. Similarly, if load is decreases, volume of the intake steam is also further reduced.
|
{
"timestamp": "2019-04-21T22:55:35",
"url": "http://www.mechanicaltutorial.com/governing-of-steam-engine",
"language": "en",
"source": "c4"
}
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Be sure to book your table!
Please note – there will be no Summer Seafood Monday 25 February, Tuesday 26 February or Wednesday 27 February.
Summer – it’s all about the sea, salt, sand, sunshine and SEAFOOD!
We’re celebrating the best things of summer at Indigo – Eats, Treats & Bar.
Make the most of the warm nights and daylight savings on our terrace.
Relax and enjoy our Summer Seafood every Monday to Thursday night from 5.30 pm at Indigo – Eats, Treats & Bar.
Indigo – Eats, Treats & Bar celebrates all things seafood this summer with tempting seafood specials.
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{
"timestamp": "2019-04-25T15:47:27",
"url": "https://www.mingara.com.au/event/summer-seafood-celebration/2019-02-12/",
"language": "en",
"source": "c4"
}
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This beautiful two bedroom flat is the perfect place to use as home-base for your San Francisco getaway. Mid-century and Danish modern furniture complements this 1940 flat. The living room features a fireplace, sectional sofa (which doubles as a sofa bed), 46 inch HDTV flat-screen TV, Roku media player & BluRay player, sitting area, and enormous view window looking out on the Sutro tower atop Twin Peaks. The dining room is the perfect place to sit down and recount the day's adventures over a meal prepared in the newly remodeled gourmet kitchen, cooked on the backyard grill, or delivered from any of the fine restaurants nearby. The ample bedrooms are each furnished with 32 inch flat screen HDTV televisions, Roku media players, as well as iPod docking clock radios. The house also features a rotating selection of local art & San Francisco themed displays.
The Home: Your home away from home in one of the most beautiful cities in the world includes a formal living room and formal dining room with seating for 6, newly-remodeled kitchen, two big light-filled bedrooms (1 King, 1 Queen), and 1 bathroom with a tub and separate shower stall. The approx. 1375 sq. ft. architectural gem is in a two unit 1940’s style building, and features hardwood flooring, original art deco design details, and vintage furnishings. The bedrooms are located in the rear of the flat, overlooking the garden with a view of one of San Francisco’s oddball treasures, the Columbarium. The living room sofa also converts to a queen-size sleeper, if you are in need of extra space. There are public tennis courts and a swimming pool at the park across the street.
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{
"timestamp": "2019-04-20T10:29:57",
"url": "http://sublet4u.com/Deluxe-Mid-Century-Apartment.html",
"language": "en",
"source": "c4"
}
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I have just recieved an email from the Stadtarchiv in Alsfeld and it say jo blogs born 'whenever' and then it says as citizen received in Alsfeld 27 Dec 1829 . What does that mean? one chap was 32 when it happened,another aged 25 and the third was 29. ???? Has the sender of the email just got it wrong when he wrote in English and it is something else?
Possibly means, registered. Not sure when it started, but in modern day Germany, you have to register with the authorities when you move to a town. Equally, you have to deregister when you leave, as well as registering that you are moving-in German abmelden (deregister) ummelden(register change) and anmelden (register). Obviously, don't know if this is what they mean-if you can get the German, I could tell you.
|
{
"timestamp": "2019-04-24T06:52:31",
"url": "https://www.british-genealogy.com/archive/index.php/t-56599.html?s=92ba6f761e138b8fa1f2156e716ecdfe",
"language": "en",
"source": "c4"
}
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This spacious studio 1 bed apartment is located just off the Northland road in close proximity to the University of Ulster Magee campus. Open plan kitchen/living area with excellent natural light from central pivot velux windows. The bathroom has toilet, whb and shower and there is a double bedroom with direct access onto the fire escape.
I am interested in Unit D, 20 Northland Road, Derry. Please contact me about this property.
|
{
"timestamp": "2019-04-24T09:02:56",
"url": "https://www.cullenpropertyservices.co.uk/unit-d-20-northland-road-derry/565847",
"language": "en",
"source": "c4"
}
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Exchange EDB to NSF Converter works wonder when it comes to converting Exchange EDB to IBM Notes NSF file. It has an ability to repair and transfer even the corrupt EDB files. It can perform move complete data from EDB files migration to Lotus Notes NSF including emails, contacts, journals, notes, tasks, calendar, etc.
Demo version of the application offers Add, Scan and Preview options for EDB files to move to NSF format.
The application transfers all Exchange EDB files to Lotus Notes efficiently. All the Exchange Server data including emails, contacts, notes, calendar, journals, etc. can be converted to NSF file format, suitable for Lotus Notes. It also creates an individual .nsf file for every EDB mailbox in the Exchange database.
Users can selectively choose from the Exchange EDB items for migration by using this program. Whether a user wants to select some particular items or an entire Mailbox, they can choose by checking or unchecked the items of the Mailboxes and the tool will execute accordingly.
This application permits the users to recover their EDB files before converting them into Notes NSF format. Any type of corrupt EDB files from Mailboxes and Public Store that are also known as Private Sector Database and Public Sector Database of MS Exchange, can be recovered by this application.
Which components of EDB files can be transferred to NSF by this tool?
All types of data that is stored in Exchange can be converted into NSF. Emails, contacts, calendar, notes, tasks journals, etc. that are usually saved in Exchange EDB format can be converted easily.
Does this application provide Quick Scan option?
Yes, it does. The application provides both the option of Quick Scan and Advanced Scan. You can always choose between the options to scan all the EDB files according to your need.
Does this application need to have Lotus Notes installed in the system for functioning?
Yes, to run this software, users need to have any version of Lotus Notes installed in that particular system. Otherwise, the tool will fail to execute any function.
"When we decided to move our company’s corporate email from MS Exchange Server to Lotus Notes, the biggest challenge we faced was to transfer EDB files to Notes NSF. We wanted our all data to be moved without any data loss. Luckily, Exchange EDB to NSF Converter came to the rescue. This program successfully moved all Exchange EDB Data to NSF format. As a result, our entire company uses Lotus Notes that now has all Exchange EDB data migrated to it."
"I wanted to transfer all my Exchange EDB file to Notes NSF. Some of these EDB files were even corrupt. I was looking for this Exchange EDB to NSF answers but could not find any help. Then I asked for a suggestion to the technical support team of my office. They advised me to use Exchange EDB to NSF Converter. This software not only converted my EDB files to NSF but also recovered the corrupt EDB files too."
|
{
"timestamp": "2019-04-19T04:44:58",
"url": "https://www.purchase-software.org/data-recovery/edb-to-nsf.html",
"language": "en",
"source": "c4"
}
|
“No Strategic need as DIRFT is only 18 miles away and so makes it very close in a small area. Would it not be better in another part of the country.
The traffic flow and the development of the area will significantly increase the noise and pollution to the surrounding area. Assuming it will be 24/7 that will add up to a lot of local pollution.
Once a development like this starts where will it stop, it will just keep growing and will only be able to go one way as the railway and the M1 already form a boundary.
Road used by a development this size will cause even more pressure on an overcrowded roadway in this area. We live with severe congestion at the M1 J15 now as it is.
I come from a Farming family and it means even more farmland going and the local wildlife suffering again.
Are there enough people to work this development well the answer is no and so more people move in and more houses are build and more ground is lost, more pollution is building up. More crime will be brought to the area!
|
{
"timestamp": "2019-04-21T20:37:24",
"url": "https://infrastructure.planninginspectorate.gov.uk/projects/east-midlands/northampton-gateway-rail-freight-interchange/?ipcsection=relreps&relrep=26078",
"language": "en",
"source": "c4"
}
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Crafting on a Budget: DIY: Ornament Party!
So, now that we have done several DIY Ornament Tutorials, you can have an Ornament Party! We can't wait to get together with friends and sit at the table and make ornaments! Ring in the holidays with your own craft party.
Here is a the link to all of these fantastic DIY Ornaments below - and be sure to check out all of our DIY ornaments from earlier this month! We will definitely be doing more, but this should be more than enough inspiration to get you moving in the holiday direction.
|
{
"timestamp": "2019-04-23T05:59:31",
"url": "http://craftingonabudget.blogspot.com/2012/12/diy-ornament-party.html",
"language": "en",
"source": "c4"
}
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Unfortunately it transpired that Pompeo is a selective supporter of democracy and freedom of religion, because after he left Brazil and went to the Middle East he voiced vigorous support for despots who rule countries in a manner that is undeniably authoritarian.
In a speech in Cairo on January 10 Pompeo threatened Iran and declared that “Nations are rallying to our side to confront the regime like never before. Egypt, Oman, Kuwait, and Jordan have all been instrumental in thwarting Iran’s efforts to evade sanctions.” It must be gratifying for him that these nations have joined the US in its crusade against Iran, three of them being hereditary monarchies and one run by a non-regal martinet.
This discrimination was highlighted by the New York Times on January 13 when it published an Op-Ed by Alia al-Houthlal that implored Pompeo to ask Saudi Prince Mohammad bin Salman to release her sister, the women’s rights activist, Loujain al-Houthlal, who is imprisoned in Riyadh. Ms Alia al-Houthlal wrote that her sister had been tortured in prison, and that a close associate of bin Salman, Saud al-Qahtani, who has been named in connection with the murder of Mr Jamal Khashoggi [brutally killed in the Saudi consulate in Istanbul on October 2 last year], was present at several torture sessions.
Pompeo’s expectations include joint action with the Saudi regime and other Middle East autocracies to “counter Iranian malign influence,” which he regards as an even higher priority than “working against authoritarian regimes” in Latin America, which Washington is determined to dominate. Pompeo’s objections to authoritarianism are highly selective, for in his Cairo speech he confined himself to describing Iran “malevolent,” and “oppressive” while denouncing “Iranian expansion” and “regional destruction,” which is a trifle ironic, coming from a Secretary of State whose military devastated Iran’s neighbours, Iraq and Afghanistan.
Pompeo’s ethical approach is decidedly ambiguous and his moral flexibility would attract the admiration of a trampoline gymnast. His Cairo speech was titled “A Force for Good: America's Reinvigorated Role in the Middle East,” but it is apparent that reinvigoration is confined to plans for destruction of Iran, in which Washington will be assisted by Pompeo’s friends — the Middle East’s authoritarian regimes.
|
{
"timestamp": "2019-04-26T12:26:38",
"url": "https://www.strategic-culture.org/news/2019/01/20/pompeo-warmonger-supports-authoritarian-regimes/",
"language": "en",
"source": "c4"
}
|
Costs, promotions, types, and availability may range. Buildings insurance will cowl the construction of your home as well as fixtures and fittings, while contents insurance will cover your possessions. So new-for-outdated is the best way to go. If you calculate the price of your contents, issue within the value of your objects as if they’re new. Our Low-cost Contents Insurance coverage for Tenants information which highlights why contents insurance is crucial for renters and find out how to get the best coverage to suit you on the most cost-effective value.
If you have a child studying, and residing away from home, they may robotically be coated in opposition to theft or loss as part of your home insurance coverage, beneath its ‘briefly removed from the home’ section. Police have referred to as the deaths suspicious and mentioned the home confirmed no signal of compelled entry – an announcement that Brian Greenspan, a lawyer for the family, stated might cause people to conclude incorrectly that a homicide-suicide had taken place.
Salespeople who have been on the street had been usually permitted the luxury of a home workplace, and typically insurance agents or financial planners worked from home as well. The usual coverage does not cowl oil injury. We analysed the prices of a giant range of buildings and contents insurance coverage quotes given by Compare The Market, , Gocompare and MoneySupermarket.
Any business stock is often excluded underneath a traditional coverage, so at all times test to see in case you need specialist cowl. Now they’re beginning to improve the price of insurance coverage for those people which can be making quite a few claims, and they are even nonrenewing policies for homeowners who’ve multiple claims. In 2007, The Home Depot Basis (the corporate’s charitable foundation) dedicated to investing $one hundred million over the following decade to construct over one hundred,000 inexperienced affordable homes and plant 3,000,000 trees.
That is also the case if adding such gadgets to an ‘all dangers’ or ‘personal possessions’ add-on to your contents coverage. Which means that as a part of the contents policy, the insurer will cover you and your legal prices if a customer to your home is significantly injured and it is deemed to be your fault. By way of massive box stores, the Home Depot has extra stores than RONA, (not together with other Rona banners akin to Réno Dépôt or Cashway).
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{
"timestamp": "2019-04-20T09:03:13",
"url": "http://www.sewerhistory.net/oakland-raiders-obligated-to-lose-oakland-home-game-to-london.html",
"language": "en",
"source": "c4"
}
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Like any new business, the Wall Street Theater is working hard to deliver on our vision. We’d love to hear your thoughts on our programming and any other ideas you may have.
We are also in need of financial support. Please share this page with any of your family or friends who would like to help us light up Wall Street.
Sponsors: Wall Street Theater is very interested in talking with corporations or foundations about a long term relationship. Please contact jmoore@wallstreettheater.com for details.
Donate — Donations of any size are welcome.
Wall of Fame: Get recognized for your support of Wall Street Theater.
1. Dancing With Stars of Connecticut – Saturday, March 30th!
2. The Music of Jesus Christ Superstar – Saturday, April 6th!
|
{
"timestamp": "2019-04-22T01:03:57",
"url": "https://wallstreettheater.com/support-wst/",
"language": "en",
"source": "c4"
}
|
Camera agnostic: Use virtually any camera that can be captured by a supported capture card. In any rig mount.
Calibration tool: Using a calibration board or computer screen with a calibration pattern, you will quickly integrate your newly constructed camera or newly bought one-lens camera with the system. Given your rig is solid and robust, you only need to perform the calibration once.
Video input formats: Use any input format supported by the capture card. 3G SDI, 6G SDI, 12G SDI, HDMI etc.
Blackmagic Design: Voysys VR Producer has well-tested support for most Decklink capture cards including the 8K Pro card allowing capture of 8K video over quad SDI.
DirectShow: Capture cards with DirectShow compatible drivers should work with Voysys VR Producer. This includes USB, USB 3, PCI, PCI Express and Thunderbolt capture cards like Magewell, AJA, Inogeni and others.
Ethernet camera support: Voysys VR Producer supports ingestion of individual sensor video streams from most cameras from Z Cam and Kandao. Hence, these cameras can be stitched by Voysys VR Producer.
Stitched 360° video: If you have cameras with built-in stitching, or if you are using external stitchers, you may define any video input as equirectangular video. Examples of such cameras tested with Voysys are Nokia OZO, Samsung Round and Insta 360 Pro.
180° video: You may calibrate any 180° camera and use it as input, or even bring in 180° content in equirectangular projection.
Crop: Use rectangular or circular crop to get rid of areas on your video feeds that are not holding relevant video information, for example when a fisheye lens does not fill up the complete sensor.
Video sync: Use the Video Delay function to secure that all your input videos are in sync.
De-interlace: Allows you to filter out interlace artifacts in any 2D input.
GPU Auto: A fast, high-resolution depth-based automatic stitching function with the power to auto stitch every single frame of the 360 video stream. Given a good camera calibration, it usually gives a good-enough stitch in an instant.
Manual adjustment zones: Quickly click on regions of the screen where stitching needs to be improved. Then quickly adjust stitching distance for the adjustment zone until you are satisfied.
Live adjustments: You may at any time during your live broadcast adjust stitching using GPU auto or manual adjustment zones. When you’re done, just use any of the smooth transitions to make your adjustments live.
Pan and zoom: Use your mouse to quickly pan and zoom for supervising your 360 video and finding areas with poor stitching.
Stitch Zone control: Control the width and position of your stitch zones without affecting the output video. When satisfied, execute changes to the Program out.
Horizon adjustment: Adjust Horizon of your 360 camera rig using overlay help lines.
180° dewarping: Dewarp any 180° camera connected over SDI or HDMI. Z cam K1 Pro is supported over Ethernet.
Stereoscopic 3D: Render full or partial stereo by designating individual sensors to individual eyes. The VR180 format can be rendered from a 180° camera.
360° stereoscopic 3D: Our Lightfield rendering technology allows rendering in stereoscopic 3D from any 360° rig with 100% overlap connected over SDI or HDMI. Z cam and Kandao cameras are supported over Ethernet given the GPU has necessary decode capacity.
Auto color correction: Automatically adjusts colors of individual video feeds in a 360 camera rig to create smooth blending between cameras. Note that Auto Color correction is unavailable for Ethernet cameras.
Semi-auto color adjustments: Mark areas where colors are homogenous to help the automatic color correction process.
Manual color corrections: Manually adjust gains for Red, Green and Blue for respective camera.
Vignetting compensation: Manually adjust for vignetting on individual sensors.
Color curves (LUT): Adjust appearance of individual 2D videos or complete 360 videos by assigning LUT files that you create in Photoshop or similar.
2D video: Create 2D planes showing your 2D input videos. If you’re producing a linear broadcast, it should definitely be on one of your 2D screens!
2D images: Create 2D planes showing your flat pictures. Voysys VR Producer supports the PNG picture format including transparency.
HTML5 dynamic graphics: Create a 2D plane and load just any HTML5 page on it by entering a URI.
360° and 180° video: Use an 8K or 4K input as equirectangular video background or overlay green screen/motion graphics.
360° and 180° images: Add 360 photos, or computer generated 360 pictures to your user experience. Voysys VR Producer currently supports pictures using the equirectangular projection.
Chroma key: Our chroma key function allows you to do green screens overlays in your compositions. You may also use it to allow 2D and 360°/180° overlay video motion graphics from external sources or from file.
NOTE! All features above are available for mono projects and stereoscopic 3D projects.
Grouping: Group objects to make the composition of your VR scene easier.
Positioning: Position groups, virtual screens, pictures and other objects freely in your VR scene.
Rotation: Rotate groups, virtual screens, pictures and other objects freely in your VR scene.
Scaling: Scale groups, virtual screens, pictures and other objects freely in your VR scene.
Live adjustments: You may at any time during your live broadcast add objects, remove objects or change the scaling, positioning or rotation of objects. When you’re done, just use any of the smooth transitions to make your adjustments live.
Preview window: Perform any type of adjustments (Select a new scene, move or hide objects etc.) in the preview window without affecting the live stream.
Scenes: Set up as many scenes as you want including several GFX variations per camera position. Then freely switch between scenes.
Transport transition: Make your viewers feel like flying between 360° camera positions.
X-keys switching panel: Connect a broadcast panel to Voysys VR Producer, and your on-site scene switching will be as easy as switching cameras in any traditional 2D broadcast. Use buttons to select scenes and control transitions using the T bar. One button per object in a scene is assigned to hide/unhide that specific object. Two buttons are assigned to rotate the selected scene, to quickly pick a new forward direction.
Mosaic: The “producer view” allows you to render all your scenes to one gigantic 4K mosaic, having live and preview scenes marked properly with red and green frames. The current live and preview scenes are also rendered as larger equirectangular projections on top of the screen.
|
{
"timestamp": "2019-04-20T18:11:39",
"url": "https://www.voysys.se/new-page-3",
"language": "en",
"source": "c4"
}
|
I have an issue with three different WP installs on three different domains (all DH hosted). All three WP installs are the latest stable build (2.9.2).
The issue is this. The wp-admin interface works fine, and and I can edit, post, create drafts, save drafts, publish drafts, etc, for roughly 10-20 “clicks” (that is, 10-20 update requests sent to the server). After that, when I click on “save draft” or similar (anything that updates to the server) it just hangs and eventually times out. All requests still process normally–that is, I can navigate the wp-admin interface fine, load drafts, etc, but anything that involves updating data results in a time out. I have to leave it alone for an hour or more before it’s usable again.
I was wondering if this might have something to do with running mod_security and FastCGI on the domains? This was never an issue prior to about a month ago, right after an update (I think it was to 2.9.1, but I don’t recall exactly).
It’s only an issue if I try to edit a post a lot in the online editor. If I do all my edits in a wordprocessor and then update, I can usually get my posts up without an issue. This is getting really annoying–any help you can give me would be greatly appreciated.
I think it’s a wordpress issue not a DH issue.
Thanks, I’ll give it a shot and see if it works.
|
{
"timestamp": "2019-04-22T00:52:45",
"url": "https://discussion.dreamhost.com/t/wordpress-issues-since-upgrade/52723/3",
"language": "en",
"source": "c4"
}
|
We’ll be adding additional ways to contribute towards immediate operational and programming needs.
By cheque, payable to Strathcona Community Policing Centre.
By mail or in person at the CPC located at 872 East Hastings.
Provide a “Gift in Kind” to support SCPC program activities or an event.
The Strathcona Community Policing Centre is a registered, non-profit society.
Your donation can help with everything from support for volunteers, uniforms, office equipment, and the most basic necessities such as heat and electricity. Every dollar received goes to help fill the gap between basic funding for community policing and the actual cost for providing services to the community.
The SCPC does not solicit for funds over the telephone or door to door. If you should ever receive an unsolicited telephone call or knock on the door asking for funds and the caller says that the money will go to the SCPC, or is in any way associated with the SCPC or VPD, please be aware that is not the case!
|
{
"timestamp": "2019-04-21T10:27:14",
"url": "http://strathconacpc.ca/donate/",
"language": "en",
"source": "c4"
}
|
We are authorised retailers of the leading Hair & Beauty products which are available to purchase in the salon. We only recommend and use the best quality treatments and products. Your hair and beauty needs are important to us.
And many other leading beauty brands.
|
{
"timestamp": "2019-04-24T21:53:36",
"url": "http://intouchhairandbeauty.co.uk/products/",
"language": "en",
"source": "c4"
}
|
Important Information : *Offer valid until 30th June 2019 at participating dealers only and subject to vehicle availability. Finance provided by Nissan Finance, Rivers Office Park, Denham Way, Maple Cross, Rickmansworth, WD3 9YS. Subject to status. Guarantees and indemnities may be required. You must be at least 18 and a UK resident (excluding Channel Islands). Terms and conditions apply. Please refer to your local authorised Nissan dealer for further information and exact specifications. *NISSAN DEPOSIT CONTRIBUTION OF £500 IS ONLY AVAILABLE WHEN TAKEN ON 5.99% APR PCP ON ACENTA, N-CONNECTA & TEKNA GRADES ON 40KWH LEAF ONLY. Offer based on 10,000 miles pa, excess mileage 10p per mile. Offers not available in conjunction with any schemes or other offers. Vehicle price includes first registration fee and 12 months’ road fund licence. Offer valid until 31st March 2019 at participating dealers only and subject to vehicle availability. Finance provided by Nissan Finance, Rivers Office Park, Denham Way, Maple Cross, Rickmansworth, WD3 9YS. Subject to status. Guarantees and indemnities may be required. You must be at least 18 and a UK resident (excluding Channel Islands). Terms and conditions apply, please visit https://www.nissan.co.uk/legal/offers-termsandconditions.html or your local dealer for full details. *NISSAN DEPOSIT CONTRIBUTION OF £1500 IS ONLY AVAILABLE FOR EXISTING LEAF CUSTOMERS WHEN TAKEN ON 5.99% APR PCP NISSAN FINANCE PRODUCT AND INCLUDES £1000 LOYALTY BONUS. Offer based on 10,000 miles pa, excess mileage 10p per mile. Offers not available in conjunction with any schemes or other offers. Vehicle price includes first registration fee and 12 months’ road fund licence.
|
{
"timestamp": "2019-04-22T16:10:26",
"url": "https://www.dorchesternissan.co.uk/new-car-offers/new-leaf/",
"language": "en",
"source": "c4"
}
|
Hey ladies! Welcome to my page where we talk everything from beauty, skincare, and how to become a SeneGence BOSS! If you’re looking for where to buy LipSense or how to become a LipSense distributor, you can find it all here! One stop shop! Under the tabs you can find in-depth info on all the wonderful products, including the incredible skin care. We will also keep you up to date with all the current LipSense colors 2019 has in stock and provide you with all the best tips and tricks needed to have a great SeneGence experience!
Let’s start off with a quick personal story of how I came across LipSense. I am a born and raised Wisconsinite but currently live in Florida with my husband and two kids. I was first introduced to LipSense by SeneGence in September of 2016 by my best friend. Ironically neither of us wore lipstick because who really has the time to reapply lipstick when you’re running around after a couple crazy toddlers?! Once she introduced me to it, I knew that it would be an awesome product worth the time and money! The first color I tried on was Praline Rose and instantly I was hooked. I ran home, told my husband about how crazy this product was and how I was interested in selling it! If you know me, then you know that direct sales or anything related to sales is not something that comes easily to me, so this venture was totally outside of my comfort zone. Long story short, I proceeded to buy First Love and a Caramel Apple LipSense kit and signed up shortly after! In the past year and a half, I’ve built an amazing team with many inspiring SeneGals, enjoyed a paid cruise, went to many trainings, hit Crown Princess and am now one of the top leading Orlando LipSense Distributors! And did I mention the only goal when I first joined was just to pay off the $55 joining fee?! Crazy I know, but here I am today, to say, if Marika Handziak, the worst salesman, the introvert who knew nothing, zero, zip, about makeup can do this, so can you!
So I’m sure if you haven’t heard about LipSense, you’re probably wondering what it is, and how it works and maybe read some reviews (LipSense reviews can be found under the menu tab)! Well, let me share with you the magical formula!
LipSense is unlike any other stain, lipstick, or lip color. SeneGence has a patented LipSense formula so it's one of a kind!
The color molecularly bonds to your lips and the gloss moisturizes (like many other long lasting colors) and seals in your color for 4-18hrs! It is literally smudge proof, kiss proof, water resistant and only comes off when you take it off! Another huge reason why I love these products is that they are all made in the US with FDA approved ingredients made in pharmaceutical grade manufacturing facilities. They are gluten-free, no animal byproducts, vegan, GMO free, lead-free, cruelty-free and wax free. No need to worry about all the cute little animals hurt by testing or putting harmful products on your body. It’s stress and worry free lipstick wearin’!
When first starting out with LipSense, it is sold as a starter kit which includes LipSense color, LipSense gloss, and remover.
The cost of the kit is $55. Individually LipSense liquid lip colors are $25 and moisturizing gloss is $20. There are over 50 different LipSense color shades and over 12 different glosses. A few of the top sellers are Goddess, Bombshell, Pink Champagne, Blu-Red along with Glossy Gloss, Matte Gloss and Bougainvillea Gloss. (You can find a LipSense color chart in Color and Gloss tab above).
Contact Here For More Info!
Not Sure Where To Begin? See Our LipSense Starter Kit!
There are so many great benefits to being apart of SeneGence. First off, the 20-50% discount on everything is amazing!
Whether you are enjoying those for yourself or to sell! The profit margin is huge! There are also many ways you can earn free product. We have two programs; the Jump Start which is where within your first 30 days, you can receive 50% off all your qualified orders and Fast Start where you can earn up to $1200 in FREE product!! Two great ways to get your business off to a good start!
Secondly? Thirdly? I’ve lost count:) There are so many amazing things to love about this company! The friends you meet! There are so many fabulous, inspiring, go getters. I’ve never met such a sisterhood of women who are all so supportive and there to build each other up. I want you to be apart of this!! It is truly amazing.
On top of those great reasons, the amazing car program, paid trips, recognition for achievements and the financial freedom it can bring is truly life-changing!
I’ve seen so many of my team able to quit their jobs, go on trips they wouldn't have been able to hire a nanny, a cleaning lady, pay for rent, or their mortgage! The opportunity right now is ground level. Though the company has been around for awhile, it is just now starting to take off. Many direct sales companies have over millions of consultants, we have only 250,000! If you are looking to make $500, $1000, $5000 a month, let's do it and get you started! I will be there to help you along the way! The business is simple yet it is work. Like anything, if you want to get paid you need to put in the work. It is relatively easy, especially when the products are amazing and actually work, so all you have to do is go out and share it!
I may not be the closest LipSense distributor near you but I have a great network of amazing ladies across the country that I host online trainings with. There are also numerous secret Facebook groups that I will add you to, that have endless amounts of information and tips to help with any questions or concerns you may have.
We offer 100% Satisfaction guarantee! So if you aren’t completely in love, exchange or return it for a refund!
While most of my original focus was on LipSense Florida distribution, SeneGence offers many other amazing products I’m now proud to offer. All the while, my business has grown more nationally and even into new countries like Mexico, Puerto Rico, Canada, Australia, New Zealand and others!
We carry a wide variety for all skin types and tones. Below I’m going to share a few of the reasons that set our makeup apart from others.
First off, the creme based products are anti-aging which is amazing! While wearing makeup you are also nourishing, moisturizing and helping your skin reverse in age! Yep, you heard that right! The main component that sets our skin care/makeup apart from others is we have a patented one of a kind technology that renews skin cells 23.3% faster. It’s a kinetic enzyme that affects the way the cells grow from the bottom layers of the skin to the top. It is called Seneplex! Not only does it renew skin cells faster but it also helps with increasing skin luminosity, smoothness, elasticity, collagen, moisture and hydration. All while decreasing wrinkles, fine lines and sagging! Hallelujah, because these babies are making me age real FAST! I need all the makeup and skincare!
Another amazing thing I want to mention is that all of these products are water resistant!
You don’t have to worry about all your makeup coming off after a swim in the pool or running on those hot and sweaty days! Because let’s be honest, we’ve all had those days where you’re worried about either your eyeliner ending up smudged on your eyelid or your lip color on your teeth. Not anymore with SeneGence!
|
{
"timestamp": "2019-04-23T10:54:53",
"url": "https://www.marikadarlings.com/",
"language": "en",
"source": "c4"
}
|
Are you an experienced Delivery Manager who has the skills needed to help shape our growing SCRUM teams to deliver against an ambitious and exciting roadmap here at BHF?
If so, we have a great job opportunity for an individual who can 'hit the ground running' and who has a proven ability of working with and managing teams through competing priorities. The right person will be able to work independently to help develop emerging SCRUM teams whilst using their exceptional communication skills to keep the digital delivery team and wider business well informed.
As Delivery Manager you'll collaborate closely with Product Managers and Business Leads to plan, deliver and maintain products and services, including online fundraising products, retail apps and cross-platform integrations.
A SCRUM Master or equivalent with strong and varied agile digital delivery expertise gained in commercial environments, you'll be passionate about embedding agile working practices in a growing team and will take a proactive role in identifying and promoting better ways of doing things.
Adapting your delivery approach and style to best fit the given context or challenge at hand will be second nature to you and you'll be used to working with Product Owners and Technical Leads while steering Developers, UX/UI Designers, Content Execs and Testers to ensure effective end-to-end digital delivery.
With excellent problem-solving and communication skills, you'll also thrive on enabling multi-disciplinary teams to work through uncertainty and competing priorities to ensure effective end-to-end delivery of high quality products.
When you work at the British Heart Foundation, you become a part of medical history. Part of a world leading organisation that has played a role in decades of life saving breakthroughs, from heart transplants and pacemakers to stents and clot busting drugs. And we're not about to stop any time soon. We are here to beat heartbreak forever; to stop heart and circulatory diseases devastating families. And if you want to help us get there sooner, you could be the Delivery Manager we need.
To apply for this role please use the apply button below. Our process involves submitting your CV and a supporting statement.
Interviews to take place on Tuesday 2 April 2019 at our head office in London.
|
{
"timestamp": "2019-04-24T14:51:30",
"url": "https://jobs.theguardian.com/job/6876435/delivery-manager-digital/",
"language": "en",
"source": "c4"
}
|
Really, this series is one of the best I've ever seen. Thank you.
Cool Movie! I Believe these are 1337 Level 4 Agents. in the 1-st Part where Only Level 1, 2 and 4. Level 3 are in ME 4. In ME 4 are and Some Level 2, But they are Rare there. And Zombies, and Grunts. Pt2 What's woth the Wall? Anyway Cool Movie.
I don't like the part when the protoganist enter the room then the morons where like panicking !!
LOL they think steve was hank friend?
See how the Eliminator is going after the gang leader in this tribute!
Splurgle is back with another gorey installment of his Madness tribute!
Here it is. The big car chase and all. 5,000 frames of goodness.
The third installment of Ace Corn's Agitation, enjoy the violence!
|
{
"timestamp": "2019-04-24T08:23:29",
"url": "https://www.newgrounds.com/portal/view/331156",
"language": "en",
"source": "c4"
}
|
The headline in The Chronicle of Higher Education says it all, but unfortunately the article says even more: that among the early victims of the financial crisis as it plays out on college campuses is likely to be schools' sustainability efforts. What for many schools has been discretionary spending--"slushy," as one college sustainability officer quoted in the article describes the funding for her job--will be curtailed as smaller colleges focus more tightly on services deemed essential.
The public's attention seems at last to have been brought to the idea that environmental sustainability is a survival issue, and forward thinkers in the education community have begun to articulate a comprehensive, integrated vision of sustainability as a strategic educational direction. It's lamentable, and possibly more, that the immediacies of faculty salaries and plant maintenance may limit or put an end to what some colleges are trying to do, just at what looks so much like the ideal "teachable moment."
New Progressivist schools at the primary and secondary levels have taken a range of approaches to the issue of sustainability, from whole-hog commitment to environmental studies, environmental action, and campus sustainability to more measured, curriculum-focused efforts to teach students the complex interrelationships between the human and natural environments, the economy, social structures, and even the arts. The common element is the desire to help students develop an awareness of the impact of their own lives--and vice versa--on the places and cultural milieus in which they live.
Among the more sophisticated approaches to issues of sustainability is "place-based education," in which Tip O'Neill's adage that "all politics are local" is extended to a deep understanding of the way historical and natural forces have converged to shape specific communities. An intensive study of a single city block or rural stream can yield extraordinary amounts of information about the way people have lived, the ways they have regarded their environments, and the ways in which stewardship for place might yet lead us out of our political, social, economic, and climatic thickets.
Rather than let operational sustainability efforts peter out in our educational institutions, I like to think that progressive educators will see the current crisis as little short of a mandate to guide students in digging even deeper into what has made aspects of our society so patently un-sustainable; this may seem re-active, but the work has already been started and needs only to be expanded and supported. Through place-based education, through the incorporation of issues of social justice and economic theory into our curricula, and through an optimistic commitment to sustainability as a mantra for building a better world, let us work as educators to keep the concept alive and well.
We'd love to have comments or be able to add links here that would provide a broad sampling of the ways that schools are approaching this topic.
|
{
"timestamp": "2019-04-24T20:53:32",
"url": "https://www.newprogressivism.org/2008/10/un-sustainability.html",
"language": "en",
"source": "c4"
}
|
These days, all kinds of media are competing for people’s attention but projection mapping truly stands out as a cool form of entertainment with an enormous wow factor. It is an impressive projection technique that creates the optical illusion of movement on static objects – in most cases buildings – and turns them into a dynamic display. Thanks to the live 3D animation, projection mapping transforms virtually any surface, even the most irregularly shaped, into attention-grabbing stages.
While bringing brands to life in popular public venues, 3D projection mappings powered by Barco projectors have been blowing audiences’ minds all around the world. Our image processing portfolio and large venue projectors offer the perfect mix of ultra-brightness, seamless image blending and rugged reliability.
Selecting the ideal lens for your application can be challenging. Our lens calculator makes that easy. It helps you in selecting the projector lens that best suits your needs.
People have been projecting images onto things since the early days of movies. However, projection mapping as it is known today is the result of a variety of different influences from the late 90s. Over the years, it has been referred to as either 3D mapping or video mapping. Early examples include images projected onto mannequins at theme parks or museums to make them appear animated. From 2007 onwards, video artists began to use it as a technique in installations, experimenting with the graphic side. Later again, it began to appear in contemporary dance and theater.
Inevitably, specialized projection mapping software began to appear. Parallel improvements in projection technology enabled it to move into the public space, and very quickly projection mapping became an urban art. The earliest examples include a hypnotic, minimalist show by French electronic artist Etienne De Crecy in 2008. VJs also started mapping at nightclubs and other events.
About the same time, mapping took a jump from 2D to 3D. Public buildings became used as what is known as "canvases" in the industry. Event organizers created increasingly sophisticated events that brought the structures to life. This required the creation of computer models of the façades that are being used. As the projectors became more powerful, so did the ambition of the designers. The projections grew in scale, and storytelling became a significant part of each event.
As a result, powerful projectors have enabled awe-inspiring projections on increasingly large structures, but also projection onto water fountains, statues and the Hoover dam.
A more recent trend is towards large-scale projection inside buildings or industrial landscapes as part of exhibitions. The pioneering Carrières de Lumière in southern France projects spectacular images from art and history inside an abandoned marble mine. The Atelier de Lumières did something similar in Paris using the works of Gustav Klimt in 2018.
One of the things that make projection mapping so powerful is that it’s ideally suited for social media. As the building’s architecture plays the leading role, it’s actually interacting with the spectators, compelling viewers to record the video projection and share it online. In this way, the message reaches an even bigger audience. Captivating audiences with an unforgettable visual experience is crucial to build brand awareness.
|
{
"timestamp": "2019-04-21T22:15:24",
"url": "https://simulation.barco.com/en/solutions/Projection-mapping",
"language": "en",
"source": "c4"
}
|
Integrates your Easy Digital Downloads store with MailerLite by letting you automatically subscribe customers to specific lists based on what they purchased.
Allow customers to opt themselves into a list during checkout.
Integrates your Easy Digital Downloads store with MailerLite by letting you automatically subscribe customers to specific lists based on what they purchased, and allowing customers to opt themselves into a list during checkout.
|
{
"timestamp": "2019-04-20T23:17:08",
"url": "https://www.cminds.com/wordpress-plugins-library/mailerlite-email-marketing-for-easy-digital-download-edd/",
"language": "en",
"source": "c4"
}
|
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