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Semen cryopreservation and radical reduction capacity of seminal fluid in captive African lion (Panthera leo).
Optimizing cryopreservation protocols for nondomestic felids contributes to the successful development of assisted reproduction techniques and genetic resource banking. In this study, we describe a simple cryopreservation procedure for African lion (Panthera leo) ejaculates, which was tested with different packaging options and different sperm numbers per dose. By applying urethral catheterization and electroejaculation, 17 ejaculates with greater than 20% motile and greater than 5% progressively motile sperm were collected. A lyophilized extender (a modified egg yolk-Tes-Tris-fructose-glycerol medium) was rehydrated and added in one step at ambient temperature (∼25 °C) to semen, which was prediluted in cell culture medium M199. After slow cooling of insulated samples to 15 °C in a refrigerator (4 °C), the samples were fast frozen over the surface of liquid nitrogen or in a dry shipper. Aliquots of 300 μL containing 20 × 106 sperm were frozen in cryovials and in 0.5-mL straws. Differences were observed in the total motility after thawing between vial (31.5 ± 14.1%) and straw freezing (20.1 ± 8.6%). However, the subpopulations of vital (22.7 ± 7.8% for vial and 19.8 ± 8.5% for straw) and progressively motile (10.0 ± 7.9% for vial and 10.0 ± 6.4% for straw) sperm after washing and 1 hour incubation at 38 °C were of similar magnitude, velocity, and linearity for both packaging options. After freezing of five ejaculates with 20, 60, and 100 × 106 sperm per dose, best results were achieved at the lowest concentration. In general, post-thaw results were highly variable (2.2% and 56.5% total motility) and not correlated to motility or morphology of the fresh semen. To further characterize semen quality, we assessed the protective potential of seminal fluid against oxidative stress, which might be challenged on freeze thawing. The capacity of seminal fluid to reduce radicals was measured in 10 semen samples by electron spin resonance spectroscopy and a spin-labeled fatty acid as a radical probe. Moreover, we determined the lysophosphatidylcholines (LPC) as potential lipid oxidation products in the sperm and erythrocytes of the males. Individuals with a high radical reduction capacity in the seminal fluid and a low LPC content in their erythrocytes showed a better cryosurvival of sperm. This is a first indication that seminal fluid may affect the freezing potential of African lion ejaculates. |
PORTLAND, Ore. – The Portland Timbers today announced that forward Jose Valencia will join Argentina first-division side Olimpo de Bahía Blanca on a season-long loan.
“Jose is a young and talented player who needs consistent playing time in order to continue in his development,” said Timbers general manager Gavin Wilkinson. “With the addition of Gastón Fernández, we felt it was best for Jose to go on loan. Olimpo is excited to have Jose on loan and the club will provide him the opportunity to gain valuable experience in a top league and will continue to push him in his development.”
Valencia, 22, made 21 regular-season appearances (5 starts) in his first full MLS season in 2013, scoring one goal and recording three assists. He also played in three matches during Portland’s run to the 2013 Lamar Hunt U.S. Open Cup semifinals and made a pair of appearances in the MLS Cup Playoffs. Valencia was the leading scorer for the Timbers Reserves in the MLS Reserve League with five goals.
From Bogotá, Colombia, Valencia joined the Timbers on Dec. 15, 2011, from Colombian side Independiente Santa Fe, where he started his professional career in 2008. He missed the 2012 campaign with Portland due to preseason knee surgery.
Valencia is a former Colombia youth international and was a standout for the Colombia U-20 National Team during the 2011 FIFA U-20 World Cup.
Olimpo is located in the city of Bahía Blanca in Argentina’s Buenos Aires Province. The club finished the Primera División’s Torneo Inicial with a record of 6-8-5 (23pts). The league’s Torneo Final runs February to May. |
A Coast Guard officer accused of stockpiling guns and compiling a hit list of prominent Democrats and network television journalists can be released on strict supervision to one of his in-laws while he awaits trial, a federal judge ruled Tuesday.
Judge Charles Day agreed to delay the release while prosecutors appeal the decision.
Christopher Hasson, 50, a Coast Guard lieutenant working in the nation's capital, was arrested Feb. 15 on drug and gun charges. Prosecutors later called Hasson a "domestic terrorist" in court filings and said he "intends to murder innocent civilians on a scale rarely seen in this country."
But Hasson has not been charged with any terrorism-related offenses and prosecutors have said they don't plan to file additional charges. Hasson's lawyer has been seeking his pretrial release for several months.
After initially denying the request, the judge agreed Tuesday to a strict release into the custody of Hasson's father-in-law or mother-in-law in Virginia, where he would have to be accompanied by someone else at all times.
Hasson will not be released yet. The judge has laid out a lengthy list of conditions for his release, which court officers must confirm have been met, and the government's appeal must be processed. If the appeal is rejected, Hasson may be released in about a week.
The judge had previously expressed his "grave concerns" about Hasson based on information prosecutors have presented. On Tuesday, Day said the allegations against Hasson made him "very nervous, but I don't think it justifies detention."
The stockpile of guns found by investigators owned by Christopher Hasson. U.S. Attorney's Office in Maryland
Hasson, a self-described white nationalist who espoused extremist views for years, stockpiled weapons and created a hit list of prominent Democrats, two Supreme Court justices, network TV journalists and social media company executives, according to prosecutors. Investigators found 15 guns, including seven rifles, and more than 1,000 rounds of ammunition at Hasson's basement apartment in Silver Spring, Maryland.
Prosecutors have said Hasson appeared to be planning attacks inspired by the manifesto of Anders Behring Breivik, the Norwegian right-wing extremist who killed 77 people in a 2011 bomb-and-shooting rampage.
In court, Hasson's attorney Liz Oyer said he has had a lifelong interest in firearms and likes to hunt and target practice. She said the number of guns he owned isn't unusual in North Carolina, where he lived for years before moving to Maryland.
Hasson pleaded not guilty in March to charges of illegal possession of firearm silencers, possession of firearms by a drug addict and unlawful user, and possession of a controlled substance. He faces a maximum of 31 years in prison if convicted of all four counts in his indictment.
Hasson, a former Marine, worked at the Coast Guard headquarters in Washington on a program to acquire advanced new cutters for the agency. A Coast Guard spokesman has said Hasson will remain on active duty until the case against him is resolved. |
Q:
How to create comma separated words
I have a Blog System Where I'm fetching category Name From Database. Here is what I've tried->
<li><span>Categories:</span>
<?php
$a = mysqli_query($connecDB, "SELECT * FROM vector_cat WHERE post_id='$puser'");
while( $b = mysqli_fetch_array($a) ){
?>
<a href="https://www.twekr.com/free-vectors/<?php echo $b['post_id']; ?>"><?php echo $b['cat_name']; ?></a>,
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This Results in -> Fashion, Technology, PHP, Mysql,
The problem I'm Facing is How can i remove the last comma from the result
A:
You can use rtrim().
This function returns a string with whitespace stripped from the end of str.
rtrim($string, ',');
Second parameter indicates the character to be deleted.
|
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Chris Moyles has admitted joining a tax avoidance scheme that would have cost the UK £290million.
The former Radio 1 DJ pretended to be a used car salesman hit by losses to save up to £1million in tax payments.
He joined a scheme called Working Wheels which boasted 450 high earning members, including celebrities.
The star, who earned £500,000-a-year at the BBC, said he accepted "full responsibility" for his actions after a tribunal ruled he took part "for no purpose other than to achieve a tax saving".
Her Majesty's Revenue and Customs claimed the closure of the scheme had saved the country £290million.
The NT Advisors scheme counted "450 fund managers, celebs and other high earners between 2006 and 2008" as members and involved a series of complex trades across tax havens.
Moyles told HMRC he had spent the 2007/8 tax year “engaged in self-employment as a used car trader”.
According to tribunal chief Judge Colin Bishopp the broadcaster claimed he had sold £3,800 of vehicles but had run up losses of £1million which he wanted to claim against his tax bill.
An HMRC insider said the scheme involved a series of "phantom" deals in cars that did not exist.
Lib-Dem Treasury Chief Secretary Danny Alexander said: "Well done to HMRC for shutting this unfair scheme.
"Message to other tax dodgers: you’ll be caught."
And Margaret Hodge, Labour chairwoman of the Commons Public Accounts Committee, added: "It is unacceptable when the majority of hard-working people pay their taxes that rich people go to such lengths to avoid paying theirs.
"These schemes should be outlawed."
And Tory Exchequer Secretary David Gauke said: "This is another example of why taxpayers should not fall for the promises of promoters selling schemes too good to be true.
"Not only will they waste money on the fees, they will still have to pay all the tax, interest and penalties."
Moyles, 40 today, claimed he had been "naive".
He said: "Upon advice, I signed up to a scheme which I was assured was legal.
"I'm not a tax expert and acted on advice I was given.
"This was a mistake and I accept the ruling without reservation.
"I have learnt a valuable lesson."
Moyles' involvement came to light after officials examined tax returns.
The ruling from the Tax Chamber of the First-tier Tribunal revealed he did not attend the hearing but gave "a brief and uninformative statement".
It said his accountant, Derek Smith, had "agreed the scale of Moyles' borrowing was driven by the amount of the tax loss he wanted to achieve, in his case £1million".
The DJ, who has been playing King Herod in Jesus Christ Superstar after quitting Radio 1, was one of three of the 450 appealing against the ruling that the scheme was unacceptable.
HMRC said: "Anyone using an avoidance scheme is playing with fire.
"We have a high success rate in defeating them."
Tax avoidance, described as bending the rules, and tax evasion, which is illegal, costs the UK £35billion a year.
As well as Working Wheels, the HMRC successfully shut down three other NT Advisor schemes.
Comedian Jimmy Carr admitted in 2012 he had "made a terrible error of judgment" when he joined a tax avoidance outfit that David Cameron called "morally wrong". |
When it comes to body butters I'm a religious follower of Bath & Body works, Boots Pharmacy Body butter, (sadly both are not very easily available in India) & The Body shop body butters (easily available but pricey).I never even look beyond these staples of mine.I'm extremely demanding of my body butters, this is one item in my beauty routine I cannot live without .Period.
Recently while shopping online I picked Vedicline Choco body butter on a lark, half expecting it to have some over powering chemical infused chocolate flavor.But this humble looking choco vanilla body butter has simply bowled me over! It has a delicious choco vanilla flavor that's as real & natural as they come.
The packaging is very basic & functional, though I would have definitely loved a fancier packaging,possibly with some images of dripping molten chocolates...I' a total sucker for fancy-schmancy body butter, but for the price & quality I've no complaints.
The quantity at 65 grams for Rs 200/- is a bit low for a body butter.. I've been using this for almost 2 weeks and am already half way through my jar.But I guess a higher quantity might have pushed it at a higher price point.
The Ingredients- All natural & tempting as hell ;)
Thick, rich, delicious smelling body butter, feels sinful on your skin and is intensely hydrating. I slather it on in the morning and its keeps my skin soft & supple through the day.It does get a bit too heavy for this sweltering heat but I love the way my skin feel soft with this baby.
It claims to be fit for both face & body application.I'm too much of a skincare snob to actually use a body butter on my face but it smelled sooooo good I broke all my cardinal body butter rules & slathered some on my face at night time just before hitting the sack- it did make me overly sweaty (I'll blame the 44-45 degrees heat for it) yet I loved the calming & soothing effect it had. My skin which was getting dry & patchy on my cheeks and forehead didn't feel quite as parched & dryness healed really quickly.
This is a sure winner & I'm so surprised that despite being a well established brand exporting to foreign countries Vedicline is not to be seen on store shelves in India and there is zero advertising about the brand.I have so far spotted these only on e-com sites.I really wish these were more easily available in stores.
I was so impressed by Vedicline Choco vanilla face &body butter that I couldn't resist buying some more Vedicilne goodies, here's what I hauled
Banana Pulp Mask
Choco Butterscotch face mask (not in pic)
Choco strawberry lip balm
Cuticle & nail cream
I just received my goodies in mail today & I have used the choco butterscotch face pack, cuticle and nail cream and Choco- strawberry lip cream, totally loving them and will be posting a detailed review soon :)
Overall Recommendation-Seriously fabulous body butter don't wait for a moment longer- you have got to try this one out!
Will I be re-purchasing Hell Yeah!
BTWJabong.com is offering Free vouchers worth Rs 2000 which can be redeemed on a minimum shopping of Rs 1500-.You get Rs 500/- off on Rs 1500/- Order- Amazing right?!- stock up on essentials in your wishlist while the offer is on :)
this sure looks good. And God the smell of the cocoa or choco body butters really ignites the craving for chocolates.
never tried vedic line, this sounds interesting. I've only tried a fab India toner and forest essentials rose water among the indian brands,, never beyond. But since u rate it better than body shop, it sure is worth a try!!! |
Gastrointestinal problems at high altitude.
Gastrointestinal (GI) problems at high altitude are commonplace. The manifestations differ considerably in short-term visitors, long-term residents and native highlanders. Ethnic food habits and social norms also play a role in causing GI dysfuntion. Symptoms like nausea and vomiting are common manifestations of acute mountain sickness and are seen in 81.4% short-term visitors like mountaineers. Anorexia is almost universal and has a mutifactorial causation including effect of hormones like leptin and cholecystokinin and also due to hypoxia itself. Dyspepsia and flatulence are other common symptoms. Diarrhoea, often related to poor hygiene and sanitation is also frequently seen especially among the short-term visitors. Peptic ulceration and upper gastro-intestinal haemorrhage are reported to be common in native highlanders in the' Peruvian Andes (9.6/10000 population per year) and also from Ladakh in India. A hig h incidence o f gastriccarcinoma is also reported, especially from Bolivia (138.2 cases per 10000 population per year). Megacolon and sigmoid volvulus are common lower GI disorders at high altitude. The latter accounted for 79% of all intestinal obstructions at a Bolivian hospital. Thrombosis of the portosystemic vascultature and splenic hematomas has been reported from India. Malnutrition is multifactorial and mainly due to hypoxia. Fat malabsorption is probably significant only at altitudes > 5000m. Neonatal hyperbilirubinemia was found to be four times more common in babies born at high altitude in Colorado than at sea level. Gall stones disease is common in Peruvian highlands. A high seroprevalence of antibodies to H pylori (95%) has been found in Ladakh but its correlation to the prevalence of upper gastro-intestinal disease has not been proven. |
Westbound Highway 401 closed this morning at Bowmanville
Fatal crash will leave highway closed for hours, OPP says
A woman is dead after a fatal crash that has closed the westbound lanes of Highway 401 in Bowmanville this morning.
Original reports suggested the crash — which happened at 4:40 a.m. — was a single-vehicle collision but the OPP has since told CBC News that a tractor-trailer was also involved.
The highway has since reopened.
The OPP say all lanes of Highway 401 between Liberty Street and Waverly Road will likely be closed for several hours.
Police say traffic heading toward Toronto took a detour off the highway at Liberty Street and merged back onto the highway at Waverly Road. The detour caused long delays for westbound drivers. The eastbound lanes were not affected. |
Q:
pling sound .net application
i have a .net winforms application that i want to be "soundless".
occasionally when a user opens a dialog or press enter a "pling" sound appears. how can i disable this on a global scale for my application?
A:
See this previous article:
How do I disable the c# message box beep?
|
Robert Archibald James Montgomerie
Rear-Admiral Robert Archibald James Montgomerie, (11 September 1855 – 1 September 1908) was a British Royal Navy officer, who received the Albert Medal for Lifesaving.
Naval career
Montgomerie joined the Royal Navy, and served on the royal yacht HMY Victoria and Albert when he was promoted to lieutenant on 13 September 1878. He served on the Nile in Egypt 1885-86.
He was promoted to commander on 24 August 1887, and to captain on 1 January 1894, and was appointed a Companion of the Order of the Bath (CB) in the 1892 Birthday Honours list on 25 May 1892. In February 1901 he was appointed senior naval officer for the protection of the Newfoundland Fisheries, with the rank of Commodore, in command of the protected cruiser HMS Charybdis based at St. John's. During his stay in North America he was in charge of a ´Particular Service Squadron´ during the Venezuelan crisis of 1902–03. As he ended his posting in Newfoundland he was appointed a Companion of the Order of St Michael and St George (CMG) in the 1904 Birthday Honours list on 9 November 1904.
Montgomerie was promoted to rear-admiral on 19 June 1905, and appointed in command of the torpedo boat and submarine flotillas in the Royal Naval Reserve.
References
Category:1855 births
Category:1908 deaths
Category:Royal Navy admirals
Category:Commanders of the Royal Victorian Order
Category:Companions of the Order of St Michael and St George
Category:Companions of the Order of the Bath |
Measuring the degree of starshape in genealogies--summary statistics and demographic inference.
The degree of starshape of a genealogy is readily detectable using summary statistics and can be taken as a surrogate for the effect of past demography and other non-neutral forces. Summary statistics such as Tajima's D and related measures are commonly used for this. However, it is well known that because of their neglect of the genealogy underlying a sample such neutrality tests are far from ideal. Here, we investigate the properties of two types of summary statistics that are derived by considering the genealogy: (i) genealogical ratios based on the number of mutations on the rootward branches, which can be inferred from sequence data using a simple algorithm and (ii) summary statistics that use properties of a perfectly star-shaped genealogy. The power of these measures to detect a history of exponential growth is compared with that of standard summary statistics and a likelihood method for the single and multi-locus case. Statistics that depend on pairwise measures such as Tajima's D have comparatively low power, being sensitive to the random topology of the underlying genealogy. When analysing multi-locus data, we find that the genealogical measures are most powerful. Provided reliable outgroup information is available they may constitute a useful alternative to full likelihood estimation and standard tests of neutrality. |
One of my best friends (bones!) sent me an email asking if I'd ever heard of this thing called Hosehead (it's a control system for an electric brewery using open source software called Strangebrew Elsinore). I had never heard of it, but had been thinking on and off for some years about converting my brew setup to be all electric. I knew the efficiency was a big positive, plus the potential of being able to brew inside made the idea a lot more attractive (even if I don't have a good indoor spot to brew right now).
As could have been predicted, I started researching the concept and fell deep down that rabbit hole. A few hours later I was convinced converting my system to all electric was not just a sound idea, but the only rational choice I could make. I decided to put together a HERMS (Heat Exchanger Recirculating Mash System). By keeping the hot liquor tank at a temp just slightly above my target temp I could recirculate the mash and raise to, or hold at, any temp I wanted. Also recirculating the mash through the grain bed would lead to clearer wort and greater efficiency. Knowing all this I was sure only a fool would pass up the opportunity to build out a system like this!
I had started brewing 10 gallon all grain batches about two years ago using a large rectangular cooler for the mash and an 80qt stainless pot from Amazon. (That's an affiliate link by the way). I would heat the mash water to roughly 10 degrees over strike temp, siphon the water into the cooler, and then mash in. I had mixed results with efficiency, but the beers were generally decent. Still, the whole process was a bit of a hassle and I was eager to improve my system.
I set to work sorting out what I had and what I would need. For the controller I decided to use a RaspberryPi (first generation) that I had sitting around. The only use it got was an occasional MAME emulator so my boys could experience the joy of Super Mario World or Donkey Kong Country now and then. Making beer with it seemed like a better use, all things considered. Then I took an inventory of what I currently had so I could get my shopping list started. I already had one 20 gallon kettle I could use, and realized I could re-purpose my retired 13 gallon "keggle" as a hot liquor tank. That meant I would only need to purchase another kettle (for boil or mash), plus "a few" other odds and ends. Like a bunch of stainless valves, cam-lock connectors, hoses, 50' of 1/2" stainless steel tubing, two pumps, heating elements, wire, a project box, a 240v circuit somewhere, and a dozen other things I would come to find need for along the way.
On the controller front, there are easier ways to do it vs putting a RaspberryPi in charge, but I really loved the idea of being able to set it up to do a step-mash and know I could go do other stuff while the controller managed things for me. It will also make neat graphs of the temperature rise (and hold) through the process (even if those graphs are not really too valuable for anything). On top of that I'd always been on the lookout for something good to use the GPIO pins on the pi for and this seemed perfect.
Speaking of components, I've added links for most of the stuff I ordered, though it's not an exhaustive list. I'm trying to avoid making a complete list of every component I purchased for this project because then I'll see the whole cost in one place and I won't be able to trick myself into believing I did this on the cheap somehow.
The first thing I started working on was the box to hold all the components. Because this would all be on a rolling cart I wanted it to be relatively portable rather than permanently mounted. If I had a spot (inside a garage, utility room or basement) I would have just used a larger electrical box mounted on the wall. Instead I found a decent size waterproof project box that I expected I could shoehorn everything into. In the end it turned out to be a little bit of a tight fit but it worked out. In the bottom left corner is the pi with a breakout board for connecting the GPIO to the onewire temperature probes and the solid state relays. To keep the 240v SSRs cool I cut holes in the case and stacked copper shims with CPU cooling grease between them and heat sinks mounted on the outside of the box. It worked out well and there haven't been any cooling issues inside the box. On the cover I put two switches for 120v outlets, plus two 240v LEDs to show which heating element was energized. I used dryer plugs and outlets for all connections so it's easy to disconnect a kettle from everything. Everything worked right on the first try too (making a wiring diagram first definitely pays off).
The next phase of the project involved drilling holes in my kettles for the heating elements and the valves. This took longer than it should have due to me starting with a dull drill bit. Eventually I wised up and got a new carbide tipped bit; combined with some oil and more pressure than usual it made quick work. I drilled 1/2" pilot holes and then used a titanium step bit to widen the holes from there as needed.
For heating I purchased these 5500w stainless 240v elements from Amazon. They've been working great, and the one in the boil kettle gets a pretty violent boil going, easily as vigorous as I used to get with gas and a big banjo burner.
The mash tun was pretty easy, I would just need to find a decent false bottom. The Fermenter's Favorites Titan from Northern Brewer was a perfect fit for the kettles I had. It's really well made and nearly eliminates dead space. You'll see in the picture below that I'm recirculating the mash through a fly-sparge attachment. In theory I am at risk of introducing off flavors through hot-side aeration, but I haven't noticed anything yet.
When it came time to add the stainless coil in the HLT I thought I'd be clever and thrifty by coiling the tubing myself. I purchased 50' of 1/2" stainless tube on Amazon and got to work trying to bend it up. I eventually made a coil but it was not pretty and it took WAY more effort than I anticipated. Along the way I kinked it up too much and basically turned out something that was unusable. I still have the tubing and expect I might use it some day for fixed runs in a more permanent brew setup. (I'm too ashamed to include a photo of that disaster...)
Seeing prices around $200 for a coil like this is what initially put me off from buying one pre-made. Then I stumbled across Stainless Brewing and was shocked to find I could get a perfectly coiled 50' run of stainless for almost the same price as the raw material. It happened to be my lucky day too as there was a 20% sale going on, so I immediately placed my order. It was a beautiful piece of work and installed easily.
One other great side effect of having a setup like this is that when I'm ready to crash-cool the brew while transferring for fermentation I just pack the HLT with ice and water and keep that circulating while the brew is pumped out through the coil. This has worked awesome and I've been able to easily drop the temp to 70 at the end of the brew.
The last thing I needed were pumps, and again those are pretty expensive. I got lucky and found a Chugger SS center-inlet pump that had been returned to amazon and could be mine for $111! The second one was more expensive than that, but I knew I was going to need two pumps for this system. During mash I would need one to recirculate the wort through the stainless coil and back on top of the mash while a second pump recirculated the water in the HLT to keep that temperature steady. Then during mash out I would need one to pump the wort into the boil kettle while the other was pumping sparge water on top of the mash.
(Don't be confused by how the pumps and hoses are connected in this picture. I was moving cleaning solution from the boil kettle into the mash tun, and had been recirculating the water in the HLT. I'll include better pictures in my typical brewday post.)
For the hoses I used high temp clear silicon. I purchased the hose from the same place I got my stainless camlock fittings and the valves as well. Bargain Fittings seemed to have the best deals I could find for most of this stuff. I got bulkheads from them as well, along with a few miscellaneous fittings to get everything connected properly.
The only other thing I needed that was a little tricky to find was a compression fitting for the temperature probes. The probes were mounted in T fittings before the valve on the lowest bulkhead in both the HLT and the mash tun. As long as the liquid is flowing past the temp sensor, it's going to be accurate. I thought about adding a thermowell into the kettles as well but realized that's not going to be really useful to me based on my brewing process. Anyway, I purchased these 1/4" compression fittings from Brewers Hardware and they worked out perfectly.
I think that about covers everything I had to piece together to make this system. My next post will cover a typical brewday with this setup. Even from the first run, I was really happy with it. I've been hitting 85% to a touch over 90% efficiency with this, and the brews are ending up higher ABV than I intended. Once I get more used to this I'll be able to cut back on my grain bill a bit and still end up with good beer!
Helpful links: |
Meningitis caused by Streptococcus suis: case report and review of the literature.
A case of purulent meningitis caused by Streptococcus suis type 2 (group R streptococcus) is described. It occurred in a 69-year-old farmer's wife who raised pigs on her farm. Here, as well as in nearly all other cases of S. suis meningitis reported to date, close occupational contact with pigs or pork preceded the infection; this epidemiological link can be explained by the frequent occurrence of S. suis as a commensal and opportunistic pathogen in pigs. Up until now, S. suis infection in man has been rare and has had a good prognosis. However, disturbances of the eighth cranial nerve have been found in many patients, even causing permanent deafness in some. These and other clinical, epidemiological and microbiological features of S. suis disease in man are discussed here. |
What the 'sequester' means for you ... and what won't change
Social Security. The program will keep paying old-age, survivors, and disability benefits. But it might be harder to get customer service help. The White House has warned that sequester would mean “a reduction in service hours to the public, and a substantial growth in the backlog of Social Security disability claims.” |
It was all too much for Majority Leader Mitch McConnell (R-Ky.), who said Warren had “impugned the motives and conduct of our colleague from Alabama.” In an extraordinary move, the Senate voted on party lines to shut her down, as The Washington Post’s Paul Kane and Ed O’Keefe reported.
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The mechanism used to silence Warren is known as Rule 19, an arcane and seldom invoked provision in the rules of the Senate. The rule states that senators may not “directly or indirectly, by any form of words impute to another Senator or to other Senators any conduct or motive unworthy or unbecoming a Senator.”
What, exactly, does it mean for one senator to “impugn” or “impute” another? That’s a matter of perspective, as congressional Democrats and other Warren defenders made clear when they rallied behind her on Twitter, launching the hashtag #LetLizSpeak to the top of the site’s trending list.
One thing’s for sure, however: The circumstances surrounding Rule 19’s creation were quite different than Tuesday’s exchange on the Senate floor.
Since its founding, the Senate has maintained an evolving list of rules governing civility and decorum in the chamber. As vice president, Thomas Jefferson included 10 rules in his Manual of Parliamentary Practice that dictated how senators were to behave.
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“No one is to disturb another in his speech by hissing, coughing, spitting, speaking or whispering to another,” reads one passage in the manual, “nor to stand up or interrupt him; nor to pass between the Speaker and the speaking member; nor to go across the chamber, or to walk up and down it, or to take books or papers from the [clerk’s] table, or write there.”
Those rules were published in 1801. The incident that paved the way for Rule 19 came more than a century later.
It was February 1902 and a feud was escalating between the two Democratic senators from South Carolina. Benjamin Tillman, the senior senator and something of a political boss in the state, had grown angry that John McLaurin, his protege, was allowing Senate Republicans to court him on some issues, including the annexation of the Philippines.
Furious that McLaurin was colluding with the other side of the aisle, Tillman used a Feb. 22, 1902, speech on the Senate floor to harangue the younger senator. Gesturing toward McLaurin’s empty chair, Tillman accused his counterpart of treachery and corruption, saying he had succumbed to “improper influences,” according to a Senate history of the dispute.
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When McLaurin caught wind of Tillman’s remarks, he rushed into the chamber and shouted that Tillman was telling a “willful, malicious and deliberate lie.”
A fistfight erupted. As Senate historians recounted, “The 54-year-old Tillman jumped from his place and physically attacked McLaurin, who was 41, with a series of stinging blows. Efforts to separate the two combatants resulted in misdirected punches landing on other members.”
When the fight ended, the Senate voted to censure the two men. A panel found that their behavior was “an infringement of the privileges of the Senate, a violation of its rules and derogatory to its high character, tending to bring the body itself into public contempt.”
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The episode prompted the senate to tighten its rules governing decorum in floor debate. Rule 19 (sections 2 and 3, to be precise) was adopted later that year.
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In the time since, the rule has rarely come up. One instance flagged by Bloomberg’s Greg Giroux occurred in 1979, when Sen. Lowell Weicker (R-Conn.) called Sen. John Heinz (R-Pa.) “an idiot” and “devious” in a debate on the Senate floor. Heinz reportedly stormed to the front of the room with a rule book and showed him Rule 19. Majority Leader Robert Byrd (D-W.Va.) defused the situation and asked them to shake hands. Other examples are hard to come by.
In Warren’s case, Senate Republicans balked at her use of the word “disgrace,” as quoted from the Kennedy letter, in reference to Sessions. But it was during her reading of the letter from King, the widow of Martin Luther King Jr., that Republicans warned her that she was violating Rule 19.
AD
Warren seemed taken aback.
“I’m simply reading what she wrote about what the nomination of Sessions to be a federal court judge meant and what it would mean in history for her,” Warren said. The letter said Sessions “lacks the temperament, fairness and judgment to be a federal judge,” and accused him of pursuing a “shabby” voter fraud case against African American activists when he was a prosecutor.
AD
“You stated that a sitting senator is a disgrace to the Department of Justice,” responded Sen. Steve Daines (R-Mont.), who was presiding during the speech.
About 25 minutes later, McConnell came in and said her quotes from King crossed the line. She was ordered to sit down.
AD
“Sen. Warren was giving a lengthy speech. She had appeared to violate the rule. She was warned. She was given an explanation,” McConnell said later. “Nevertheless, she persisted.”
As the exchange spread on social media, some were quick to point out that McConnell was recently the target of a personal attack on the Senate floor. In 2015, Sen. Ted Cruz (R-Tex.) accused him of lying to his colleagues and the press, saying “he is willing to say things that he knows are false.” There was no Rule 19 invocation then.
The vote against Warren means she’ll be barred from speaking further in the floor debate over Sessions’s nomination. But that didn’t stop her from reading the text of King’s letter and streaming it live Tuesday night.
“I am surprised,” Warren said, “that the words of Coretta Scott King are not suitable for debate in the United States Senate.” |
Q:
Spring Boot Configuration + RepositoryRestResource + Authentication
I am trying to create a Spring Boot application which stores user/password combination in a users document with MongoDB. I was able to successfully set up a repository extending MongoRepository and all works fine. Now, I would like to set up authentication based on the data source my repository is connecting to. Is there a quick way to do this just using the default connection, or do I need to specifically define a DataSource to do this?
@Autowired
public void configureGlobal(AuthenticationManagerBuilder auth) throws Exception {
auth.jdbcAuthentication().dataSource(dataSource);
}
Here we should assume a dataSource is defined, but if I already have a REST repository set up, I don't have that yet. Do I need an intermediary step here?
A:
I think that in this case UserDetailsService interface will be your best friend
You have to implement the UserDetailsService interface and make sure that your Mongo DB Repository is injected into the UserDetailsService implementation that you create. After that let's implement the loadUserByUsername method in order to return a org.springframework.security.core.userdetails.User object and fill it with the Mongo DB user information.
import org.springframework.security.core.userdetails.User;
@Service
public class MyUserService implements UserDetailsService {
@Autowired
MyMongoRepo myMongoRepo;
@Override
public UserDetails loadUserByUsername(String s) throws UsernameNotFoundException {
List<SimpleGrantedAuthority> dummyAuthorityForExample = Arrays.asList(new SimpleGrantedAuthority("ROLE_ADMIN"));
MyMongoUser mongoUser= myMongoRepo.findByUsername(s);
User user = new User(mongoUser.getUsername(), mongoUser.getPassword(),dummyAuthorityForExample);
return user;
}
}
And finally inject the UserDetailsService to your AuthenticationManagerBuilder
@Autowired
UserDetailsService userDetailsService;
@Autowired
public void configureGlobal(AuthenticationManagerBuilder auth) throws Exception {
auth.userDetailsService(userDetailsService);
}
|
Peak Limiter. Digital Audio High-Quality Sound Reinforcement
Peak Limiter
processes your 16-bit sound files using a sophisticated algorithm. Single peaks exceeding
a user-defined level are softly compressed in such a way that the result cannot be
distinguished from the original by the human ear. This permits rising the main volume of
the sound file considerably without causing clipping or distortion!
Peak Limiter can be used for CD mastering to make all
the tracks equally loud. Peak Limiter enhances single sound samples, fully arranged music
recordings and digitized speech. The result sounds more direct, voluminous, and even. It
is more likely not to harm your equipment during high-volume playback and it is less
inclined to suffer from noise added later on. These are optimum conditions for both
playback and further processing. In batch mode, Peak Limiter is even able to process
several files at a time. |
Hepatic fascioliasis: report of two cases.
Two cases of hepatic fascioliasis with characteristic features in US examinations and CT scans are presented. In both modalities they show tunnel-like branching and clustered areas of low echogenicity/density, which reach subcapsular regions. These cases are presented to recall the imaging features in hepatic fascioliasis especially outside endemic regions. Not only CT but also US is able to detect these characteristic lesions, which may help to make the diagnosis of hepatic fascioliasis in patients with clinical symptoms suggestive of parasitic disease. |
Fuente: LA NACION - Crédito: Dante Cosenza
María Ayzaguer Comentar Me gusta Me gusta Compartir E-mail Twitter Facebook WhatsApp Guardar 10 de septiembre de 2018 • 16:35
EEl gobierno porteño y el Banco Ciudad presentaron ayer Cuenta Consorcio, un paquete totalmente gratuito al que podrán acceder las administraciones de edificios de la Capital y que les permitirá obtener una cuenta corriente, gestionar créditos para infraestructura y hasta cuentas individuales para los vecinos.
Se trata de una cuenta corriente en pesos, a nombre del consorcio, sin costos mensuales de mantenimiento y con servicios gratuitos de transferencias bancarias sin tope de monto y emisión de chequeras. Así, se busca que los vecinos puedan tener mayor control de sus fondos y ahorrar gastos de mantenimiento bancario, que pueden suponer unos $7200 al año.
Carolina Rojo vive en un departamento de tres ambientes en el barrio de Belgrano, por el que cada mes paga $4500 de expensas. De los $77.000 que pagan todos los vecinos, $849 corresponden a gastos bancarios. "Si bien no cambia mucho, me parece perfecto que permitan hacerlo gratuitamente porque todo suma. Terminan siendo $10.000 al año", dice. A unas diez cuadras de ahí, las expensas de agosto del edificio en el que vive Emilse Saldías consignaron $3332 en concepto de gastos bancarios. "Un disparate", según sus palabras.
La Cuenta Consorcio incluye una cuenta corriente con chequera para efectuar pagos a proveedores, permite al administrador habilitar servicios de recaudación como débito automático, transferencias por home banking y depósitos por terminales de autoservicio. Además, bonifica al 100% las cuentas sueldo que necesite el consorcio para el personal del edificio.
También permite acceder a los servicios de banca electrónica para empresas, mediante los que se puede realizar el pago de impuestos y servicios, así como obtener el resumen de cuenta electrónica, entre otros.
En cuanto a los integrantes del consorcio, el Banco Ciudad otorgará a cada consorcista e inquilino una caja de ahorro gratuita y una tarjeta de débito que les permitirá acceder a todos los descuentos y beneficios que la entidad bancaria ofrece en convenio con supermercados, tiendas de electrodomésticos, comercios de ropa, restaurantes, librerías y demás. Asimismo, permitirá realizar el pago de expensas de forma electrónica.
Batería de medidas
Los edificios que ya tengan cuenta corriente en el Banco Ciudad podrán solicitar la bonificación en la sucursal donde esté radicada.
Desde el gobierno porteo recuerdan que la Cuenta Consorcio es la cuarta medida de un plan de 14 para bajar los costos de las expensas, un ahorro que quisieran llevar al 20% de los valores actuales. Las anteriores acciones incluyeron permitir que los vecinos decidan la frecuencia de las fumigaciones (un ahorro que estiman puede llegar a los $20.000 anuales), derogar el certificado de "edificio seguro" que rondaba los $14.000 y la eliminación del libro de datos periódicos ($1000). Con estos cuatro cambios se estima que un edificio tipo de diez pisos y 20 unidades podría acercarse a un total de ahorro anual estimado de $40.200.
"Seguimos adelante con el plan de medidas para reducir los costos que engrosan nuestras expensas. Hemos realizado un trabajo en conjunto con el Banco Ciudad para que ofrezca una cuenta gratuita que cubra todas las necesidades de los consorcios, como el pago a proveedores, la inclusión de las cuentas sueldo para el personal y distintas líneas de créditos que permitirán mejorar la situación de los edificios", afirmó Facundo Carrillo, secretario de Atención Ciudadana.
La semana pasada la Legislatura porteña aprobó en primera lectura otras dos medidas importantes del plan para reducir expensas: ya no será obligatorio construir edificios con vivienda para encargados ni mantener las instalaciones fijas secas contra incendio. Con la eliminación de la vivienda para el encargado, todas las unidades aportarán al pago de expensas, lo que se estima puede representar un incremento en la recaudación para un edificio tipo de $57.800 al año. En cuanto a las mangueras para incendios, se trata de aquellas que se enrollan en los descansos de las escaleras, no son utilizadas por los bomberos, su mantenimiento es obligatorio y cuesta unos $21.000 por año en promedio.
"Esta iniciativa acompaña las acciones del gobierno de la ciudad para que la gestión de los consorcios sea más eficiente, económica, transparente y participativa. Con este producto, buscamos colaborar con el millón de vecinos porteños que habitan en edificios de propiedad horizontal", explicó Javier Ortiz Batalla, presidente del Banco Ciudad.
¿Cómo se puede obtener?
Completando un formulario web para ser contactado por un oficial del Banco Ciudad
En forma presencial en todas las sucursales del Banco Ciudad de la CABA y del GBA.
Conforme a los criterios de Más información |
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Full throttle Remastered: First Look Trailer
Posted bySpaff
One minute you’re on the road, riding, not a care in the world. Then some guy in a suit comes along and says he’s got a deal for you and your gang. But when you come to, you’ve got a lump on your head, the law on your back, and a feeling in your gut that the road you’re on is about to get a lot rougher…
Originally released by LucasArts in 1995, Full Throttle is a classic graphic adventure game from industry legend Tim Schafer, telling the story of Ben Throttle; butt-kicking leader of biker gang the Polecats, who gets caught up in a tale of Motorcycles, Mayhem and Murder.
Now over 20 years later, Full Throttle is back in a remastered edition that features all new hand-drawn and 3D high-resolution artwork with remastered audio and music.
Players will be able to switch back and forth between classic and remastered modes, and mix-n-match audio, graphics and user interface options to their heart’s desire. Also included is a concept art browser with work from Peter Chan, and a commentary track with the game’s original creators.
Full Throttle was the first game with Tim Schafer as sole project lead, and a much beloved cult classic! This special edition has been lovingly restored and remade with the care and attention that can only come from involving the game’s original creators. It’s headed to PS4, PS Vita and PC in 2017! |
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<xpath expr="." position="inside">
<script type="text/javascript" src="/google_spreadsheet/static/src/js/add_to_google_spreadsheet_menu.js"></script>
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|
When Durant wrote of OKC on Twitter, “He didn’t like the organization or playing for Billy Donovan. His roster wasn’t that good, it was just him and Russ” Westbrook, it created a firestorm, mainly because he seemed to finally be revealing his true feelings for leaving Oklahoma City for Golden State, but also because it lead to widespread questions about whether he operates burner accounts to defend himself in the third person. It was one of the more bizarre NBA stories in a slew of strange sagas.
It also ate him up inside. “I didn’t eat yesterday,” Durant told GQ the day after he threw Donovan and company under the bus. “I wanted to go disappear. I didn’t even feel like that when I switched teams.”
In the immediate aftermath of the since-deleted tweets, Durant offered an equally odd explanation, saying he woke up from a nap and fired off the tweets without think. “I just don’t remember it,” he told USA Today’s Sam Amick. “I remember what I said and how I said it, but I just forget everything else.”
“My peers are going to look at me like an idiot,” Durant added. On stage of TechCrunch’s Disrupt SF 2017 event the next day, he expressed remorse for “using my former coach’s name and my former organization that I played for,” he said. “That was childish, that was idiotic, all those types of words.”
All that was covered in the GQ piece, too, but the profile’s behind-the-scenes look at just how deeply the Twitter drama effected Durant raised a few interesting points. First of all, “one of the worst days of his life” is serious business for a guy whose career has seen injury and championship heartbreak. Beyond that, though, it offered a window into the human side of a seemingly superhuman athlete.
“I still struggle to feel confident in myself,” Durant told a couple high school students while the story was still the subject of sports debate, according to GQ. “I still struggle with seeking approval from others sometimes, not realizing that I’m winning in life. Sometimes I tend to go backwards. But that’s just part of life. Don’t feel down about it. Don’t feel upset. Don’t feel embarrassed, even though you are embarrassed at times. … I’m having a bad day today. But you guys are giving me life.”
To understand how an MVP bound for the Hall of Fame could struggle with confidence is to appreciate Durant’s reasons for joining the Warriors. We’ve gone over them ad nauseam over the past 16 months. Essentially, he just wanted to concentrate on becoming the basketball player he could be in a system that allowed him the freedom to do so. He had outgrown Oklahoma City, and Golden State offered all he ever wanted in basketball, with the added bonus of meeting his outside interests in the Bay Area.
The narrative nationally was that he was either a traitor for leaving the Thunder behind or a ring-chaser for joining a 73-win Warriors team that had just knocked him out of the playoffs. Or both.
And there may even be a hint of truth to the ring-chasing bit. “Steph Curry is the face of the franchise, and that helps me out, because I don’t have to,” Durant told GQ. “I don’t want to have to be the leader. I’m not a leader. I’m bad at saying, ‘Stand behind me and follow me.’ No. I’m one of those guys that’s just like, ‘Let’s do this shit together. Let’s just work everybody together. I don’t mind being on the front line with you, but let’s come and do it together.’ That’s my way of leadership. I’m leading by example.”
But from the perspective of a 29-year-old still in search of himself, it takes a look inward and some stones to realize who you are, embrace those qualities, and take a leap of faith. And this is quite a reward: “I came here to play basketball in the exact same way I’m playing it right now,” Durant told GQ.
“Kyrie’s always been his own man, always been his own entity,” Durant told The Athletic’s Anthony Slater from a late-night practice in Boston. “Nobody made him. Nobody in this league did. He kind of did this on his own. So seeing him in Boston, seeing what he’s doing now, it’s no surprise to me. And I’m pretty sure it’s no surprise to any other player in the league because they know what he can do.
“But when you make the move he made and all the stuff that comes with it, a lot of people start to look at him a little different now — well, not different, but look at him more now than they did before and in a different way,” added Durant, fully relating to Irving. “And he’s proven a lot of people, well, I don’t know whether it’s right or wrong, I guess both. But he’s playing some really good basketball.”
And isn’t that what it’s all about for a basketball player — finding the right fit for you? That’s most definitely not what it’s all about if you’re a fan of the Thunder or Cavaliers and your team just lost a perennial All-Star to free agency or a trade request, but that’s because there’s an irrationality to fandom that doesn’t allow us to see them as ourselves, in search of that better work-life balance.
“We always had the power, as players,” Durant told GQ’s Zach Baron in late September. “We’re just realizing it now. It’s like when you wake up — we woke now. And a lot of people didn’t want us to be woke. They wanted us to stay in this trance, that we felt like we had to live our life based on what somebody else does. They can move us when they want to, they can sign us when they want to. … We got control of that now.”
Durant credited LeBron James for showing him the path upon leaving Cleveland for the Miami Heat and returning to the Cavaliers four years later. He “gave me the courage to do that,” Durant told GQ. “Now, I could have did a better job studying how he approached everything after that. But I did it my way. And the next guy is gonna look at me as an example. We’re all working together now.”
In that sense, Durant has followed LeBron into becoming a leader. Isaiah Thomas cited Durant’s free agency decision when he brought the hypocritical nature of NBA loyalty to the forefront in a Players’ Tribune piece after being unceremoniously traded from the Celtics to the Cavaliers over the summer:
“I was thinking about that last year with KD and his free agency — about how people gave him such a hard time for doing what he felt was best for him and his future. How they turned him into a villain, just for doing what was his right to do as a free agent in this league. Suddenly, it was, ‘Oh, he’s selfish,’ or, ‘Oh, he’s a coward.’ Suddenly, just for doing business on his end, and doing right by himself, he was portrayed as this bad guy.
“But that’s what I think my trade can show people. I want them to see how my getting traded — just like that, without any warning — by the franchise that I scratched and clawed for, and bled for, and put my everything on the line for? That’s why people need to fix their perspective. It’s like, man — with a few exceptions, unless we’re free agents, 99 times out of 100, it’s the owners with the power. So when players are getting moved left and right, and having their lives changed without any say-so, and it’s no big deal … but then the handful of times it flips, and the player has control … then it’s some scandal? Just being honest, but — to me, that says a lot about where we are as a league, and even as a society.”
There’s little doubt Durant’s quest for his own basketball nirvana played some role, however indirectly or minuscule, in Irving’s own recognition that there is more to basketball than playing second fiddle on a successful team. Irving’s trade request begot the Isaiah Thomas deal, and the business of basketball came full circle, so seize what you can while you can, because it can all be gone tomorrow.
Just don’t throw your old coworkers under the bus on Twitter when you’re done. If you do, well, take a cue from Durant, who realized his struggles with self-confidence can lead him to some pretty dark places, but overcoming them has taken him to some pretty cool spots, too. And maybe that’s what I’m on about here: This is a new NBA generation, one in touch with their psyche, and we can learn from it. |
Q:
how compile SynEdit in Delphi 7?
I tried to load and use 'SynEdit_D7.dpk' and 'SynEdit_R7.dpk' in Delphi 7 to install but following error raised:
[Fatal Error] SynEditHighlighter.pas(57): File not found: 'SynEditHighlighterOptions.dcu'
I did:
downloaded SynEdit-2_0_8.zip
Extracted somewhere and opened Delphi 7.
Loaded SynEdit_D7.dpk.
Clicked on install.
Received error.
A:
I should add source files path to Delphi library path (Tools | Environment options) and then build without problems!
I built SynEdit_D7.dpk without SynEdit_R7.dpk.
Problem Solved.
I don't have sufficient points to add image! added link.
|
Sumo wrestlers vs crying babies
Updated: Apr 29, 2013 18:04 IST
1/11
A baby held by a student sumo wrestler cries during the "Baby-cry Sumo" competition at Sensoji temple in Tokyo. Japanese parents believe that sumo wrestlers can help make babies cry out a wish to grow up with good health. (AFP) |
Disk drives are well known in the computer art for providing secondary mass storage with random access. A disk drive comprises one or more magnetic data storage disks rotated on a spindle by a spindle motor within an enclosed housing. A magnetic transducer head is placed on an actuator arm and positioned very closely to a corresponding disk surface by a slider suspended upon an air bearing. Servo information is typically written in servo sectors which are interleaved between data sectors or blocks. Servo information provides a servo controller with head position information to enable a head positioner, such as a rotary voice coil motor (VCM), to move the actuator arm and therefore the head from track-to-track during random access track seeking operations, and to maintain the head in proper alignment with a track centerline during track following operations when user data is written to or read from the available data sectors of the disk surface. As such, the servo controller controls head positioning as the head is moved transversely across the tracks by the actuator arm, and maintains the head over a particular track as the disk spins. The servo controller also controls the acceleration of the head which results from a force supplied by the VCM to the actuator arm.
The servo controller receives head position readings from the head. The head position is determined from the servo information written directly onto the disk by e.g. a servo writer as part of the manufacturing process. The servo information may include the track number and indicate how far the head is from the track centerline. That is, certain information on each track is reserved for indicating head position. As the head passes over the servo information, the track identification and position indicators are read by the head and supplied to the servo controller. The position indicators are at regularly spaced locations. Thus, the servo controller input from the head is not continuous but is sampled.
The servo writer is typically stabilized on a large granite base to minimize unwanted vibration and employs an encoder (e.g. laser interferometry) for position measurements. The servo writer supplies power to the spindle motor for rotating the disk. The servo writer may include a fixed head for writing a clock track onto one disk surface. The servo writer may also include a positioning system for moving a push-pin which extends through an opening in the disk drive housing and mechanically contacts the actuator arm. The positioning system uses the push-pin to move the actuator arm and the head radially across the disk, and the head writes the track address and the servo information at several specified locations called servo wedges that extend radially across the tracks. The servo wedges provide servo sectors for each track on the disk.
The servo writer attempts to write the servo information in circular tracks that are evenly spaced across the disk surface. However, because of mechanical and electrical limitations, it not possible to obtain even track spacing. This track mispositioning is referred to as “squeeze” which limits the off-track read capability (OTRC) of the disk drive and can cause encroachment (overwrite) leading to data loss. Existing methods of correcting squeeze and encroachment are not effective when two adjacent tracks are radially positioned too close to or too far from one another.
This problem is increasingly significant as track densities (measured in tracks-per-inch (TPI)) are increased. Increased TPI makes track spacing errors and the resulting squeeze more significant to data integrity. Existing methods of detecting squeeze include detecting data corruption due to encroachment. For example, during disk drive manufacturing, a flaw scan test identifies the disk locations which do not provide reliable read and write operations. These disk locations are logged within the disk drive and mapped out of the available customer data area. However, such techniques are time consuming and expensive.
There is, therefore, a need to efficiently detect squeeze during disk drive manufacturing. There is also a need for correcting squeeze in order to prevent encroachment and degradation in the OTRC of the disk drive. |
[DO NOT PUBLISH]
IN THE UNITED STATES COURT OF APPEALS
FOR THE ELEVENTH CIRCUIT
________________________ FILED
U.S. COURT OF APPEALS
No. 10-10313 ELEVENTH CIRCUIT
Non-Argument Calendar OCTOBER 29, 2010
________________________ JOHN LEY
CLERK
D.C. Docket No. 1:08-cr-00419-CAP-AJB-1
UNITED STATES OF AMERICA
lllllllllllllllllllllPlaintiff-Appellee,
versus
ADOLPHUS DIXON,
lllllllllllllllllllllDefendant-Appellant.
________________________
Appeal from the United States District Court
for the Northern District of Georgia
________________________
(October 29, 2010)
Before CARNES, MARCUS and PRYOR, Circuit Judges.
PER CURIAM:
Adolphus Dixon appeals his convictions for five counts of armed
commercial robbery, 18 U.S.C. § 1951, five counts of using a firearm during a
crime of violence, id. § 924(c), and one count of attempted bank robbery, id.
§ 2113(a), and appeals his ten sentences of imprisonment for life and a sentence of
240 months of imprisonment, all of which are to be served concurrently. Dixon
raises four issues on appeal: (1) that the district court erred in overruling his
objection that the government used its peremptory challenges in a gender-
discriminatory manner; (2) that the district court erred by denying his motion for a
mistrial after a witness testified that Dixon’s fingerprint records were in the
database of the Federal Bureau of Investigation; (3) that the district court erred in
denying his motion in limine to exclude any in-court identifications made by
government witnesses who had not made prior out-of-court identifications of him;
and (4) that the district court erred in enhancing his sentences, id. § 3559, after he
exercised his Fifth Amendment right against self-incrimination. Dixon’s
arguments fail. We affirm for the following reasons.
We first consider Dixon’s argument about the peremptory challenges of
women by the government. The Supreme Court has established a threshold
inquiry for determining whether a prosecutor’s peremptory challenges violated the
Equal Protection Clause. See Batson v. Kentucky, 476 U.S. 79, 93–94, 106 S. Ct.
1712, 1721 (1986); J.E.B. v. Alabama ex rel. T.B., 511 U.S. 127, 144–45, 114 S.
2
Ct. 1419, 1429–30 (1994) (extending Batson to gender-based claims). “First, the
district court must determine whether the party challenging the peremptory strikes
has established a prima facie case of discrimination by ‘establishing facts
sufficient to support an inference of [gender] discrimination.’” United States v.
Ochoa-Vasquez, 428 F.3d 1015, 1038 (11th Cir. 2005) (quoting Cent. Ala. Fair
Hous. Ctr. v. Lowder Realty Co., 236 F.3d 629, 636 (11th Cir. 2000)). “‘[T]he
establishment of a prima facie case is an absolute precondition to further inquiry
into the motivation behind the challenged strike.’” Id. (quoting Lowder, 236 F.3d
at 636). In determining whether a prima facie case of discrimination has been
established, a court must consider “whether the totality of the circumstances shows
a ‘pattern’ that creates an inference of discrimination.” Id. at 1044. In doing so,
the court may consider a variety of factors, including (1) “whether members of the
relevant [gender] group served unchallenged on the jury”; (2) “whether there is a
substantial disparity between the percentage of jurors of a particular [gender]
struck and the percentage of their representation on the venire”; and (3) “whether
there is a substantial disparity between the percentage of jurors of one [gender]
struck and the percentage of their representation on the jury.” Id. at 1044–45
(internal quotation marks omitted). We give great deference to the determination
3
of the district court about whether a prima facie case of discrimination has been
established. Id. at 1039.
In the light of the lack of disparity between the percentage of women struck
by the government and the make-up of both the venire and the jury, the district
court did not clearly err in finding that there was no inference of discrimination on
the basis of gender. The government used 67 percent of its peremptory challenges
against women, but that percentage was consistent with both the percentage of
women on the venire, which was 17 of 28 or 61 percent, and the percentage of
women who served on the jury, which was 8 of 12 or 67 percent. The district
court was entitled to find that Dixon failed to prove a pattern of discrimination.
We affirm that decision.
We next consider Dixon’s argument about the denial of his motion for a
mistrial. Because the “district court is in ‘the best position to evaluate the
prejudicial effect of a statement or evidence on the jury,’” we review the denial of
a motion for a mistrial for abuse of discretion. United States v. Emmanuel, 565
F.3d 1324, 1334 (11th Cir.) (quoting United States v. Newsome, 475 F.3d 1221,
1227 (11th Cir. 2007)), cert. denied, 130 S. Ct. 1032 (2009). Dixon “must show
that his ‘substantial rights [were] prejudicially affected,’ [such that] there is a
reasonable probability that, but for the remarks, the outcome of the trial would
4
have been different.’” Id. (quoting Newsome, 475 F.3d at 1227). “The mere
utterance of the word jail, prison, or arrest does not, without regard to context or
circumstances, constitute reversible error per se.” Id. Particularly “where the
comment is brief, unelicited, and unresponsive, adding nothing to the
government’s case, the denial of a mistrial is proper.” Id.
Dixon’s argument that he was entitled to a mistrial following a witness’s
testimony that “[t]he FBI fingerprint database produced [a] fingerprint record” for
Dixon fails. That testimony did not necessarily suggest that Dixon had a prior
criminal record, and the testimony was a “brief, unelicited, and unresponsive”
answer that did not otherwise support the prosecution. In the light of the
overwhelming evidence of Dixon’s guilt, and the insignificance of the witness’s
remark, we conclude that the district court did not abuse its discretion when it
denied Dixon’s motion for a mistrial.
We next consider Dixon’s argument about the denial of his motion about in-
court identifications. We review de novo whether an in-court identification
violates a defendant’s Fifth Amendment right to due process. United States v.
Douglas, 489 F.3d 1117, 1126 (11th Cir. 2007). To prevail, a defendant “must
convince us that the identification procedure was ‘so impermissibly suggestive as
to give rise to a very substantial likelihood of misidentification.’” Code v.
5
Montgomery, 725 F.2d 1316, 1319 (11th Cir. 1984) (quoting Neil v. Biggers, 409
U.S. 188, 197, 93 S. Ct. 375, 381 (1972)). Even an identification based on a
suggestive procedure may still be admitted when the identification is otherwise
reliable. Manson v. Brathwaite, 432 U.S. 98, 110–14, 97 S. Ct. 2243, 2251–53
(1977).
In determining the reliability of an in-court identification, we “must
consider the totality of the circumstances, including ‘the opportunity of the
witness to view the criminal at the time of the crime, the witness’ degree of
attention, the accuracy of the witness’ prior description of the criminal, the level of
certainty demonstrated by the witness at the confrontation, and the length of time
between the crime and the confrontation.’” Code, 725 F.2d at 1320 (quoting Neil,
409 U.S. at 199–200, 93 S. Ct. at 382). A defendant’s right to due process is not
violated when a witness who is subject to cross-examination and had a substantial
opportunity to view the offender during the crime makes an in-court identification
without having first identified the defendant in a pretrial lineup. Id. at 1320.
Moreover, an in-court identification is not unduly suggestive or lacking in
reliability merely because the defendant was the only African-American seated at
the defense table. Douglas, 489 F.3d at 1126–27.
6
The district court did not err in admitting the in-court identification of
Dixon by the several witnesses to his robberies. Each witness had a substantial
opportunity to observe Dixon during the robbery that was the subject of his or her
testimony, paid particular attention to Dixon, provided a reasonably accurate
description of him following the crime, and identified him in court without
hesitation. Based on the totality of the circumstances, Dixon failed to establish
that the in-court identifications were unreliable, such that there was a substantial
likelihood of misidentification. We affirm the denial of Dixon’s motion in limine.
Finally, we address Dixon’s argument about the enhancement of his
sentence. 18 U.S.C. § 3559. We review constitutional challenges to a sentence
enhancement de novo, but will reverse only for harmful error. United States v.
Paz, 405 F.3d 946, 948 (11th Cir. 2005). Under section 3559(c)(4), the
government filed a criminal information about Dixon’s prior convictions.
Although the district court may inquire “whether [the defendant] affirms or denies
that he has been previously convicted as alleged in the information,” 21 U.S.C.
§ 851(b), the district court is not required to do so “‘where a defendant, as a matter
of law, is precluded from attacking the conviction forming the basis of the
enhancement information.’” United States v. Weaver, 905 F.2d 1466, 1482 (11th
Cir. 1990) (quoting United States v. Nanez, 694 F.2d 405, 413 (5th Cir. 1982)). A
7
defendant is barred from challenging the validity of his prior convictions, when
the convictions are more than five years old. 21 U.S.C. § 851(e).
We affirm the enhancement of Dixon’s sentence. Because his prior felonies
were more than five years old, Dixon is barred from successfully challenging any
error the district court might have made in inquiring whether Dixon affirmed or
denied his convictions. Furthermore, there was sufficient evidence to establish
that Dixon had been convicted of the prior felonies that served as the basis for the
sentence enhancement.
Dixon’s convictions and sentences are
AFFIRMED.
8
|
Plain of the Cul-de-Sac
Plain of the Cul-de-Sac (, also known as the Cul-de-Sac Plain, or the Cul-de-Sac Depression) is a fertile lowland on the island of Hispaniola. It extends from southeastern Haiti into the southwestern Dominican Republic, where it is known as the Hoya de Enriquillo.
Geography
Covering an area of 28 000 km² around with a length of 32 km long and 25 km wide, the Plain of the Cul-de-Sac is bounded to the north and south by high mountains and to the west by the Gulf of Gonâve on edges of which is the Haitian capital of Port-au-Prince and to the Plaine de l'Arcahaie that extends to the west. The Plain of the Cul-de-Sac extends eastward into the Dominican Republic.
This valley was once an arm of the sea and upon withdrawal of the latter during the uprising Oligocene Miocene, salt water was trapped in the lowest points of depression resulting in two grand lakes; the Etang Saumâtre (also called "Lake Azuéi") in Haiti and Lake Enriquillo in the Dominican Republic and a small freshwater pond called Trou Caïman, also in Haiti.
The plain has always been a farming region. In the colonial era, indigo was cultivated there. Over the decades, this production lost its momentum, giving way to fields of sugar cane. The Rivière Blanche (Ouest), through its irrigation system and channeling of part of its journey to the Canal Boucanbrou, trickles down this vast plain. In its southern part, the Plain of Cul-de-Sac is crossed by the Rivière Grise.
References
External links
Plaine du Cul-de-Sac coordinates
Category:Landforms of Haiti
Category:Landforms of the Dominican Republic
Category:Plains of North America |
"Not only does this move help thousands of people in New Jersey get the health care they need, but it sends a clear signal that the eight years of harming women’s health we saw under Chris Christie are over."
On Tuesday, New Jersey Gov. Phil Murphy announced several new cabinet appointment nominations, the majority of whom are female, a first in state history, he says.
Eduardo Munoz Alvarez/Getty Images
New Jersey Gov. Phil Murphy (D) on Wednesday will sign a bill to restore Planned Parenthood funding lost under former Gov. Chris Christie (R).
“When the Christie administration defunded Planned Parenthood and women’s health clinics, tens of thousands of women throughout New Jersey lost access to quality, affordable primary care. It’s time to right that wrong,” Murphy wrote in a social media post. Planned Parenthood’s outgoing president, Cecile Richards, is expected to join the governor when he signs the pro-choice bill Wednesday morning.
Christie’s vetoes over seven years added up to more than $50 million in lost investments in women’s health. It led six of 58 clinics statewide to close and 14 others to scale back hours. It led to soaring rates of sexually transmitted disease.
Murphy’s signature this week will restore $7.45 million to women’s health care centers, and a separate bill, still pending in the state assembly but passed in the state senate, would expand eligibility for people to get family planning services under Medicaid. The money would help thousands of New Jersey residents access birth control, cancer screenings, and sexually transmitted infections testing and treatment.
Sex. Abortion. Parenthood. Power. The latest news, delivered straight to your inbox. SUBSCRIBE
“New Jersey shows what’s possible when we unite and work to pass policies that protect people’s rights and access to health care. We need to build on this momentum and fight forward state by state and bill by bill,” Dawn Laguens, executive vice president of Planned Parenthood Federation of America, told Rewire. “In this moment of tremendous grassroots energy and activism, it’s not enough to fight against bad policies. We need to push for good ones that benefit people.”
This will be one of the first state-level proactive reproductive rights bills signed into law in 2018 and will hopefully be “a harbinger for a new day for women’s health around the nation,” Kelly Baden, director of Reproductive Rights at State Innovation Exchange, told Rewire.
“The restoration of family planning funding in New Jersey is a clear sign that it is a new day for reproductive health in the Garden State. Not only does this move help thousands of people in New Jersey get the health care they need, but it sends a clear signal that the eight years of harming women’s health we saw under Chris Christie are over,” she said.
Murphy has promoted a progressive agenda after eight years of his predecessor’s regressive policies. Murphy’s other health-care priorities include lowering insurance premiums, expanding addiction treatment access, and providing health insurance for the state’s 75,000 uninsured children.
He has already acted on some of his campaign promises.
In his first week, Murphy signed an executive order promoting equal pay and has since outlined an ethics order, an order to improve Affordable Care Act enrollment, supported labor union rights, and joined a federal lawsuit to protect Deferred Action for Childhood Arrivals recipients.
On Tuesday, he announced several new cabinet appointment nominations, the majority of whom are female, a first in state history, he says.
The restoration of Planned Parenthood funding was passed in the majority-Democratic New Jersey General Assembly last Thursday, according to news reports. The legislation was sponsored by Senate Majority Leader Loretta Weinberg (D-Bergen) and Senate President Steve Sweeney (D-Gloucester), along with state Sen. Christopher “Kip” Bateman (R-Somerset).
Democrats had previously tried to restore the money but Christie repeatedly vetoed their efforts. |
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Any necessary follow-up medical treatment is going to be offered for residents and their families free below the medical care card scheme. Another major component in finding approval is in order to apply to a marijuana-friendly life insurance policy company. Therefore you must be quite serious in locating all essential details it would never make you truly feel disappointed in any respect.
Marijuana Medical Card – Overview
The procedure is extremely straightforward, simply asking you some questions and checking your eligibility. To hold a second-class airman medical certificate, an individual has to be in generally good health and have zero condition that limits their capacity to safely carry out the duties of the certificate. The number india viagra. of paperwork generated in the medical field can appear massive.
Obtaining Californian cannabis tags are often quite complex, taking into consideration the stress levels of the entire approach. Employing REMPEN can spare you money at the end because you’re getting more effects from some relatively little amounts of the medical marijuana. Patients have to be at least 21 decades old. |
WOOOOHOOOOOO justice prevails , along with common sense 18 months of suffering for Brett and all his family , im sure we all have so much hatred for the girl and her family involved but i dont care anymore i cant wait to see Brett smiling again. it brought a tear to my eye reading those words
Thanks for the updates throughout the trial DSM5 and for getting the verdict on here so quickly!
Must be a HUGE relief to the Stewart family and now they can get on with their lives.
Mr Gallop has a LOT to answer regarding playing judge, jury and chief executioner to Brett! His silence has been deafening throughout the trial and he owes many people a lot of apologies. His actions have shown him up to be the News Ltd stooge that he really is and an A1 arse clown to boot....
Bring on 2011!
Awesome NEWS!!!! Well done To the Manly Club for always sticking by him. I wonder if any other Coach/Club would have visited the guy at the cop shop when he was being charged/interviewd.
So happy for Brett and his family and friends who can move on from this and concentrate back on living. Hope they can put it all behind them and move forward with the their lived.
Joe Kramer link said:
Mike Gibson from foxtels the back page who slammed the guy.
Click to expand...
Mike Gibson is a D-Head, he went from Praising the manly players attitudes and demeanor when he saw them at a pub to absolutely lynching the guy before ANY F A C T S had come out. I stopped watching the Back Page after that.
[/quote]
Mike Gibson is a D-Head, he went from Praising the manly players attitudes and demeanor when he saw them at a pub to absolutely lynching the guy before ANY F A C T S had come out. I stopped watching the Back Page after that.
[/quote] He is a bitter Bears fan and the sooner he is given the ass like his club was the better the world will be |
Expression cloning of a rat testicular transcript abundant in germ cells, which contains two leucine zipper motifs.
The aim of the present study was to identify specific, novel germ cell markers that could be used to monitor normal and abnormal spermatogenesis. Of several cloned cDNAs isolated from an adult rat testis cDNA library using an expression screening strategy, clone 813B4 (700 base pairs) hybridized exclusively to three mRNA transcripts in samples isolated from rat testes on and after Day 21 of life and to epididymides from some, but not all, adult rats. After further screening, two identical clones encoding a 2.2-kilobase cDNA (KTT4) were isolated and found to contain an open reading frame of 578 amino acids including two leucine zipper motifs. On Northern blots, KTT4 mRNA was abundant in samples from round spermatids, and homologous mRNAs were present in testes from mice and marmosets. A zoo blot revealed that the KTT4 gene is conserved in humans, monkeys, mice, dogs, and cattle. On sections of rat testes, KTT4 mRNA was first detectable in pachytene spermatocytes at stage VII and thereafter was abundant in round and elongating spermatids until step 15. Expression of KTT4 was not altered by ethane dimethane sulphonate-induced androgen withdrawal, but in rats treated 14 days previously with methoxyacetic acid, a marked reduction in KTT4 was noted associated with the depletion of round spermatids. In conclusion, the present study identified a conserved gene expressed in meiotic and post-meiotic germ cells; database searches have shown it to be homologous to recently published sequences for an outer dense fiber protein of the sperm tail (Odf2/Odf84). |
---
abstract: 'We propose a method for achieving dynamically controllable transport of highly mobile matter-wave solitons in a driven two-dimensional optical lattice. Our numerical analysis based on the mean-field model and the theory based on the time-averaging approach, demonstrate that a fast time-periodic rocking of the two-dimensional optical lattice enables efficient stabilization and manipulation of spatially localized matter wavepackets via induced reconfigurable mobility channels.'
author:
- Jasur Abdullaev
- Dario Poletti
- 'Elena A. Ostrovskaya'
- 'Yuri S. Kivshar'
title: 'Controlled transport of matter waves in two-dimensional optical lattices'
---
Controlled manipulation of stable, spatially localized matter waves, similar to routing of optical pulses in photonic devices, is a very attractive goal from the viewpoint of emerging integrated technologies based on the use of ultracold atomic gases - Bose-Einstein condensates [@chip]. In recent years optical lattices have been suggested as an instrument for such a control. Long-distance transport of ultracold atoms in a one-dimensional Bessel optical lattice potential was demonstrated experimentally [@transport_1d]. Theoretical studies of matter-wave solitons, loaded into a rapidly driven asymmetric one-dimensional optical lattice, have demonstrated that such an “optical ratchet” could enable their mass-dependent transport [@dario]. Transport of matter waves in a two- or three-dimensional trapping geometry is a more complex and challenging task, especially considering the intrinsic instability of the self-localizing condensate with the negative scattering length.
Nonlinearly localized atomic wavepackets - matter-wave solitons, created in a two- or three-dimensional trapping geometry, are predicted to be stabilized by static optical lattices [@2d_3d_ol]. Other methods of stabilization rely on the time-periodic management of the condensate properties or non-local interaction between atoms [@santos]. Stability of the matter waves in two-dimensional optical lattices and under different conditions of the time-periodic management (see, e.g., [@burlak]) has been extensively studied. The main challenge still remains: To suggest an efficient method for non-destructive, dynamically controlled transport of the stabilized atomic wavepackets.
The problem of transport of localized nonlinear excitations is acutely posed in several cross-disciplinary areas of physics (see, e.g., Ref. [@malomed_book] and references therein) because periodic systems, in general, greatly inhibit the mobility of the localized states. In particular, mobility of discrete solitons is an important problem in nonlinear photonics and lattice dynamics [@ref1; @ref2]. In periodic structures and waveguide arrays, the motion of spatially localized optical beams is affected substantially by the lattice periodicity, so that the effective Peierls-Nabarro potential [@ref2] induced by the lattice prevents their free motion. It was shown that moving solitary waves in discrete lattices require special type of saturable nonlinearity [@ref3], and can move only at some limited velocities [@ref4]. Mobility of discrete optical solitons in two-dimensional photonic lattices was also found for the case of quadratic nonlinear response that leads to parametric coupling of the fundamental and second-harmonic fields and results in their mobility after an initial kick [@ref5].
In this Letter we propose and analyze the mechanism for controlled transport of two-dimensional matter-wave solitons, created in a Bose-Einstein condensate of atoms with a negative scattering length. The transport is realized by means of a rocking two-dimensional optical lattice [@rocking], where the term “rocking” refers to time-periodic shaking of the lattice [@rocking_theory]. Our analysis, based on the mean-field model, demonstrates that the fast rocking of the lattice enables dynamical creation of reconfigurable mobility channels for matter waves. Similar channels were previously studied in the context of lattices that do not coincide in dimensionality with the wavepacket and guide a matter wave along the fixed free spatial direction [@malomed]. Here we show that the rocking optical lattices enable both the efficient stabilization and dynamical “routing" of nonlinearly localized matter wavepackets.
To describe the dynamics of solitons in a Bose-Einstein condensate loaded into a two-dimensional lattice, we consider a mean-field model of an ultracold atomic cloud in a pancake trapping geometry with an optical lattice potential aligned with the weak trapping directions. As long as the transverse collective modes of the condensate in the direction perpendicular to the optical lattice are not excited, the system can be treated as two-dimensional and described by the Gross-Pitaevskii equation: $$\label{GP2D}
i\frac {\partial \psi} {\partial t}+\nabla^2_\perp
\psi+|\psi|^2\psi+ V_{\rm OL}({\bf r},t)\psi=0,$$ where $\nabla^2_\perp\equiv \partial^2/\partial {\bf r}^2$, and ${\bf r}=(x,y)$. This model is derived by assuming the units of energy, length, and frequency: $E_L=\hbar^2k^2_L/(2m)$, $a_L=1/k_L$, and $\omega_L=E_L/\hbar$, respectively, where $m$ is the atomic mass, and $k_L$ is the wavevector of the optical lattice. The three-dimensional mean-field model is reduced to the two-dimensional equation by assuming that the wavefunction is separable: $\psi_{3D}({\bf r},z)=\psi_{2D}({\bf r})\phi_{1D}(z)$, where $\phi_{1D}(z)$ is the normalized ground state wavefunction of a one-dimensional harmonic potential with the trapping frequency $\omega_z$. With these assumptions, the wavefunction $\psi$ in Eq. (\[GP2D\]) relates to $\psi_{2D}$ as follows: $\psi=\psi_{2D}\sqrt{g_{2D}}$, where $g_{2D}=4\sqrt{\pi}(a_s/a_0)(\omega_z/\omega_L)^{1/2}$ is the renormalized coefficient that characterizes interaction of the condensate atoms with the s-wave scattering length $a_s$. The number of atoms is given by: ${\cal N}=N/g_{2D}$, where $N=\int
|\Psi|^2 dx$ is the norm of the dimensionless wavefunction.
For the $^7Li$ atoms with $a_s=-0.21$ nm, trapped using a CO$_2$ laser with $\lambda=10.62$ $\mu$m [@BEC_soliton], the physical values of the characteristic scales are: $a_0=845$ nm, $\omega_0=2\pi \times 2039$ Hz. Consequently, the rescaled interaction coefficient is $g_{2D}=1.03\times 10^{-3}$, and the typical soliton has the norm $N\approx 10$, which corresponds ${\cal N}\sim 10^4$.
![(Color online) Norm of the wavefunction corresponding to a stationary soliton state in a rocking lattice potential $V_{\rm OL}({\bf r},t)$ at $t=0$ (curve $a-b$) and in a time-averaged potential $V_s({\bf R_s})$ (curve $c-d$) with $Y_0=0$, $X_0=2.4$ . (a-d) Spatial density structure of the matter-wave solitons at the marked points on the top panel.[]{data-label="fig:families"}](allsolitons_v2.eps){width="7.5cm"}
The optical lattice potential in Eq. (\[GP2D\]) is created by two pairs of counter-propagating laser beams and has the following form: $$\label{pot}
V_{\rm OL}({\bf r},t)=V_{x}\cos[x+X(t)]+V_y\cos[y+Y(t)].$$ It is driven periodically, i.e. the phase detuning between the laser beams forming the lattice is modulated as: $X(t)=X_0\sin(\omega t)$, and $Y(t)=Y_0\sin(\omega t)$. By using Fourier decomposition, one can see that the optical lattice has both a static “backbone" and a time-dependent component. This distinguishes transport in the potential (\[pot\]) from the ratchet-type transport of matter-wave solitons [@dario]: Here the time-average force acting upon a wave-packet at any given point in space is non-zero.
![(Color online) Dynamics of a moving soliton in the rocking lattice obtained by solving Eq. (\[GP2D\]) numerically with periodic boundary conditions. Initial states are: (a) a stationary soliton of the potential $V_{\rm OL}({\bf r},0)$ at $\mu=-0.7$ \[Fig. \[fig:families\] (b)\] and (b) a stationary soliton of the time-averaged potential $V_s({\bf R_s})$ at $Y_0=0$, $X_0=2.4$, $\mu=-0.7$ \[Fig. \[fig:families\](d)\]. []{data-label="fig:dynamics"}](compmotion.eps){width="\columnwidth"}
At $\omega=0$ (or $t=0$), the static optical lattice $V_{\rm OL}({\bf r},0)$ supports stationary matter-wave solitons [@2D_soliton] in the form: $\psi({\bf r},t)=\Psi({\bf r})\exp(-\mu t)$ at the values of chemical potential, $\mu$, below the lower edge of the first spectral band (see Fig. \[fig:families\]). These are found numerically by solving the stationary version of the model Eq. (\[GP2D\]) [@yang]. According to the Vakhitov-Kolokolov stability criterion, such localized states are dynamically stable away from the band edge, where $d\mu/dN<0$ [@2d_3d_ol]. The mobility of the solitons is suppressed due to the energy difference between the nonlinear localized states with the same $N$ but different symmetry, that needs to be overcome in order to move the initially stationary state across the lattice. This is analogous to the Piers-Nabarro potential in discrete systems [@ref2]. On the other hand, it is the coupling to the lattice that both stabilizes the solitons against the collapse and allows us to manipulate the localized states by changing parameters of the lattice. The typical norm of a two-dimensional soliton considered in our dynamical simulations below is near the collapse threshold for a free soliton, which for our normalization is: $N^*=11.7$ [@burlak].
To find the regime of enhanced mobility in the lattice we assume that a mobile soliton does not significantly change its shape and can be described solely by the dynamics of the center of mass, ${\bf r_0(t)}=(x_0(t),y_0(t))$. This assumption is valid provided that the driving frequency, $\omega$, is much greater than the eigenfrequency of soliton width oscillations ($\omega_0\sim 1$ in our system). Following the treatment in [@dario2], the Hamiltonian theory that treats the soliton as a classical particle in an effective potential [@soliton_particle] can then be invoked to derive the equations of motion for the center of mass. The matter-wave soliton loaded into the lattice is approximated by the Gaussian function: $$\Psi_0({\bf r}(t),{\bf r_0}(t))=A\exp\left[-\frac{(x-x_0)^2+(y-y_0)^2}{2a^2}\right].$$ The variational theory (see, e.g., [@burlak]) shows that this approximation is in good agreement with the exact stationary solutions for values of $\mu$ far from the band edge, where the soliton is well localized. In this case the soliton’s amplitude and width are related as follows: $N=\pi A^2 a^2$, and $N=2\pi[2-V_0a^4\exp(-a^2/4)]$. The effective potential for the soliton-as-particle motion is then found as follows: $$V_{\rm eff}({\bf r_0},t)=\frac{1}{N}\int^\infty_{-\infty}|\Psi_0({\bf r},{\bf r_0})|^2V_{\rm OL}({\bf r},t)d{\bf r},$$ where $d{\bf r}\equiv dxdy$, and the equations of motion for the center of mass, $d^2{\bf r_0}/dt^2=-dV_{\rm eff}({\bf r_0})/d{\bf r_0}$, read: $$\frac{d^2x_0}{dt^2}=V_xe^{-\frac{a^2}{4}}\sin(x_0-X), \,
\frac{d^2y_0}{dt^2}=V_ye^{-\frac{a^2}{4}}\sin(y_0-Y).$$ The motion of the soliton’s center of mass can be separated into the slow and fast components: $x_0(t)=X_s(t)+\xi(t)$, $y_0(t)=Y_s(t)+\eta(t)$, where the typical evolution of the slow variables ${\bf R_s}=(X_s,Y_s)$ occurs on the time scale $\tau\gg \omega^{-1}$. The time averaging procedure [@dario2; @landafshitz] is then applied to derive equations of motion for the slow (compared to $\omega$) dynamics of a soliton center of mass in a driven lattice: $d^2{\bf R_s}/dt^2=-dV_{\rm s}({\bf R_s})/d{\bf R_s}$. The time-averaged effective potential is separable: $$V_s({\bf R_{s}})=A_{sx}\cos(2X_s)+A_{sy}\cos(2Y_s),
\label{veff}$$ with the strength explicitly depending on the driving frequency, $\omega$, and on the characteristic width of the soliton loaded into the lattice, $a$: $$\begin{aligned}
A_{sx} &=& {\displaystyle \frac{V_x^2}{8\omega^2}e^{-\frac{a^2}{2}}\left\{4\left[J_1(X_0)\right]^2- \left[J_2(X_0)\right]^2\right\},} \nonumber \\
A_{sy} &=& {\displaystyle \frac{V_y^2}{8\omega^2}e^{-\frac{a^2}{2}}\left\{4\left[J_1(Y_0)\right]^2- \left[J_2(Y_0)\right]^2\right\},} \nonumber\end{aligned}$$ where $J_n$ are Bessel functions of the first kind. We stress that the time-averaged potential is conservative even in the presence of driving at certain values of $(X_0,Y_0)$, namely such that $J_0(X_0)=0$ or $J_0(Y_0)=0$.
The time-averaged conservative potential, $V_s$, supports stationary matter-wave soliton solutions depicted by the family (c-d) in Fig. \[fig:families\]. These solitons may be dynamically stable in the entire existence region of the solitons supported by the static lattice potential $V_{\rm OL}({\bf r},0)$ [@2D_soliton] due to the fact that the band edge in $V_s$ is shifted to lower values of the chemical potential, $\mu$ (dashed line Fig. \[fig:families\]). This indicates that the driving may stabilize a moving solitons below the collapse threshold, as predicted in [@burlak] for amplitude-modulated optical lattices. In addition, for the same values of $\mu$, the mobility of the solitons supported by $V_s$ is expected to be enhanced compared to those in the static lattice $V_{\rm OL}({\bf r},0)$ due to the selectively suppressed spatial modulation.
In order to confirm the predictions of improved mobility of the localized states in the driven lattice, we compare the dynamics of two initially stationary states corresponding to $\mu=-0.7$ and supported by $V_{\rm OL}({\bf r},0)$ and $V_s$ potentials (see Fig. \[fig:dynamics\]). At the time $t=0$ both the initial states are given exactly the same initial velocity in the $x$-direction. Nevertheless, the soliton, supported by the static optical lattice $V_{\rm OL}({\bf r},0)$ (point $b$ in Fig. \[fig:families\]) decays almost instantly, whereas the soliton supported by the $V_s$ in the driven lattice (point $d$ in Fig. \[fig:families\]) moves and retains its shape \[Fig. \[fig:dynamics\] (b)\].
![(Color online) Dynamical control of the optical lattice parameters enabling creation and switching of the soliton mobility channels in the time-average potential. Left column: Rocking optical lattice potential, $V_{\rm OL}({\bf r},t)$ at the instances of time $t_1$ and $t_2$; the lines marking $x=0$ and $y=0$ are a guide to the eye. Middle column: Time dependence of the rocking amplitudes. Right column: Time-averaged lattice potential, $V_s({\bf R_s})$, corresponding to $Y_0=0$, $A_{sy}=0.5$, $A_{sx}=0.002$ (at $t_1$) and $X_0=0$, $A_{sx}=0.002$, $A_{sy}=0.5$ (at $t_2$).[]{data-label="fig:switching"}](Fig1_ol.eps){width="\columnwidth"}
![(Color online) (a,b) Center of mass trajectory of a moving soliton corresponding to $\mu=-2.0$ in a rocking lattice potential $V_{\rm OL}({\bf r},t)$, superimposed onto the contour plot of the potential at $t=0$, and, in (c), onto the density profile of the moving soliton. Sharp turning points correspond to the switching of the mobility channels as shown in Fig. \[fig:switching\]. (d) The profiles of the moving soliton corresponding to the points $1$ (solid), $2$ (dashed), and $3$ (dash-dotted) in (c). []{data-label="fig:trajectories"}](trajectories_sm.eps){width="\columnwidth"}
Next, we explain the basic principles of dynamical transport control of the mobile solitons in the driven lattice. While the lattice potential, $V_{\rm OL}({\bf r},t)$ is not static, and the positions of its maxima and minima are different at various times (see Fig. \[fig:switching\], left column), its action on the soliton center of mass during the periods of time $\tau \gg \omega^{-1}$ can be described by the conservative potential $V_s$. By examining the form of the time-averaged potential (\[veff\]), one can see that the amplitude of the spatial modulation can be effectively suppressed in one of the orthogonal directions by controlling the amplitude of the periodic driving. The most dramatic example of such suppression is presented in Fig. \[fig:switching\]. During the periods of time when the amplitudes of driving $X_0$ and $Y_0$ are kept constant (segments marked by the points $t_1$ and $t_2$ in Fig. \[fig:switching\], middle column), one of the amplitudes, $X_0$ or $Y_0$, is set to a value such that the time-averaged potential has a form of a two-dimensional lattice with the spatial modulation amplitude $A_{sx}$ or $A_{sy}$ radically suppressed, but not equal to zero (see Fig. \[fig:switching\], right column). Thus the mobility channels for a localized state are effectively created in the two-dimensional lattice along one of the orthogonal directions. This effective lattice is fully reconfigurable in real time, since direction of the mobility channels can be switched as shown in Fig. \[fig:switching\]. During the switching time, which is short compared to $\omega^{-1}$, the concept of time-averaged potential is not applicable.
To demonstrate the transport of a matter-wave soliton in the dynamically reconfigurable driven lattice, we prepare the initial state in the form of the exact stationary soliton supported by the potential $V_s$ \[point (c) in Fig. \[fig:families\]\]. We then load it into the lattice (\[pot\]) driven with the frequency $\omega=10$ and the amplitudes $X_0=2.4$, $Y_0=0$, and let it evolve. At the time $t\approx 60$ the driving amplitudes are rapidly switched to the values $X_0=0$, $Y_0=2.4$, as shown in Fig. \[fig:switching\] (middle panel). The resulting trajectory of the soliton’s center of mass is shown in Fig. \[fig:trajectories\](a) against the contours of the potential $V_{\rm OL}$ at $t=0$. The trajectory is easily reconfigurable by changing the sequence of switching \[see Fig. \[fig:trajectories\](b)\]. A more complex routing of the soliton along orthogonal directions in the lattice can also be realized, as shown in Fig. \[fig:trajectories\](c). In agreement with our initial assumption, the center-of-mass trajectory consists of slow (compared to $\omega$) motion perturbed by small amplitude fast oscillations. By examining the cross-sections of the soliton profile, we also observe that the localized state is only weakly affected by these dynamical manipulations \[see Fig.\[fig:trajectories\](d)\], which justifies our soliton-as-particle approach.
In conclusion, we have demonstrated, both analytically and numerically, that time-modulated optical lattices enable realization of clean, controlled transport of matter waves in more than one spatial dimensions. In doing so, we have used physical parameters relevant to experiments with the ultracold atoms. This work opens up a fascinating possibility to realize transport and routing of matter-wavepackets in lattice potentials of more complex symmetry, as well as in fully three-dimensional trapping geometry. Additional challenge is to achieve the transport of gap solitons supported by a lattice in a condensate with a positive scattering length, that are strongly “pinned” by the lattice and typically immobile. The work along these directions is currently underway.
This work was partially supported by the Australian Research Council (ARC). The authors are grateful to Dr. T. Alexander for stimulating discussions.
[99]{} A.D. Cronin [*et al.*]{}, Rev. Mod. Phys. [**81**]{}, 1051 (2009); M. Nest [*et al.*]{}, arXiv:0912.1454v1 (2009). S. Schmid [*et al.*]{}, New J. Phys. [**8**]{}, 159 (2006). D. Poletti [*et al.*]{}, Phys. Rev. Lett. [**101**]{}, 150403 (2008). B.B. Baizakov [*et al.*]{}, Europhys. Lett. [**63**]{}, 642 (2003). P. Pedri and L. Santos, Phys. Rev. Lett. [**95**]{}, 200404 (2005). G. Burlak and B.A. Malomed, Phys. Rev. A [**77**]{}, 053606 (2008). B. A. Malomed, [*Soliton management in periodic systems*]{} (Springer, New York, 2006). O. M. Braun and Yu. S. Kivshar, [*The Frenkel-Kontorova Model: Concepts, Methods, and Applications*]{} (Springer, Berlin, 2004). Yu.S. Kivshar and G.P. Agrawal, Optical Solitons: From Fibers to Photonic Crystals (Academic, New York, 2003). L. Hadzievski, [*et al.*]{}, Phys. Rev. Lett. [**93**]{}, 033901 (2004). T.R.O. Melvin, [*et al.*]{}, Phys. Rev. Lett. [**97**]{}, 124101 (2006). H. Susanto [*et al.*]{}, Phys. Rev. Lett. [**99**]{}, 214103 (2007). V.V. Ivanov [*et al.*]{}, Phys. Rev. Lett. [**100**]{}, 043602 (2008). Th. Mayteevarunyoo and B. A. Malomed, Phys. Rev. A [**80**]{}, 013827 (2009). B. B. Baizakov [*et al.*]{}, Phys. Rev. A [**70**]{}, 053613 (2004). L. Khaykovich [*et al.*]{}, Science [**296**]{}, 1290 (2002). J. Yang and T.I. Lakoba, Stud. Appl. Math. [**120**]{}, 265 (2008). N. K. Efremidis [*et al.*]{}, Phys. Rev. Lett. [**91**]{}, 213906 (2003). D. Poletti [*et al.*]{}, Physica D, [**238**]{}, 1338 (2009). R. Scharf and A.R. Bishop, Phys. Rev. E [**47**]{}, 1375 (1993). L.D. Landau and E.M. Lifshitz, [*Mechanics*]{} (Pergamon, Oxford, 1960); Yu.S. Kivshar [*et al.*]{} Phys. Rev. E [**49**]{}, 4542 (1994).
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Solyndra, Inc. was supposed to have showcased the effectiveness of the Obama administration’s stimulus and green jobs initiatives, but instead it has become the center of congressional attention for waste, fraud and abuse of such programs.
According to a Feb. 17 letter signed by Energy and Commerce Committee Chairman Fred Upton, Michigan Republican, and Oversight Subcommittee Chairman Cliff Stearns, Florida Republican, to Energy Secretary Steven Chu, the Fremont, Calif.-based solar panel manufacturer should never have received a $535 million loan guarantee from the stimulus.*
The company became the first recipient of an Energy Department loan guarantee under the stimulus in March 2009, which was intended to “finance construction of the first phase of the company’s new manufacturing facility” for photovoltaic solar panels.
The Energy Department estimated in a March 20, 2009 press release that the loan guarantee would create 3,000 construction jobs and a further 1,000 jobs after the plant opened.
And President Barack Obama and Vice President Joseph Biden each personally showcased Solyndra as an example of how stimulus dollars were at work creating jobs, during appearances at the company over the course of the following year.
Biden personally announced the closure of Solyndra’s $535 million loan guarantee in a Sept. 9, 2009 speech, delivered via closed-circuit television, on the occasion of the groundbreaking of the plant.
The vice president justified the federal government’s investment in Solyndra in front of employees and other dignitaries, including Secretary Chu and former Calif. Gov. Arnold Schwartzenegger, saying the jobs the company intended to create would “serve as a foundation for a stronger American economy.”
“These jobs are the jobs that are going to define the 21st century that will allow America to compete and to lead like we did in the 20th century,” Biden said.
According to Biden’s speech, the $535 million loan guarantee was a smaller part of the $30 billion of stimulus money the administration planned to spend as part of its Green Jobs Initiative.
Obama made similar claims in a May 26, 2010 speech at the plant, but the 1,000 jobs he and Biden touted in their respective speeches failed to materialize.
Instead, Solyndra announced on Nov. 3 it planned to postpone expanding the plant, which put the taxpayers on the hook to the tune of $390.5 million taxpayers**, or 73 percent of the total loan guarantee, according to the Wall Street Journal.
It also announced that it no longer planned to hire the 1,000 workers that Obama and Biden had touted in their speeches and that it planned to close one of its older factories and planned to lay-off 135 temporary or contract workers and 40 full-time employees.
A closer look at the company shows it has never turned a profit since it was founded in 2005, according to its Securities and Exchange Commission (SEC) filings.
And Solyndra’s auditor declared that “the company has suffered recurring losses, negative cash flows since inception and has a net stockholders’ deficit that, among other factors, [that] raise substantial doubt about its ability to continue as a growing concern” in a March 2010 amendment to its SEC registration statement.
“While we understand the purpose of the Loan Guarantee Program is to help private companies engaging in clean energy products to obtain financing by providing loan guarantees, subsequent events raise questions about Solyndra was the right candidate to receive a loan guarantee in excess of half a billion dollars,” Upton and Stearns wrote.
A June 2010 Wall Street Journal report indicating that Solyndra’s majority owner, Oklahoma billionaire George Kaiser, was a major fundraiser for the 2008 Obama-Biden campaign has stimulus opponents such as Citizens Against Government Waste crying foul.
“We have said this is pork-barrel spending since the beginning,” Leslie Page, spokeswoman for Citizens Against Government Waste, told The Daily Caller. “And the one thing about pork is its corruptive influences.”
Kaiser flatly denied he had anything to do with the loan guarantee when he was asked by the Journal, but Page nonetheless sees cronyism in the loan guarantee because personal involvement of the president and vice president in the project.
“This seems like a quid pro quo, and it raises a lot of questions,” Page said.
Other stimulus critics say Solyndra shows just how flawed the program has been from the beginning and how it has failed to create jobs and needs further oversight.
“It would have been a lot more effective to put money into the hands of the private sector,” said Alex Cortes, chairman of the Restore the Dream Foundation and DefundIt.org. “This is just another example of the failure of the stimulus.”
Solyndra is just the tip of the iceberg, according to Cortes, who plans to raise awareness of other stimulus pork projects such as an approximately $800,000 television ad campaign in New York aimed at promoting healthy eating habits.
“While that’s all well and good … it doesn’t do anything to create jobs,” Cortes said.
And Mattie Corrao, government affairs manager with Americans for Tax Reform, said the Solyndra loan shows how hollow Obama’s promise to keep close track over how stimulus money has been spent has been.
“[The administration] is trying to pretend we’re creating jobs and hoping the taxpayers are dumb enough and blind enough to believe the lie,” Corrao said. “But after two years of unemployment about 9 percent, people aren’t going to believe it anymore.”
Solyndra did not respond to a request for comments.
*Correction: The sentence originally stated the money was squandered.
**Correction: The article originally stated the postponement cost $390.5 million, instead of put the taxpayers on the hook for $390.5 million. |
/// \file
/// \ingroup tutorial_eve
///
/// \image html eve_hierarchical_scene.png
/// \macro_code
///
/// \author Matevz Tadel
const Int_t Ns = 7;
void add_blobs(TEveElement* p, Float_t rad, Float_t height, Float_t size,
Int_t level)
{
if (level <= 0) return;
for (Int_t i = 0; i < Ns; ++i) {
auto x = new TEveGeoShape("SS");
x->SetShape(new TGeoSphere(0, size));
Double_t phi = TMath::TwoPi() * i / Ns;
x->RefMainTrans().SetPos(rad*TMath::Cos(phi),
rad*TMath::Sin(phi),
height);
x->SetMainColor(TColor::GetColorPalette
(gRandom->Integer(TColor::GetNumberOfColors())));
p->AddElement(x);
add_blobs(x, 0.8 * rad, 0.8 * height, 0.8 * size, level - 1);
}
}
void hierarchical_scene()
{
TEveManager::Create();
TColor::SetPalette(1, 0);
gRandom = new TRandom3(0);
auto s = gEve->SpawnNewScene("Hierarchical Scene", "OoogaDooga");
s->SetHierarchical(kTRUE);
gEve->GetDefaultViewer()->AddScene(s);
add_blobs(s, 6, 4, 0.5, 4);
gEve->Redraw3D(kTRUE);
}
|
/** \file
* \brief Bindig of iupim functions to Lua.
*
* See Copyright Notice in "iup.h"
*/
#ifndef __IUPLUAIM_H
#define __IUPLUAIM_H
#ifdef __cplusplus
extern "C" {
#endif
#ifdef LUA_NOOBJECT /* Lua 3 */
void iupimlua_open(void);
#endif
#ifdef LUA_TNONE /* Lua 5 */
int iupimlua_open(lua_State * L);
#endif
#ifdef __cplusplus
}
#endif
#endif
|
"Right around the world, developed countries are being encouraged to put an end to subsidies for fossil fuels and invest more in renewable energy," Aly said, before citing Australia's recent refusal to sign up to a communique to end government subsidies for fossil fuels at the Paris climate change conference. Waleed Aly takes on Andrew Bolt over climate change science on The Project. Credit:Screenshot Australia declined to sign on to the statement of support last week, with Prime Minister Malcolm Turnbull expressing concern about the definition of a "subsidy" in the statement and arguing the country's controversial diesel fuel rebate did not constitute a subsidy. The Project host acknowledged ending the subsidies would be politically difficult in Australia, then went on to pre-empt criticism from columnist and host of The Bolt Report, Andrew Bolt, who frequently lampoons commentators and journalists, including Aly, on his blog, for their views and reporting on climate change.
A clip from Bolt's program showed the News Corp columnist flashing a graphic he uses frequently on screen to demonstrate there had been "no warming of the earth's atmosphere for around 18 years now". "Let me nip this in the bud, Andrew Bolt, before you launch into your whole 'but it has stopped warming' line that you've been running for the last few years," Aly said. "This is Carl Mears, the guy whose graph you keep using. We tracked him down, he has a message for you." The show then played a clip of Mears, a climate scientist and the vice president for research at Remote Sensing Systems, who contradicted Bolt's position and said the globe had indeed warmed in the preceding decades. "It's pretty clear that the globe has warmed over the last 18 years," said Mears. "When you do real science you can't just use the data sets that fit your pre-drawn conclusions, but you really need to look at all the data together."
Aly concluded by saying: "We can't go on denying climate change is real and we can't go on finding emotional or even incorrect reasons not to act on it. We stopped subsidising the local car industry when we realised it had no future ... if we don't stop subsidising fossil fuels, then it's us, our children, their children, whose futures will be in doubt." "Now is not the time for our leaders to just walk away." The segment was co-authored by Aly and his producer Tom Whitty. Fairfax Media |
#ifndef BOOST_THREAD_CONDITION_VARIABLE_WIN32_HPP
#define BOOST_THREAD_CONDITION_VARIABLE_WIN32_HPP
// Distributed under the Boost Software License, Version 1.0. (See
// accompanying file LICENSE_1_0.txt or copy at
// http://www.lslboost.org/LICENSE_1_0.txt)
// (C) Copyright 2007-8 Anthony Williams
// (C) Copyright 2011-2012 Vicente J. Botet Escriba
#include <lslboost/thread/win32/thread_primitives.hpp>
#include <lslboost/thread/win32/thread_data.hpp>
#include <lslboost/thread/win32/thread_data.hpp>
#include <lslboost/thread/win32/interlocked_read.hpp>
#include <lslboost/thread/cv_status.hpp>
#if defined BOOST_THREAD_USES_DATETIME
#include <lslboost/thread/xtime.hpp>
#endif
#include <lslboost/thread/mutex.hpp>
#include <lslboost/thread/thread_time.hpp>
#include <lslboost/thread/lock_guard.hpp>
#include <lslboost/thread/lock_types.hpp>
#include <lslboost/assert.hpp>
#include <lslboost/intrusive_ptr.hpp>
#ifdef BOOST_THREAD_USES_CHRONO
#include <lslboost/chrono/system_clocks.hpp>
#include <lslboost/chrono/ceil.hpp>
#endif
#include <limits.h>
#include <algorithm>
#include <vector>
#include <lslboost/config/abi_prefix.hpp>
namespace lslboost
{
namespace detail
{
class basic_cv_list_entry;
void intrusive_ptr_add_ref(basic_cv_list_entry * p);
void intrusive_ptr_release(basic_cv_list_entry * p);
class basic_cv_list_entry
{
private:
detail::win32::handle_manager semaphore;
detail::win32::handle_manager wake_sem;
long waiters;
bool notified;
long references;
public:
BOOST_THREAD_NO_COPYABLE(basic_cv_list_entry)
explicit basic_cv_list_entry(detail::win32::handle_manager const& wake_sem_):
semaphore(detail::win32::create_anonymous_semaphore(0,LONG_MAX)),
wake_sem(wake_sem_.duplicate()),
waiters(1),notified(false),references(0)
{}
static bool no_waiters(lslboost::intrusive_ptr<basic_cv_list_entry> const& entry)
{
return !detail::interlocked_read_acquire(&entry->waiters);
}
void add_waiter()
{
BOOST_INTERLOCKED_INCREMENT(&waiters);
}
void remove_waiter()
{
BOOST_INTERLOCKED_DECREMENT(&waiters);
}
void release(unsigned count_to_release)
{
notified=true;
detail::win32::ReleaseSemaphore(semaphore,count_to_release,0);
}
void release_waiters()
{
release(detail::interlocked_read_acquire(&waiters));
}
bool is_notified() const
{
return notified;
}
bool wait(timeout abs_time)
{
return this_thread::interruptible_wait(semaphore,abs_time);
}
bool woken()
{
unsigned long const woken_result=detail::win32::WaitForSingleObject(wake_sem,0);
BOOST_ASSERT((woken_result==detail::win32::timeout) || (woken_result==0));
return woken_result==0;
}
friend void intrusive_ptr_add_ref(basic_cv_list_entry * p);
friend void intrusive_ptr_release(basic_cv_list_entry * p);
};
inline void intrusive_ptr_add_ref(basic_cv_list_entry * p)
{
BOOST_INTERLOCKED_INCREMENT(&p->references);
}
inline void intrusive_ptr_release(basic_cv_list_entry * p)
{
if(!BOOST_INTERLOCKED_DECREMENT(&p->references))
{
delete p;
}
}
class basic_condition_variable
{
lslboost::mutex internal_mutex;
long total_count;
unsigned active_generation_count;
typedef basic_cv_list_entry list_entry;
typedef lslboost::intrusive_ptr<list_entry> entry_ptr;
typedef std::vector<entry_ptr> generation_list;
generation_list generations;
detail::win32::handle_manager wake_sem;
void wake_waiters(long count_to_wake)
{
detail::interlocked_write_release(&total_count,total_count-count_to_wake);
detail::win32::ReleaseSemaphore(wake_sem,count_to_wake,0);
}
template<typename lock_type>
struct relocker
{
BOOST_THREAD_NO_COPYABLE(relocker)
lock_type& lock;
bool unlocked;
relocker(lock_type& lock_):
lock(lock_),unlocked(false)
{}
void unlock()
{
lock.unlock();
unlocked=true;
}
~relocker()
{
if(unlocked)
{
lock.lock();
}
}
};
entry_ptr get_wait_entry()
{
lslboost::lock_guard<lslboost::mutex> internal_lock(internal_mutex);
if(!wake_sem)
{
wake_sem=detail::win32::create_anonymous_semaphore(0,LONG_MAX);
BOOST_ASSERT(wake_sem);
}
detail::interlocked_write_release(&total_count,total_count+1);
if(generations.empty() || generations.back()->is_notified())
{
entry_ptr new_entry(new list_entry(wake_sem));
generations.push_back(new_entry);
return new_entry;
}
else
{
generations.back()->add_waiter();
return generations.back();
}
}
struct entry_manager
{
entry_ptr const entry;
lslboost::mutex& internal_mutex;
BOOST_THREAD_NO_COPYABLE(entry_manager)
entry_manager(entry_ptr const& entry_, lslboost::mutex& mutex_):
entry(entry_), internal_mutex(mutex_)
{}
~entry_manager()
{
lslboost::lock_guard<lslboost::mutex> internal_lock(internal_mutex);
entry->remove_waiter();
}
list_entry* operator->()
{
return entry.get();
}
};
protected:
template<typename lock_type>
bool do_wait(lock_type& lock,timeout abs_time)
{
relocker<lock_type> locker(lock);
entry_manager entry(get_wait_entry(), internal_mutex);
locker.unlock();
bool woken=false;
while(!woken)
{
if(!entry->wait(abs_time))
{
return false;
}
woken=entry->woken();
}
return woken;
}
template<typename lock_type,typename predicate_type>
bool do_wait(lock_type& m,timeout const& abs_time,predicate_type pred)
{
while (!pred())
{
if(!do_wait(m, abs_time))
return pred();
}
return true;
}
basic_condition_variable(const basic_condition_variable& other);
basic_condition_variable& operator=(const basic_condition_variable& other);
public:
basic_condition_variable():
total_count(0),active_generation_count(0),wake_sem(0)
{}
~basic_condition_variable()
{}
void notify_one() BOOST_NOEXCEPT
{
if(detail::interlocked_read_acquire(&total_count))
{
lslboost::lock_guard<lslboost::mutex> internal_lock(internal_mutex);
if(!total_count)
{
return;
}
wake_waiters(1);
for(generation_list::iterator it=generations.begin(),
end=generations.end();
it!=end;++it)
{
(*it)->release(1);
}
generations.erase(std::remove_if(generations.begin(),generations.end(),&basic_cv_list_entry::no_waiters),generations.end());
}
}
void notify_all() BOOST_NOEXCEPT
{
if(detail::interlocked_read_acquire(&total_count))
{
lslboost::lock_guard<lslboost::mutex> internal_lock(internal_mutex);
if(!total_count)
{
return;
}
wake_waiters(total_count);
for(generation_list::iterator it=generations.begin(),
end=generations.end();
it!=end;++it)
{
(*it)->release_waiters();
}
generations.clear();
wake_sem=detail::win32::handle(0);
}
}
};
}
class condition_variable:
private detail::basic_condition_variable
{
public:
BOOST_THREAD_NO_COPYABLE(condition_variable)
condition_variable()
{}
using detail::basic_condition_variable::notify_one;
using detail::basic_condition_variable::notify_all;
void wait(unique_lock<mutex>& m)
{
do_wait(m,detail::timeout::sentinel());
}
template<typename predicate_type>
void wait(unique_lock<mutex>& m,predicate_type pred)
{
while(!pred()) wait(m);
}
#if defined BOOST_THREAD_USES_DATETIME
bool timed_wait(unique_lock<mutex>& m,lslboost::system_time const& abs_time)
{
return do_wait(m,abs_time);
}
bool timed_wait(unique_lock<mutex>& m,lslboost::xtime const& abs_time)
{
return do_wait(m,system_time(abs_time));
}
template<typename duration_type>
bool timed_wait(unique_lock<mutex>& m,duration_type const& wait_duration)
{
return do_wait(m,wait_duration.total_milliseconds());
}
template<typename predicate_type>
bool timed_wait(unique_lock<mutex>& m,lslboost::system_time const& abs_time,predicate_type pred)
{
return do_wait(m,abs_time,pred);
}
template<typename predicate_type>
bool timed_wait(unique_lock<mutex>& m,lslboost::xtime const& abs_time,predicate_type pred)
{
return do_wait(m,system_time(abs_time),pred);
}
template<typename duration_type,typename predicate_type>
bool timed_wait(unique_lock<mutex>& m,duration_type const& wait_duration,predicate_type pred)
{
return do_wait(m,wait_duration.total_milliseconds(),pred);
}
#endif
#ifdef BOOST_THREAD_USES_CHRONO
template <class Clock, class Duration>
cv_status
wait_until(
unique_lock<mutex>& lock,
const chrono::time_point<Clock, Duration>& t)
{
using namespace chrono;
chrono::time_point<Clock, Duration> now = Clock::now();
if (t<=now) {
return cv_status::timeout;
}
do_wait(lock, ceil<milliseconds>(t-now).count());
return Clock::now() < t ? cv_status::no_timeout :
cv_status::timeout;
}
template <class Rep, class Period>
cv_status
wait_for(
unique_lock<mutex>& lock,
const chrono::duration<Rep, Period>& d)
{
using namespace chrono;
if (d<=chrono::duration<Rep, Period>::zero()) {
return cv_status::timeout;
}
steady_clock::time_point c_now = steady_clock::now();
do_wait(lock, ceil<milliseconds>(d).count());
return steady_clock::now() - c_now < d ? cv_status::no_timeout :
cv_status::timeout;
}
template <class Clock, class Duration, class Predicate>
bool
wait_until(
unique_lock<mutex>& lock,
const chrono::time_point<Clock, Duration>& t,
Predicate pred)
{
while (!pred())
{
if (wait_until(lock, t) == cv_status::timeout)
return pred();
}
return true;
}
template <class Rep, class Period, class Predicate>
bool
wait_for(
unique_lock<mutex>& lock,
const chrono::duration<Rep, Period>& d,
Predicate pred)
{
return wait_until(lock, chrono::steady_clock::now() + d, lslboost::move(pred));
}
#endif
};
class condition_variable_any:
private detail::basic_condition_variable
{
public:
BOOST_THREAD_NO_COPYABLE(condition_variable_any)
condition_variable_any()
{}
using detail::basic_condition_variable::notify_one;
using detail::basic_condition_variable::notify_all;
template<typename lock_type>
void wait(lock_type& m)
{
do_wait(m,detail::timeout::sentinel());
}
template<typename lock_type,typename predicate_type>
void wait(lock_type& m,predicate_type pred)
{
while(!pred()) wait(m);
}
#if defined BOOST_THREAD_USES_DATETIME
template<typename lock_type>
bool timed_wait(lock_type& m,lslboost::system_time const& abs_time)
{
return do_wait(m,abs_time);
}
template<typename lock_type>
bool timed_wait(lock_type& m,lslboost::xtime const& abs_time)
{
return do_wait(m,system_time(abs_time));
}
template<typename lock_type,typename duration_type>
bool timed_wait(lock_type& m,duration_type const& wait_duration)
{
return do_wait(m,wait_duration.total_milliseconds());
}
template<typename lock_type,typename predicate_type>
bool timed_wait(lock_type& m,lslboost::system_time const& abs_time,predicate_type pred)
{
return do_wait(m,abs_time,pred);
}
template<typename lock_type,typename predicate_type>
bool timed_wait(lock_type& m,lslboost::xtime const& abs_time,predicate_type pred)
{
return do_wait(m,system_time(abs_time),pred);
}
template<typename lock_type,typename duration_type,typename predicate_type>
bool timed_wait(lock_type& m,duration_type const& wait_duration,predicate_type pred)
{
return do_wait(m,wait_duration.total_milliseconds(),pred);
}
#endif
#ifdef BOOST_THREAD_USES_CHRONO
template <class lock_type, class Clock, class Duration>
cv_status
wait_until(
lock_type& lock,
const chrono::time_point<Clock, Duration>& t)
{
using namespace chrono;
chrono::time_point<Clock, Duration> now = Clock::now();
if (t<=now) {
return cv_status::timeout;
}
do_wait(lock, ceil<milliseconds>(t-now).count());
return Clock::now() < t ? cv_status::no_timeout :
cv_status::timeout;
}
template <class lock_type, class Rep, class Period>
cv_status
wait_for(
lock_type& lock,
const chrono::duration<Rep, Period>& d)
{
using namespace chrono;
if (d<=chrono::duration<Rep, Period>::zero()) {
return cv_status::timeout;
}
steady_clock::time_point c_now = steady_clock::now();
do_wait(lock, ceil<milliseconds>(d).count());
return steady_clock::now() - c_now < d ? cv_status::no_timeout :
cv_status::timeout;
}
template <class lock_type, class Clock, class Duration, class Predicate>
bool
wait_until(
lock_type& lock,
const chrono::time_point<Clock, Duration>& t,
Predicate pred)
{
while (!pred())
{
if (wait_until(lock, t) == cv_status::timeout)
return pred();
}
return true;
}
template <class lock_type, class Rep, class Period, class Predicate>
bool
wait_for(
lock_type& lock,
const chrono::duration<Rep, Period>& d,
Predicate pred)
{
return wait_until(lock, chrono::steady_clock::now() + d, lslboost::move(pred));
}
#endif
};
BOOST_THREAD_DECL void notify_all_at_thread_exit(condition_variable& cond, unique_lock<mutex> lk);
}
#include <lslboost/config/abi_suffix.hpp>
#endif
|
In the central nervous system (CNS), oligodendrocytes extend processes that form highly organized membrane wraps around axons[@b1]. These so-called myelin sheaths form the structural basis for rapid conduction of nervous impulses[@b1] and have important protective and trophic functions[@b2][@b3].
Loss of myelin occurs in a number of neurological disorders. In the most prominent demyelinating disease, multiple sclerosis (MS)[@b4][@b5][@b6][@b7], myelin sheaths are damaged by an autoimmune process[@b8]. With the advent of new drugs that slow the progression of the autoimmune disease, the question of how the regeneration of myelin sheaths can be enhanced is receiving increasing attention. However, so far, no remyelination-promoting therapy is available in a clinical setting.
Failure of remyelination can occur as a consequence of insufficient recruitment of oligodendrocyte progenitor cells (OPCs) into demyelinating lesions[@b9]. Furthermore, intrinsic changes within OPCs and factors that accumulate in MS lesions are able to inhibit OPC differentiation[@b10][@b11][@b12][@b13]. Lesion-associated inhibitors regulate distinct signaling cascades in OPCs, and it may be possible to manipulate them pharmacologically to promote myelin regeneration. For example, we recently demonstrated that inhibition of Phosphodiesterase (PDE)4 is able to promote CNS remyelination[@b14]. Other approaches include inhibiting Leucine rich repeat and Immunoglobin-like domain-containing protein (Lingo)-1[@b15], Wingless/mouse mammary tumor virus integration site (Wnt) signaling[@b16] and Retinoic acid receptor (RXR)-**γ**[@b17].
Previous studies, including our own work, demonstrated that myelin proteins, which accumulate following demyelination, are able to inhibit remyelination by blocking the differentiation of oligodendrocyte progenitor cells (OPCs)[@b18][@b19][@b20]. Investigating the underlying mechanisms we found that myelin proteins inhibit OPC differentiation by modulating RhoA and PKCα signalling[@b21][@b22]. On the basis of these results, we investigated the potential of PKCα inhibitors to overcome the myelin-associated differentiation block to promote OPC differentiation. We found that tamoxifen promoted this most effectively, albeit via an alternative mechanism.
Results
=======
Prompted by our previous findings[@b22], which showed that OPC-differentiation-inhibiting myelin breakdown products activate protein kinase C (PKC)α signalling, we investigated the potential of PKCα inhibitors to promote OPC differentiation in the presence of myelin protein extracts by assessing the expression of O4 ([Fig. 1](#f1){ref-type="fig"}). Of the drugs tested (UCN01, midostaurin, staurosporine, bryostatin-1, rottlerin, and tamoxifen), tamoxifen showed particularly potent differentiation-inducing effects. Addition of tamoxifen to OPCs plated on control substrates or to cells on myelin substrates increased the number of MBP+ and CNP+ cells respectively ([Fig. 1c](#f1){ref-type="fig"}, e--i). Quantitative RT-PCR assessment of *Mbp* relative to *Gapdh* mRNA expression demonstrated that tamoxifen treatment induced *Mbp* expression on the transcriptional level ([Fig. 1d](#f1){ref-type="fig"}). The increase of MBP+ cells in response to tamoxifen was concentration dependent ([Fig. 1e](#f1){ref-type="fig"}).
Tamoxifen is known to modulate estrogen receptor signaling and PKCα activity
----------------------------------------------------------------------------
Tamoxifen has been used for the treatment of breast cancer since the early 1970s[@b23]. In addition to inhibiting PKCα activity, tamoxifen is known to modulate estrogen signaling ([Fig. 2a](#f2){ref-type="fig"}). So far, two classes of estrogen receptors have been identified: the nuclear estrogen receptors alpha (ERα) and beta (ERβ), and a membrane-bound G-protein-associated estrogen receptor (GPR30). Whereas ERα and ERβ are estrogen-responsive nuclear receptors that act as transcriptional regulators[@b24], GPR30 is known to modulate several signaling pathways such as the phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways[@b25].
Estrogen receptors are positive regulators of OPC differentiation
-----------------------------------------------------------------
The literature suggests that all three ER receptor types are expressed in oligodendrocyte lineage cells[@b26][@b27][@b28][@b29][@b30][@b31][@b32][@b33][@b34]. To investigate whether sex influences ER expression of neonatal rat OPCs were separately derived from female and male pups. We found that *Er-α*, *Er-β*, or *Gpr30* expression was comparable in both genders ([Supplementary Fig. 1](#S1){ref-type="supplementary-material"}). Based on these results we continued to use OPCs derived from pooled rat pups including both genders.
An interesting property of tamoxifen is that, depending on the cell type, it can act as agonist or antagonist on estrogen receptors[@b35]. For example, it has an *agonistic* effect in the uterus and skeleton but *antagonistic* activity in the breast, where it has been used for several years for the treatment of breast cancer.
We first sought to elucidate how ER or PKCα signaling affects the differentiation of OPCs into oligodendrocytes. For this purpose we transfected OPCs with small interfering (si)RNA directed against individual ERs and PKCα ([Fig. 2](#f2){ref-type="fig"}). Individual silencing of *Er-α, Er-β*, or *Gpr30* resulted in decreased OPC differentiation reflected by reduced mRNA expression of the differentiation markers cyclic nucleotide 3′-phosphodiesterase (*Cnp)* and myelin basic protein *(Mbp)* ([Fig. 2b--g](#f2){ref-type="fig"}).
In contrast, gene silencing of PKCα did not alter the differentiation of OPCs on control substrates ([Fig. 2](#f2){ref-type="fig"}). This was expected as with the culture conditions applied, inhibition of PKCα only shows effects in the presence of inhibitory myelin substrates[@b22]. Taken together these results confirm that ERα, ERβ, and GPR30 have important functional roles during the process of OPC differentiation (see also [Supplementary Fig. 3](#S1){ref-type="supplementary-material"}).
Tamoxifen-induced OPC differentiation depends on the presence of ER
-------------------------------------------------------------------
To investigate the mechanism by which tamoxifen promotes OPC differentiation, we silenced ERα, ERβ, GPR30, and PKCα in cells treated with tamoxifen. Similar to OPCs cultured in the absence of tamoxifen, silencing of ERα, ERβ, or GPR30 negatively affected the differentiation of cells in the presence of tamoxifen, indicating that the differentiation-inducing effects of tamoxifen are dependent on the presence of each of the ERs tested ([Fig. 3a--f](#f3){ref-type="fig"} and see [Supplementary Fig. 4a--h](#S1){ref-type="supplementary-material"} for calculations of the difference in *Cnp* or *Mbp* mRNA expression between "siRNA - tamoxifen" and "siRNA + tamoxifen conditions").
On the other hand, gene silencing of PKCα in combination with tamoxifen treatment resulted in increased *Mbp* expression at early time points as compared to tamoxifen treatment alone ([Fig. 3g,h](#f3){ref-type="fig"}). Tamoxifen therefore seems to exert OPC-differentiation-inducing effects via ERs but not via PKCα.
Assessing the effects of tamoxifen in an *in vivo* model of remyelination
-------------------------------------------------------------------------
We next sought to investigate whether tamoxifen can promote OPC differentiation in a model of CNS remyelination. The largest targeted demyelinating lesions in a rodent model have so far been achieved by injection of ethidium bromide (EB) into white-matter tracts of the rat brainstem. Since the efficiency of remyelination is inversely correlated with lesion size, this model is advantageous for studying the kinetics of CNS remyelination[@b36]. Application of EB results in rapid and complete depletion of glial cells, including astrocytes and oligodendrocyte lineage cells, within 3 days with good preservation of axons. As a consequence the axons become demyelinated. This is followed by a highly predictable sequence of events during which the lesion becomes fully remyelinated[@b37]. In young-adult rats, remyelination is complete within 28 days.
Estrogen receptors and active PKCα are expressed by oligodendrocyte lineage cells *in vivo*
-------------------------------------------------------------------------------------------
To confirm that ERα, ERβ, and GPR30, as well as activated PKCα, are present in remyelinating lesions, we carried out immunohistochemical staining using antibodies directed against the respective antigens and included co-stainings for the oligodendrocyte lineage cell-specific transcription factor OLIG2. This confirmed the presence of all three ERs and active PKCα in oligodendrocyte lineage cells within remyelinating lesions ([Fig. 4](#f4){ref-type="fig"}).
Tamoxifen induces OPC differentiation in demyelinated lesions
-------------------------------------------------------------
To investigate whether tamoxifen treatment is able to induce OPC differentiation *in vivo*, animals receiving daily intraperitoneal injections of tamoxifen at two different doses (0.5 mg/day and 2 mg/day) were compared with controls receiving vehicle injections. Several stage-specific molecular markers were used to characterize the OPC response to tamoxifen in remyelinating lesions. We analyzed lesions 7 days post lesion induction (pli) to assess the recruitment of OPCs and lesions 14 days pli to assess the differentiation of OPCs into mature oligodendrocytes ([Fig. 5a--e](#f5){ref-type="fig"}). Whereas the number of immature *Pdgfrα* OPCs or "activated" NKX2.2-expressing OPCs was comparable between the groups 7 and 14 days pli ([Fig. 5f--j](#f5){ref-type="fig"}), a significant increase in cells expressing the mature oligodendrocyte markers adenomatous polyposis coli (APC(CC1)) and proteolipid protein (*Plp*) was detected in animals receiving the higher treatment dose 14 days pli ([Fig. 5k--o](#f5){ref-type="fig"}). These findings indicate that tamoxifen treatment induced the differentiation of OPCs in the lesions.
However, myelin-sheath formation is also regulated at levels downstream of the transcriptional program. Does the enhanced expression of mature markers therefore correlate with an accelerated formation of new myelin sheaths?
Tamoxifen promotes CNS remyelination
------------------------------------
To investigate the extent of CNS remyelination at 14 days, the experiments were repeated using the higher dose of tamoxifen and the tissue was embedded into resin for ultrastructural analysis. Investigator-blinded rank analysis demonstrated that tamoxifen significantly increased the number of remyelinated axons ([Fig. 6a](#f6){ref-type="fig"}). This was confirmed by determining the number of remyelinated axons on high-power digitized micrographs of caudal cerebellar peduncle lesions ([Fig. 6b](#f6){ref-type="fig"}). The relative thickness of newly formed myelin did not differ between the groups ([Fig. 6c--h](#f6){ref-type="fig"}). Taken together, these data demonstrate that tamoxifen treatment resulted in accelerated remyelination at 14 days pli.
Tamoxifen treatment does not alter the macrophage response
----------------------------------------------------------
Our *in vitro* data indicate that tamoxifen can directly regulate OPC differentiation. However, it is possible that tamoxifen also modulates the function of other cell types in demyelinated lesions. In particular, macrophages are important determinants for the efficiency of remyelination[@b38][@b39]. We initially assessed the number of osteopontin-positive macrophages in the lesions. No differences were detected between the groups with respect to the overall macrophage presence ([Supplementary Fig. 5](#S1){ref-type="supplementary-material"}). Recent findings highlight the importance of macrophage activation, specifically of M1 and M2 phenotypes[@b40]. Quantification of the presence of CCR7^+^-M1 and Arginase1^+^-M2 macrophages 7 days post lesion induction did not show significant differences between the tamoxifen treated and control animals. Furthermore, assessment of phagocytic activity in remyelinating lesions by staining intracellular myelin-derived neutral lipids with Oil Red-O did not detect differences between the groups. Nevertheless, further indirect effects of tamoxifen cannot be ruled out entirely.
Discussion
==========
Here we have shown that tamoxifen induces OPC differentiation and remyelination *in vitro* and *in vivo*, and that this relies on modulation of the estrogen receptors ERα, ERβ, and GPR30. The effects of tamoxifen do not involve the PKCα pathway.
Estrogen receptors play an important role in OPC differentiation and remyelination[@b31][@b32][@b33][@b41]. Similarly, in our experiments, silencing of ER resulted in impaired OPC differentiation *in vitro*, even estrogen was not specifically added to the medium. However, fetal calf serum (FCS) used in the OPC media does contain several components, which could activate estrogen receptors in a ligand-independent manner. Picard 2003, describes a list of molecules which could cross-talk with the estrogen receptors without physically interacting with them, for example, insulin (which forms an important component of the differentiation medium), IGF and FGF[@b42]. Moreover, testosterone (present in FCS) could be converted by aromatase, which is expressed in low levels in glial cells (<http://web.stanford.edu/group/barres_lab/brain_rnaseq.html>), into estrogen and therefore, activate all estrogen receptors. As a results, silencing of ER is likely to impair OPC differentiation in our culture model.
When estrogen receptors were silenced, the differentiation-inducing effects of tamoxifen were reduced, indicating an involvement of ER (or GPR30) in tamoxifen-mediated effects. In contrast, tamoxifen treatment in combination with silencing of PKCα did not reduce the efficiency of tamoxifen-induced OPC differentiation. In fact we observed transiently increased MBP expression at day 4 compared with tamoxifen treatment alone. While this is only a transient finding at a single time point, it may indicate that combinatorial treatment of tamoxifen and inhibition of PKCα may act synergistically to accelerate OPC differentiation. Nonetheless it can be concluded that differentiation-inducing effects of tamoxifen do not rely on inhibition of PKCα.
Our results also confirm previous reports[@b22] that the inhibition of PKCs does not promote differentiation by itself when cells are cultured in serum containing media. Conversely, in the presence of myelin debris, the inhibition of PKCα neutralizes myelin-associated inhibitors and promotes differentiation[@b22].
The majority of the reported pharmacological (metabolism and toxicology) studies of tamoxifen use the free base form of tamoxifen and not the soluble forms (citrate tamoxifen and/or 4-OH tamoxifen). Therefore, the present *in vitro* and *in vivo* experiments were also conducted with tamoxifen in its free base form. However, a recent paper by Barrat *et al.* evaluated metabolites of tamoxifen (4-hydroxytamoxifen and endoxifen) as well as tamoxifen citrate, a water-soluble version on a rat glia restricted precursor cell line[@b43]. They found that all metabolites promoted the expression of late stage markers of OPC differentiation, such as *Cnp* and *Mbp*, which is consistent with our findings using primary rat OPC cultures. In addition, the effect of tamoxifen was blocked when a pan-antagonist was added to the media, supporting our finding that tamoxifen acts as an estrogen receptor agonist in OPC differentiation.
Apart from oligodendroglial cells, tamoxifen potentially also acts on other cell types. We therefore assessed activated macrophages/microglia, which are known to play a key role in remyelination. We did not observe changes in the number of recruited cells or the myelin debris removal at 7 and 14 pli. Furthermore, no differences were observed regarding the number of the pro-inflamatory (M1) or anti-inflammatory (M2) macrophages. Nevertheless, these results cannot entirely rule out potential indirect effects such as differential release of cytokines or chemokines mediated by tamoxifen. The role of astrocytes was not evaluated since their role during remyelination is less clear.
To limit the biological variation and to increase the challenge of the experimental treatment by using a paradigm of efficient remyelination, only young adult female rats were included in the present *in vivo* experiments. The literature indicates that sex-related differences exist with respect to the efficiency of remyelination: whilst in young rats the rate of remyelination is comparable between the sexes, it is more efficient in aged female rats as compared to male rats[@b44]. Estrogen signalling plays a distinctive role in females. However, investigating OPCs derived from segregated female and male pups with respect to expression of estrogen receptors and their response to tamoxifen did not show any sex-related differences. Nevertheless, it cannot be ruled out that indirect systemic effects exist and that male rats may react differently to tamoxifen treatment. The main reasons why we decided to use female rats in our study were comparability to previous studies and the fact that MS often affects female patients.
In a clinical setting for the treatment of breast cancer tamoxifen was used at doses ranging from 20--40 mg per day. With an estimated average weight of females at 65 Kg, this translates into 0.3--0.6 mg/Kg. The estimated human equivalent in our experiments is 0.27 mg/Kg, which is in keeping with current treatment paradigms in human.
Steroid hormones are known to influence the course of MS and also to modulate demyelination in animal models. During pregnancy, a reduction in the frequency of relapse rate in patients with relapsing--remitting MS (RRMS) has been reported[@b45][@b46][@b47]. Similarly, a decrease in the severity of the symptoms in comparison with a nonpregnant control group was detected in pregnant mice affected by experimental autoimmune encephalomyelitis, a model of the autoimmune destruction of myelin sheaths occurring in MS[@b48]. Interestingly, the administration of estriol to nonpregnant women with RRMS showed a reduction in the number of Th1 cells, which are involved in the autoimmune response, and also in the clinical score of the disease[@b49]. Furthermore, there is evidence that steroid hormones promote myelin repair: administration of progesterone to cerebellar slices after lysolecithin-induced demyelination showed an increase in remyelination[@b50] and recently, the same group has shown that administration of progesterone promotes myelin regeneration in chronic demyelinated lesions in the corpus callosum of mice after being fed with cuprizone[@b51]. These data support the positive effects of steroid hormones and their potential for the treatment of demyelinating diseases.
Considerable efforts are currently being made to develop remyelination-enhancing drugs. The use of tamoxifen has several advantages over the development of new drugs. For example, it has an excellent safety profile that has undergone the test of time by exhaustive application in the clinic. In our study, tamoxifen emerges as a good candidate for testing in an experimental medicine study specifically designed to assess remyelination in MS patients.
Our findings also have important implications for basic research: experiments investigating the function of specific molecules in the CNS on the basis of the widely used CreERT2Lox system rely on the tamoxifen-dependent activation of Cre recombinase for the induction of genetic changes. Our data demonstrate that administration of tamoxifen has a strong influence on CNS stem/precursor cells. To rule out any unintended effects of tamoxifen on the increasingly used inducible CreERT2-rat transgenic models, and potentially also for CreERT2 mice models, the inclusion of adequate controls is advised.
Methods
=======
Preparation of primary OPC cultures
-----------------------------------
Primary OPC cultures were isolated from neonatal Sprague Dawley (postnatal day 0--3) rat forebrains following a standard protocol[@b20][@b22] Neonatal pups were euthanized according to "Schedule 1" regulations from the Home Office Animal Procedures Committee UK. Sex-segregated cultures were prepared from female and male only pups. The male-derived OPCs was confirmed by genotyping for the presence of the SRY gene, present only in the Y chromosome (data not shown). Differentiation was induced using Sato's medium supplemented with 0.5% fetal calf serum (FCS). For all *in vitro* experiments, only cultures with ≥94% purity were used.
Preparation of myelin-membrane substrates and myelin-protein extracts
---------------------------------------------------------------------
Myelin was purified following two rounds of centrifugation using a discontinuous density gradient of sucrose and osmotic disintegration as described previously[@b20][@b52]. After centrifugation for 1 h at 100,000 × *g*, the interface between the two sucrose solutions was collected, washed with water and pelleted again at 55,000 × *g* for 10 min. The pellet was dissolved in water and incubated for 1 h on ice to introduce an osmotic shock. The solution was then centrifuged again at 55,000 × *g* for 10 min. The resulting pellet was purified by repetition of the sucrose gradient step described above. The myelin-containing interface was collected and, after two washing steps, a pure myelin pellet was obtained and frozen at −80 °C. The frozen myelin pellets were thawed and resuspended in 1% *N*-octyl-β-D-glucopyranoside, 0.2 M Na~3~PO~4~, pH 6.8, 0.1 M Na~2~SO~4~, and 1 mM EDTA, and incubated at 23 °C for 2 h. Following an ultracentrifugation step (100,000 × *g*, for 30 min at room temperature) the supernatants (which are myelin protein extract, MPE) were collected and stored at 80 °C until further use. To test OPC differentiation, slides were coated with MPE following application of poly-[l]{.smallcaps}-lysine (PLL) to promote cell attachment to the well.
Small molecule experiments in OPC cultures
------------------------------------------
Estrogen receptors' agonist/antagonist as well as PKC inhibitors (Tocris Bioscience, Bristol, UK) were dissolved in DMSO, water or ethanol as stated in the according data sheet and added to Sato's differentiation medium in concentrations stated. Dissolved small molecule stock solutions were diluted at least by 1:10000 when added to the cells eliminating eventual side effect of the dissolving agent. Concentrations of the PKC inhibitors were determined in independent dose-finding experiments. Concentrations used for the experiments included in the present study were as followed, 7-hydroxystaurosporine (UCN01): 10 nM, midostaurin: 1 nM, staurosporine: 25 nM, bryostatin-1: 5 nM, rottlerin: 5 nM and tamoxifen: 50 nM.
Immunocytochemical analysis *in vitro*
--------------------------------------
OPCs were seeded onto eight-well chamber slides (2 × 10^4^ cells/well) coated with PLL alone or PLL plus MPE. Following 2 days of differentiation, cells were stained with anti-O4 (1:100; Millipore Corporation, Billerica, MA) and anti-MBP (1:300; Millipore Corporation) antibodies. Secondary antibodies conjugated with Alexa 488 and Alexa 555 were used to visualize positive cells (1:300; Invitrogen, Carlsbad, CA)[@b22]. To assess OPC differentiation, the percentage of O4- or MBP-positive cells relative to \>100 DAPI-stained nuclei per experiment for each condition and each experiment in randomly selected eye fields was determined, with the investigator being blind to treatment group. To assess expression of estrogen receptors in male and female OPCs, OPCs isolated from sex-segregated mixed glia cultures were seeded on PLL-coated glass coverslips on 24-well plates (7 × 10^4^ cells/well). Following 2 and 4 days of differentiation, cells were stained with anti-ERα (1:300; Abcam), anti-ERβ (1:300; Abcam), anti-GPR30 (1:300; Invitrogen) and anti-OLIG2 (1:1000; Millipore) or anti-O4 (1:200; SIGMA), followed by staining with the secondary antibodies indicated above. The percentage of ERα, ERβ or GPR30-positive cells relative to \>100 oligodendrocyte lineage cells (O4-positive or OLIG2-positive) per experiment for each condition was determined in randomly selected eye fields. Following immunocytochemistry, cells were mounted with Prolong gold antifade mounting medium (Invitrogen). Cells were visualized and digitized at ambient temperature on an LSM 700 confocal microscope (Zeiss, Thornwood, NJ) at 20× and 40× magnification using Zen Application software (Zeiss).
RNA extraction and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR)
-----------------------------------------------------------------------------------------
A minimum of 50,000 oligodendrocytes were washed twice with ice-cold phosphate-buffered saline (PBS). OPCs were lysed, and total RNA was extracted and purified using the RNAeasy Mini kit (Qiagen, Hilden, Germany) according to the manufacturer's protocol. qRT-PCR was conducted as previously described on an Applied Biosystems 7500HT Fast Real-time PCR system[@b22] (Applied Biosystems, Foster City, CA). Values are represented as target gene/glyceraldehyde-3-phosphate dehydrogenase (*Gapdh*) ratios. Triplicate measurements were made on three biological replicates.
siRNA transfections
-------------------
OPC cultures were kept overnight in Sato's proliferation medium without antibiotic supplement. On the following day, siRNA smart pool (for details of siRNAs used see [Supplementary Table 1](#S1){ref-type="supplementary-material"}) and lipofectamine RNAiMAX were dissolved separately in OptiMem medium (LifeTech, Gaithersburg, MD). Lyophilized ON TARGET plus smart pool siRNA (Dharmacon/ThermoScientific, Waltham, MA) was dissolved in 5 × RNAi buffer, divided into aliquots, and stored at −20 °C. OPCs were transfected using lipofectamine RNAiMAX (Invitrogen) according to the manufacturer's instructions and using a 1:400 dilution of lipofectamine and 50 nM of siRNA smart pool per reaction. To determine the silencing efficiencies, cell samples were collected at 48 h and 72 h after transfection for RNA extraction ([Supplementary Fig. 2](#S1){ref-type="supplementary-material"}).
Induction of focal demyelination
--------------------------------
All experiments were conducted in accordance with the UK Home Office's animal-welfare regulations and institutional guidelines for animal care and handling and approved to be performed by UK Home Office's and University Biomedical Support Service under project license number: 70/7715, formerly 80/2228. Female Sprague Dawley rats in estrum (200--220 g) were anesthetized using a combination of 2% isoflurane in oxygen (as carrier gas) and a subcutaneous injection of buprenorphine hydrochloride 0.03 mg/kg (Vetergesic, Animalcare Ltd, Hull, UK). Demyelinated lesions were induced bilaterally by stereotactic injection of EB (0.01%, 4 ml) into the caudal cerebellar peduncle, −10.4 mm caudal, ±2.6 mm lateral, and −7.3 mm ventral from bregma[@b36][@b37]. Tamoxifen (Sigma-Aldrich, St. Louis, MO) was dissolved in 100% ethanol and diluted with corn oil (Sigma-Aldrich) to a final concentration of 10% ethanol. The treatment animals were injected intraperitoneally with tamoxifen equivalent to 0.5 mg/Kg/day or 2 mg/Kg/day, and the control group received an equivalent volume of the vehicle. In both groups, drug and vehicle were injected on the third day post-lesion (dpl) for 11 days until 14th day post-lesion. Animals were sacrificed after 7 and 14 dpl. To rule out any effects attributable to the size of the lesion, the density of *Plp*-positive cells was assessed in PBS-treated animals by linear regression (GraphPad, Prism, San Diego, CA). The inclusion of lesions smaller than 0.2 mm^2^, which were strongly populated with *Plp*-positive cells, resulted in a significant non-zero slope indicating an effect of the lesion size on the cell density, as shown in previous studies[@b14]. This may be explained by the fact that in small lesions, recruitment of OPCs and the clearance of myelin debris are more efficient, and thus remyelination becomes more efficient than with larger lesions. No significant correlation between the size of the lesion and the density of *Plp*-positive cells was observed in lesions larger than 0.2 mm^2^, and so only lesions larger than 0.2 mm^2^ were included in the analysis.
*In situ* hybridization
-----------------------
The expression of a number of marker mRNA species in demyelinated lesions was examined by *in situ* hybridization with digoxigenin-labeled cRNA probes; *Pdgfr-α*, *Plp*, and osteopontin were kindly provided by Dr. Chao Zhao, University of Cambridge. Animals were perfused with 4% paraformaldehyde (PFA) via the left ventricle. The tissue was extracted, postfixed in 4% PFA overnight at 4 °C, and cryoprotected in 20% sucrose. *In situ* hybridizations were carried out on cryostat sections (12 μm) using established protocols[@b19][@b53]. ImageJ 1.44 (Wayne Rasband, National Institutes of Health, Bethesda, MD) was used to determine the number of positive cells within the lesions on digitized sections. All analyses were conducted with the investigator blind to the treatment group.
Immunohistochemical analysis *in vivo*
--------------------------------------
Immunohistochemistry was performed on 12-μm-thick sections of 4% PFA-fixed tissue. Antigen was retrieved using 0.01 M citrate buffer (Dako) at pH 6.0 for 10 min in a 95 °C water bath, and slides were rinsed in PBS (pH 7.4) thee times (10 min each at room temperature). Then, sections were incubated with the blocking solution containing 5% inactivated normal donkey serum (Abcam, Cambridge, MA) and Triton X-100 (0.1%) in PBS for 60 min at room temperature. The following antibodies were stained: anti-OLIG2 (1:300; Millipore), anti-APC(CC1) (1:300; Calbiochem, La Jolla, CA), anti-NKX2.2 (1:300; DHSB), anti-ERα (1:300; Abcam), anti-ERβ (1:300; Abcam), anti-GPR30 (1:300; Invitrogen), and anti-PKCα-p (1:300; Santa Cruz Biotech, Santa Cruz, CA). Sections were incubated with primary antibody overnight, washed three times in PBS, and then incubated with appropriate Alexa 488- or 594-conjugated secondary antibodies (Invitrogen) for 3 h at room temperature. They were then counterstained with DAPI (Sigma-Aldrich). Prolong gold antifade mounting medium (Invitrogen) was used to mount the slides. Slides were examined in a fluorescence microscope (Nikon TE-2000; Nikon, Düsseldorf, Germany), and images were taken by confocal microscopy (Zeiss LSM-700). All quantifications were conducted with the investigators blind to the treatment group. Data are given as mean ± SEM and statistically analyzed. Three sections per marker per animal were analyzed, and a minimum of four animals were used.
Oil Red-O staining
------------------
Sections from control and treatment group were left to dry at room temperature and then placed in a Coplin jar containing propylene glycol (100%) for 5 min. Prewarmed Oil Red-O solution (0.5% in propylene glycol, Sigma-Aldrich) was stained at 65 °C for 10 min. Following incubation for 5 min with differentiation solution (85% propylene glycol), slides were rinsed twice with water and then mounted using a jelly-based mounting media. Representative images of Oil Red-O stained lesions were digitized, and, using ImageJ software, the intensity of the lesion area was measured from the red channel. Data are given as mean ± SEM and statistically analyzed. Three sections per marker per animal were analyzed, and a minimum of four animals were used.
Histological analysis of remyelination
--------------------------------------
To assess the extent of remyelination, the tissue was fixed in 4% glutaraldehyde, osmicated, and processed into resin (TAAB Laboratories Equipment Ltd, Reading, UK)[@b29]. Sections (1 mm) were stained with 1% toluidine blue. The extent of remyelination was then assessed by light and electron microscopy (see below). Based on the thickness (or absence) of myelin sheaths, demyelinated axons, axons bearing native myelin sheaths, and remyelinated axons on light and electron micrographs can unambiguously be distinguished[@b54]. Lesions were ranked according to the extent of remyelination by two blinded investigators and statistically analyzed using a two-tailed Mann--Whitney test. Increased remyelination corresponds to a higher rank value. In addition, demyelinated versus remyelinated axons were manually counted on 100× digitized pictures randomly taken from the lesion border. Ratios of remyelinated and demyelinated versus the total number of axons were analyzed using Student's *t*-test.
Electron microscopy
-------------------
Ultra-thin sections (1 μm) containing the lesions were stained with aqueous 4% uranylacetate and lead citrate. The sections were visualized on an electron microscope (Hitachi H-600 electron microscope; Hitachi, Tokyo). A minimum of five micrographs per lesion were analyzed from the border of the lesion. The G-ratios (the ratio of axon circumference to myelin circumference) of oligodendrocyte-remyelinated axons were calculated using ImageJ and statistically analyzed (lower G-ratios indicate thicker myelin sheaths) using Student's *t*-test.
Statistical analysis
--------------------
Data were analyzed using GraphPad software (Prism). Student's *t*-test was performed for single-group comparisons (control vs treatment), and multiple-group comparisons were conducted using one-way ANOVA followed by Dunnett's post-test. qRT-PCR data were analyzed using one-way ANOVA followed by Bonferroni's post-test. For rank analysis, a two-tailed nonparametric Mann--Whitney *U* test was used.
Additional Information
======================
**How to cite this article**: Gonzalez, G. A. *et al.* Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system. *Sci. Rep.* **6**, 31599; doi: 10.1038/srep31599 (2016).
Supplementary Material {#S1}
======================
###### Supplementary Information
This work was supported by grants from Wings for Life and the UK Multiple Sclerosis Society. M.R.N.K. holds an NIHR CL award and a Sir David and Isobel Walker fellowship. G.A.G. was supported by CONICYT (Becas Chile) scholarship, and M.P.H. was supported by a Sir David and Isobel Walker studentship. Research in the author's laboratory is supported by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. We acknowledge expert technical assistance from Dr. Daniel Morrison for electron microscopy expertise and are very grateful for the support of Prof. Robin J.M. Franklin. We also gratefully acknowledge editorial assistance by Ana Sharman, Cofactor Ltd., Editing, training and consultancy in scientific publishing. This report is independent research arising from a Clinician Scientist Award, CS-2015-15-023, supported by the National Institute for Health Research. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.
The authors declare no competing financial interests.
**Author Contributions** G.A.G., M.P.H. and M.R.N.K. designed the experiments. G.A.G. and J.R. performed the *in vivo* experiments; C.Z. and S.R. assisted with the *in vivo* experiments. M.P.H., Y.A.S. and A.I.A performed the *in vitro* experiments. G.A.G., M.P.H., Y.A.S., A.I.A. and M.R.N.K. analyzed the data. G.A.G., Y.A.S. and M.R.N.K. wrote the paper.
{#f1}
{#f2}
{#f3}
{#f4}
{#f5}
{#f6}
[^1]: These authors contributed equally to this work.
|
ect to z.
-1
Let u(b) be the first derivative of -b**10/504 - b**6/120 + b**3/3 - 3. Let p(l) be the third derivative of u(l). Find the third derivative of p(d) wrt d.
-1200*d**3
What is the first derivative of 18*c**4 + 28*c**4 + 8 - 104*c - 47*c**4 wrt c?
-4*c**3 - 104
Suppose -2*z - 14 = -5*a, -2*a + 3*z - 1 = -0. Let s be (42/a)/(2/8). Differentiate 7*g - 47 + s - 2*g wrt g.
5
What is the second derivative of -702*n**3 + 96*n + 36*n - 99*n + 17*n + 60*n wrt n?
-4212*n
Let w(d) = d**3 - 17*d**2 + 3*d - 38. Let c be w(17). What is the third derivative of 43*i**3 + 8*i**2 - c*i**2 + 22*i**2 wrt i?
258
Let i(v) be the third derivative of v**6/120 - v**5/60 - v**3/6 + 2*v**2. Let s(k) = 20*k**3 + 2*k**2 + 23. Let l(n) = 2*i(n) + s(n). Differentiate l(q) wrt q.
66*q**2
What is the third derivative of 10*b**2 + 3 - 9 + 6 - 71*b**4 wrt b?
-1704*b
Let n = -68 + 71. Find the second derivative of -15*l + 19*l + 3*l + 30*l**n wrt l.
180*l
Let v = 458/3 - 148. Let j(g) be the first derivative of -v*g**3 - 2*g**4 + 0*g**2 + 4 + 0*g. Find the third derivative of j(y) wrt y.
-48
Let m(n) be the first derivative of 11*n**4/4 + 2*n**3 + 19*n - 8. Let h(a) = 11*a**3 + 5*a**2 + 18. Let t(f) = 6*h(f) - 5*m(f). Differentiate t(x) wrt x.
33*x**2
Find the first derivative of -23*p + 47 - 40 + 143 wrt p.
-23
Let g be -5 - 80/(-6) - (-2)/(-6). Find the third derivative of -11*m**2 + m**6 + 6*m**6 + 2*m**6 - g*m**2 wrt m.
1080*m**3
Let i be (2 - 6 - -4) + 2. Find the third derivative of 1165 - 18*s**4 - 18*s**i - 1165 wrt s.
-432*s
Let r(k) = -404*k**3 - 9*k**2 - 11*k - 710. Let d(m) = -203*m**3 - 4*m**2 - 5*m - 355. Let p(j) = -9*d(j) + 4*r(j). What is the first derivative of p(q) wrt q?
633*q**2 + 1
Suppose -6 = -8*v + 5*v. Let g(o) = 3*o**2 - 2*o + 2. Let j be g(v). Find the third derivative of 8*l**6 - 19*l**6 - l**6 + 0*l**2 + j*l**2 wrt l.
-1440*l**3
Let m(a) = -a**2 - 12*a - 15. Let j be m(-10). Find the second derivative of 1887*l**3 + 2*l - 1887*l**3 - 12*l**j wrt l.
-240*l**3
Let j(m) be the third derivative of m**8/336 - m**7/14 - 61*m**4/24 - 2*m**2 - 8*m. Find the second derivative of j(k) wrt k.
20*k**3 - 180*k**2
Let d(w) be the first derivative of -13*w**4/24 - w**3/3 - 3*w**2 + 5. Let x(a) be the second derivative of d(a). Differentiate x(q) wrt q.
-13
Suppose 3*v = 31 - 25. Suppose 2*f + 2*q = -v*f + 68, 2*f - q - 42 = 0. What is the derivative of 1 + 9*d**3 - 12 - f*d**3 wrt d?
-30*d**2
Suppose 4*r - 35 = -7. Suppose -3*f + 4*f - 2 = 0. What is the second derivative of 3*c**f - 3*c + r*c - 2*c wrt c?
6
Suppose -o = -3*x - 6 - 3, -5*x = -2*o + 16. Find the second derivative of 0*n**3 - 8*n**3 - n**o - n + 20*n wrt n.
-54*n
Suppose 28*b = 26*b + 12. Find the third derivative of 2*h**b - 5*h**3 - 31*h**2 + 11*h**3 - 6*h**3 wrt h.
240*h**3
Suppose -4*h = -10 + 2. Suppose -5*v - 5 = -10*c + 7*c, 0 = 3*v - 6. Differentiate m + 14 + h*m - c wrt m.
3
Let u(d) = -211*d**4 - 3*d**2 - 45*d - 3. Let y(t) = 423*t**4 + 5*t**2 + 90*t + 6. Let w(o) = 5*u(o) + 3*y(o). What is the second derivative of w(f) wrt f?
2568*f**2
What is the first derivative of 886*i + 198 - 14 - 632*i wrt i?
254
Let f(a) = 55*a**2 + 6*a + 21. Let o(j) = 164*j**2 + 17*j + 63. Let u(v) = 8*f(v) - 3*o(v). What is the second derivative of u(s) wrt s?
-104
Suppose -95*h + 426 = -92*h. What is the third derivative of 5*a**2 - h - 2*a**2 + 142 + 19*a**3 wrt a?
114
Let j = 70 - 67. What is the third derivative of -29*k**2 + 9*k**3 + 19*k**3 + 3*k**j - 13*k**3 wrt k?
108
Let y(d) = -d - 1. Let x(i) = 7*i - 2. Let g(h) = -x(h) - 6*y(h). Let v be g(5). Find the third derivative of -5*k**2 + k**3 + 8 + v*k**2 - 8 wrt k.
6
Let m = 43 + -31. Let n = -4 + m. What is the first derivative of -n*l**2 + 31 - 16 - 13 wrt l?
-16*l
Let c(m) be the second derivative of -3*m**3 - 41*m + 7/10*m**6 + 0*m**5 + 0 + 0*m**4 + 0*m**2. Find the second derivative of c(p) wrt p.
252*p**2
Suppose 24 + 6 = 5*j. Let h(v) be the first derivative of 0*v**4 + 7 + 0*v**3 + 2*v**2 - 7/6*v**j + 0*v + 0*v**5. What is the second derivative of h(s) wrt s?
-140*s**3
Let d(k) be the second derivative of k**6/72 + 7*k**5/40 + k**4/12 + 6*k. Let w(j) be the third derivative of d(j). Find the first derivative of w(q) wrt q.
10
Suppose -5*x + 4*y + 377 = 0, -4*x + 3*x + 3*y = -71. What is the third derivative of x*l**5 - l**5 + 15*l**2 - 32*l**5 wrt l?
2640*l**2
Let t(a) be the first derivative of 131*a**4/4 - 273*a + 356. Differentiate t(j) wrt j.
393*j**2
Let l(z) be the first derivative of -18*z**4 + 150*z - 144. What is the derivative of l(v) wrt v?
-216*v**2
Let u = -1927 + 1929. Let y(v) be the third derivative of 0 + 0*v + 8*v**u + 1/3*v**3 + 0*v**4 + 1/20*v**5. Differentiate y(t) with respect to t.
6*t
Let b = -22 + 25. Find the second derivative of -2 - 23*m + 18*m + 2 + 11*m**b wrt m.
66*m
Let j = -1 + 14. Find the second derivative of j*p + 39*p**2 - 36*p**2 - 33*p wrt p.
6
Find the third derivative of -384*o**4 + 148*o**4 - 7*o**2 - 2*o - 155*o**2 + 3*o - 3*o**2 wrt o.
-5664*o
Let p(q) be the second derivative of -32*q + 0 - 17/6*q**3 - 9/2*q**2. What is the derivative of p(t) wrt t?
-17
Let g(s) = -s**3 - 1. Let w(h) = -210*h**3 - 66*h**2 + 12. Let p(j) = -12*g(j) - w(j). Find the third derivative of p(y) wrt y.
1332
Let z(o) be the second derivative of o**7/420 - o**6/60 + 2*o**4/3 - 10*o. Let l(q) be the third derivative of z(q). Find the second derivative of l(n) wrt n.
12
Let t = 33 - 31. What is the third derivative of -t*l**2 + 2*l**3 - 9*l**2 + 0*l**2 + l**2 wrt l?
12
Let j(s) = s**2 - 7*s - 4. Let i(c) = -3 + 9*c - 26*c + 10*c. Let d be 16/6*3/2. Let t(x) = d*i(x) - 3*j(x). Find the second derivative of t(r) wrt r.
-6
Let l(f) be the third derivative of -86*f**7/105 - 5*f**3/2 - 2*f**2 - 4. Find the first derivative of l(j) wrt j.
-688*j**3
Let y(x) = 2*x**2 - 4*x**2 - 7 - 713*x**3 + 714*x**3. Let n(c) = c**3 - c**2 - 5. Let u(v) = -7*n(v) + 5*y(v). Find the third derivative of u(l) wrt l.
-12
Let w(l) = -l**4 - 3*l**3 + l**2 - l - 1. Let q(i) = -2*i**4 - 3*i**3 + 50*i**2 - i - 351. Let c(o) = q(o) - w(o). What is the first derivative of c(x) wrt x?
-4*x**3 + 98*x
Let x(y) be the second derivative of -37*y**8/28 + 7*y**4/6 - 11*y**2 + 520*y. What is the third derivative of x(h) wrt h?
-8880*h**3
Suppose -4*q = -4*h + 72, -5*h - 2*q = -0*q - 90. Find the first derivative of h*s + 40 - 4*s - 16 wrt s.
14
What is the second derivative of -35*t**3 + t + 2*t - 11 - 14*t**5 + 35*t**3 wrt t?
-280*t**3
Suppose -2*g + 3 + 7 = 0. What is the derivative of 7*a**3 + g*a**3 - 4*a**3 + 19 wrt a?
24*a**2
Let o(x) be the first derivative of -4*x**4/3 - 5*x**2/2 - 13*x - 13. Let r(a) be the first derivative of o(a). Find the first derivative of r(s) wrt s.
-32*s
Let n(g) be the second derivative of 17*g**5/20 + g**4/12 - 155*g**3/3 - 2*g - 22. Find the second derivative of n(z) wrt z.
102*z + 2
Let t(k) be the first derivative of 2 + 0*k**2 + 1/5*k**5 + 0*k**4 + 0*k - 5*k**3. What is the third derivative of t(h) wrt h?
24*h
Suppose -13*x = -14*x + 309. What is the second derivative of 4*n**2 + 11*n - x + 309 wrt n?
8
Let s(w) be the third derivative of 1/24*w**4 + 0*w + 1/6*w**5 + 0*w**6 - 1/210*w**7 + 0*w**3 + 0 - 35*w**2. Find the third derivative of s(q) wrt q.
-24*q
Let h(n) be the second derivative of 61*n**7/42 + 13*n**3/3 + 80*n. Find the second derivative of h(r) wrt r.
1220*r**3
Find the second derivative of -154*p**5 - 390416*p**3 + 2 + 105*p + 390416*p**3 wrt p.
-3080*p**3
Suppose 60 = 9*l - 5*l. What is the third derivative of 7*q**2 - l*q**3 + 25*q**3 + 6*q**2 + 2*q**2 wrt q?
60
Let h(z) be the second derivative of 7*z**6/30 + z**4/6 - 82*z**2 - 6*z - 8. What is the first derivative of h(i) wrt i?
28*i**3 + 4*i
Suppose -2*u - 24 = -34. Find the third derivative of -535*q - 12*q**4 + 5*q**2 + 531*q + u*q**2 wrt q.
-288*q
Let i(h) = -711*h**3 + 9*h**2 + 1161. Let z(s) = 179*s**3 - 2*s**2 - 290. Let q(t) = -2*i(t) - 9*z(t). Differentiate q(g) with respect to g.
-567*g**2
What is the third derivative of 39030 - 60*z**3 - 39033 - 87*z**3 - 2*z**2 wrt z?
-882
Let l(r) be the third derivative of 443*r**6/120 - 79*r**5/20 + r**3/3 + 327*r**2. What is the third derivative of l(t) wrt t?
2658
Let k(d) = 32*d**3 + 27*d**2. Let |
Last year Nautilus lost the ability to show desktop icons — now GNOME developers plan to drop another familiar feature.
According to a code commit on Gitlab the famous file manager is set to lose the ability to run binaries and launch apps directly.
Or, to put it another way, you won’t be able to double-click on programs, scripts or apps to launch them using Nautilus.
This change could affect:
Binary .bin and .run files
App Images (.appimage)
Program shortcuts (.desktop)
Scripts (e.g., .sh)
It’s a bit of a head-scratcher; why is GNOME doing this?
Why GNOME developers are making this change
GNOME developers has reverted this change since this article was published. Discussions are taking place with community members about different approaches to address the “issue”.
GNOME developer Carlos Soriano made the commit referenced above.
In it, he reasons that without a desktop on which to place app shortcuts and binaries the express need to launch apps using Nautilus is ‘not as useful’ as it once was.
After all, the GNOME Shell desktop comes with a full-screen app launcher by default, and a slate of third-party app menu extensions are available.
Apps should be launched from an app launcher, and the file manager should manage files
Plus, for those who can put up with its slow start-up times — which is being worked on this cycle — the GNOME Software store offers ‘launch’ buttons beside apps you have installed.
“It was [once] common for apps to be delivered in a tarball, nowadays that’s out of question,” Soriano says.
“Not only that, but we are moving towards a more sandboxed system, and we should use the standard and system wide support for launching apps based on users choices.”
It’s a sound reasoning to be fair: Software should handle software and Files should handle, uh, files.
But there is a perhaps a more pressing reason why GNOME want to make this change.
Improving Security
Removing the ability to run binary files from Nautilus will help to improve security
Although it’s easy to joke about GNOME developers do not remove, retire or evolve features for fun or to spite anyone (at least, I hope not). All changes, even potential unpopular ones like this, tend to have one core goal in mind: improve the end-user experience.
In this instance, removing the ability to run binary files helps to improve security.
Containerised apps like Flatpak and Snappy offer system isolation and other security benefits, and Software stores are now common place. Most of us have little real need to install or run random binary blobs we download from the web, and if we do, we’re better off using the terminal to do it.
“As we saw in the past we allowed untrusted binaries to be launched [in Nautilus] and therefore we had a CVE (CVE-2017-14604) […] we are not in a position that we can let this issues slip,” Soriano notes.
By removing the ability to run binaries from Nautilus GNOME is trying to help to protect users machines from rogue and malicious code. The “run” option won’t be shown for untrusted or trusted launchers.
You Can Still Run Binary Apps Though
If you need to launch apps using a file manager there are alternatives
Corner cases exist, naturally.
There will be times when you need to run an app you download from the web, or which is provided in the form of a script, and so on. So while Nautilus (the file manager) is dropping the ability run binary files the GNOME desktop at large isn’t.
The command line is (as always) but a few key presses away, and other GUI tools for managing and launching apps are available.
And for those who really cannot cope without using a file manager to launch their favourite apps there is, as ever, the option to use a Nautilus alternative like Dolphin, Nemo, PCManFM, Caja, etc.
You might not be able to double-click on a binary to run it, but you can still right click > open with…
Another point to keep in mind is that just because Nautilus won’t handle running binaries (like AppImages) directly is perfectly possible that a Nautilus plugin or facilitator app could take over the task instead.
For example, instead of double-clicking on a binary to run it you would right-click > open with… > and select a compatible app.
Which brings me on to the final point I should stress: this change does not affect the “Open With…” option; Nautilus will continue to be able to open files with/in apps.
Will This Affect You?
Do you regularly run/launch software using Nautilus? Do you agree this change will make using GNOME safer? Let us know what you think about this issue in the comments below, but please try to keep things civil and constructive. |
203 A.2d 252 (1964)
Edward LIFMANN, Plaintiff,
v.
Harry ARONSON, Lawrence M. Aronson, Morris Draft, Seymour Rady, Clifford L. J. Siegmeister, Ben Cole, Saul Rubin, Donald Pollack, Charles J. Schaniel, Abe Fell, M. F. Lewis, Herman Segall, and Waltham Watch Company, Defendants.
Court of Chancery of Delaware, New Castle County.
August 28, 1964.
N. Maxson Terry and William H. Draper, Jr., Dover & James A. Thomas, Jr., of Lewis, MacDonald & Varian, New York City, for plaintiff.
Irving Morris and Joseph A. Rosenthal, of Cohen, Morris & Rosenthal, Wilmington, for defendants Harry Aronson, Lawrence M. Aronson, Morris Draft, Seymour Rady, and Waltham Watch Co.
MARVEL, Vice Chancellor.
Plaintiff claims to have been a stockholder of Waltham Watch Company since June 1961 and brings this suit derivatively for the alleged benefit of Waltham. He complains that the individual defendants Aronson, Draft and Rady, under the leadership of Harry Aronson, have controlled and improperly *253 managed the affairs of Waltham since 1959 so as to cause it compensable injury as hereinafter set forth. Plaintiff also charges that the above named defendants have conspired with the non-director Segall to conceal the true facts of the transactions complained of. He seeks joint and several accountings from the directors allegedly in control of the corporation as well as from the defendant Segall and the other named director defendants of Waltham.
The individual defendants Aronson, Draft and Rady as well as the corporation have appeared and filed a motion for summary judgment of dismissal of plaintiff's first and second causes of action on the ground that further judicial action on said causes is barred under the doctrine of res adjudicata, the claims therein asserted having been allegedly adjudicated in earlier New York and Delaware actions. Following an approved settlement in New York of the case of Fistel v. Aronson,[1] this Court granted summary judgment of dismissal of the Delaware consolidated Civil Action[2] Nos. 1159 and 1219 after finding that the allegations in the New York action and those asserted in the Delaware actions were identical in all material respects. This is the opinion of the Court on defendants' motion, it being assumed but not decided for the purposes of this motion that plaintiff is capable of bringing this suit.
In his first cause of action plaintiff alleges that from the year 1961 until the present the individual defendants have wrongfully concealed from Waltham and its stockholders the fact that they had improperly caused Waltham to assume certain contractual arrangements entered into by them with ten Swiss suppliers of watch movements. It is claimed that such undertaking was first saddled on Hallmark, Inc. when the individual director defendants were officers and directors of that corporation. The complaint goes on to allege that the individual defendants, having thereafter gained control of Waltham, caused Waltham to assume such improper obligation, said assumption having been designed and carried out in order to repay the Swiss suppliers for moneys advanced by them to the individual defendants to enable the latter to gain control of Waltham. The device used to bring about such repayment is alleged to have been a hidden premium consisting of 2.4 Swiss francs[3] charged on each of one million of watch movements to be purchased by Waltham from the Swiss suppliers over a term of five years. Plaintiff further alleges in his first cause of action that it had been orally agreed between the individual defendants and the Swiss suppliers that the premium referred to above should be hidden by being included on each invoice for watch movements as a payment "for research and development." According to plaintiff, the scheme outlined in his first cause of action resulted in a loss to Waltham of not less than $750,000, exclusive of interest payments, for which the individual defendants are individually and personally liable to Waltham. It is further contended that notwithstanding a purported settlement of litigation bearing on the matters complained of, Waltham has been further damaged in an amount in excess of $200,000 by reason of continuing payments being made under the improper premium arrangement referred to above.
While a second cause of action set forth in the complaint is concerned with the same matter complained of in the first cause of action, it is therein contended that the acts complained of resulted from a conspiracy entered into in January 1959 between the individual defendant directors and officers, *254 the defendant Segall and the Swiss suppliers for the purpose of concealing from Waltham's stockholders the improper premium arrangement alluded to in the first cause of action. Such second cause of action apparently seeks damages from the alleged conspirators in the same amounts sought in the first cause of action, namely $750,000 for damages sustained during the entire period of the allegedly continuing conspiracy and not less than $200,000 for the period from 1962 to date.
First of all, notwithstanding plaintiff's reliance on what he terms a plan of concealment as a basis for his suit, I am satisfied that the basic transaction here complained of was one of the subject matters of earlier stockholder complaints filed and adjudicated both in this Court and in the Supreme Court of New York, said complaints having sought relief from wrongs caused by the allegedly improper transfer of voting control of Waltham from the Axlers to the Aronsons, although such earlier complaints encompassed a number of other alleged breaches of fiduciary duty not mentioned in the present complaint. Thus, it was alleged in an uncontradicted affidavit filed on April 27, 1960 in the New York action of Fistel v. Axler[4] in support of defendants' motion for summary judgment that as an incident to transfer of the Axler stock carried out in connection with Mr. Harry Aronson's efforts to extricate Waltham from serious financial difficulties "* * * a group of approximately twelve Swiss watch suppliers designated Seymour Rady, Esq., an attorney of Chicago, Illinois, to act in their behalf in negotiations with the Axlers to purchase their stock of Waltham for a price not to exceed $650,000, provided that such purchase would be conditioned upon the net worth of Waltham, as determined by an independent audit, being shown to be not less than a stated minimum figure. * * *" (Para. 19, affidavit of Robert Schur). In fact, there is no real disagreement in the papers before me on defendants' motion as to the fact that a group of some ten or twelve Swiss watch manufacturers participated in a 1959 business transaction which led to the disposal by the Axlers of their 120,000 shares of Waltham and the loss on their part of voting control over the affairs of Waltham as part of a complicated arrangement which culminated in an exchange of Hallmark stock for that of Waltham. What plaintiff here seeks to counter, on his theory of concealment, are the inferences to be drawn from the fact that the plaintiffs in the New York actions failed in their efforts to establish that the Aronsons rather than the Swiss manufacturers were the true owners of the 120,000 Waltham shares. And while, to be sure, the first dispositive step in the case in which the Schur affidavit was filed was, perhaps by inadvertence, a severance and dismissal on the merits merely as to the Axlers, the charges concerning the Aronsons were later specifically dealt with judicially by the New York and Delaware courts. Thus, in the Delaware Fistel action, after a similar judgment as to the Axlers had been entered, the complaint was amended so as to plead in detail the same allegedly improper premium arrangement here complained of and such action (Civil Action 1159) was then consolidated with the Pohl action (Civil Action 1219) for the purposes of trial. Thereafter, after discovery had proceeded in both New York and Delaware, the several pending cases involving the remaining charges against the Aronsons were consolidated in the Supreme Court of New York and paragraph 19 concerning the acquisition of the 120,000 shares of Waltham stock owned by the Axlers and the arrangement for their payment through the alleged fraudulent device of a payment of 2.5 francs per movement disguised as a charge "* * * to cover research and development * * *", as set forth in the Delaware Fistel case, was incorporated in haec verba in the New York complaint in a similarly numbered paragraph.
*255 Meanwhile, however, general counsel for plaintiffs in the New York actions reached an agreement with counsel for the defendants whereby in return for dismissal of their consolidated action and the furnishing of releases the Aronson defendants agreed to transfer to Waltham 30,000 shares of Waltham stock, the equivalent of 150,000 shares of Waltham stock as of the time of their exchange for Hallmark shares in April 1959. Such proposed settlement was then referred to a referee for consideration. Having evaluated the various causes of action leveled against the Aronsons, including the one which charged "* * * the Aronsons with a plan to acquire control of Waltham with the use of Waltham's funds * * *", the referee reached the following conclusion and made the following recommendation as to such claim, namely, "* * * I conclude that the plaintiffs' second cause of action is not supported by the evidence submitted to me, nor has there been a showing of fraud * * *". The overall conclusion of the referee was that the proposed settlement was fair and adequate and that it should be approved and confirmed. Thereafter, the referee's report having been mailed to each stockholder of record of Waltham together with notice of a hearing date, such a hearing was held, the settlement was approved, the action dismissed with prejudice, and releases ordered to be given to the Aronson defendants. Finally, as noted earlier, on the basis of such judgment, this Court dismissed Civil Action Nos. 1159 and 1219 with prejudice.
Faced with the defense of res adjudicata, plaintiff does not attempt a collateral attack, professing that he does not "* * * seek to overturn the prior judgment of the New York court, or the subsequent judgment of this Court, based solely on New York's settlement * * *". He rather contends that he merely seeks to obtain relief for claims which were not dealt with in the prior litigation. However, I am satisfied that although plaintiff has made every effort to characterize his claim concerning the so-called hidden premium arrangement as different than that asserted in the earlier litigation, placing reliance on alleged oral contracts and on a so-called different theory of action, what he actually seeks is an opportunity to introduce additional trial evidence concerning a transaction which, in my opinion, has been put to rest in earlier litigation. This he may not do, Epstein v. Chatham Park, Inc., 2 Storey 56, 52 Del. 56, 153 A.2d 180. Plaintiff's grievances about the results of the earlier litigation would, if given the hearing he seeks, destroy the salutary effects of modern procedures for the settlement of stockholder derivative suits after notice to all stockholders of record. See Hornstein, Corporation Law and Practice § 731, and compare Barroway v. Reynolds (Del.Ch.) 176 A.2d 850. Finally, plaintiff's reliance on Darraugh v. Carrington, Sup., 50 N.Y. S.2d 481, aff'd 270 App.Div. 932, 62 N.Y. S.2d 241, is misplaced. In that case stockholders suing derivatively had not had their day in court in California on claims asserted in New York, it being pointed out in the opinion of the Appellate Division that prior to the entry of the California judgment relied on by defendants there was not "* * * an unequivocal calling upon the plaintiff in such action to introduce evidence in support of his claims."
To be sure, there may be error in the prior proceedings here relied on both as to facts and law, and a better settlement might perhaps have been made. Nonetheless, the New York judgment relied on by defendants, having become final after a settlement hearing, stands unimpeached, a final judgment on the merits rendered by a court of competent jurisdiction being conclusive as to the rights of the parties and their privies. There is no doubt but that the same evidence which would have successfully established the claim made in the earlier litigation based on allegedly improper methods used by officers and directors to gain control of 120,000 shares of Waltham stock would be required to establish the claim made here. Plaintiff's grievance *256 simply stated is that plaintiffs in the New York action were not sufficiently diligent and failed to unearth evidence which plaintiff professes to have now or to anticipate. This is no basis for a trial de novo. The point is, of course, that while counsel for plaintiffs in New York were commended by the referee "* * * for the zeal with which they pursued this cause of action by obtaining depositions and documentation in Switzerland * * *", such counsel were not satisfied with the evidence they developed in New York and Delaware discovery as a basis for trial. They thereupon negotiated an overall settlement which the referee agreed was fair and adequate and which the Supreme Court of New York approved. Such a judgment clearly has a res adjudicata effect, Rome v. Archer (Sup.Ct.Del.) 197 A.2d 49.
While the defendants Rady and Draft were not parties to the earlier litigation, Rady become a director of Waltham in February 1959 and Draft was elected a director on April 17, 1959. They could in no possible way be held liable to their corporation on plaintiff's theory of his case other than by reason of their participation in the steps taken towards acquisition of and payment for the Axlers' Waltham shares. Such transaction having been an integral part of the prior complaints and the claims thereon having been dismissed, the judgments therein entered enure to the benefit of the defendants Rady and Draft as well as to the benefit of the Aronsons, Coca-Cola Co. v. Pepsi-Cola Co., 6 W.W. Harr. 124, 36 Del. 124, 172 A. 260.
On notice, an order will be entered granting the motion of the appearing defendants for summary judgment of dismissal of plaintiff's first and second causes of action.
NOTES
[1] Supreme Court of the State of New York, County of New York, Index No. 9411-1959.
[2] Fistel v. Axler and Pohl v. Axler.
[3] At the argument on defendants' motion, counsel for plaintiff stated that the premium was actually 2.5 Swiss francs and that the figure of 2.4 set forth in the complaint was a typographical error. See also affidavit of James A. Thomas, Jr., in opposition to defendants' motion.
[4] Supreme Court of the State of New York, County of New York, Index No. 9411-1959.
|
Q:
Headphone jack not working in Windows 7
My headphone jack doesn't work under Windows 7 64 bit.
I tried the following things:
3 different headphones speakers
2 different versions of the Realtek driver (2.7 / 2.6)
Standard Windows 7 drivers
I can't see anything apart from "Speakers" in the playback devices (I have enabled Show hidden / deactivated devices). Under Ubuntu there is no problem whatsoever!
When I used the Realtek configurator I wanted to disable the auto-detection of plugged in speakers, but the option (the little folder icon) wasn't there, in neither version.
I use HDMI to connect my screen from time to time. The audio jack from the screen does work (sometimes!). But I guess that's unrelated, because even when I boot Windows without the screen, it still doesn't work.
A:
Try completely uninstalling the realtek drivers and then reboot and see if Windows propitery audio drivers detect.
Hopefully the audio device has been correctly detected by Windows, to check it go to "Device Manager"
|
A chromenoquinoline-based fluorescent off-on thiol probe for bioimaging.
A new chromenoquinoline-based fluorescent off-on thiol probe 2 is reported. In aqueous buffer solutions at physiological pH, the probe exhibited 223-fold enhancement in fluorescence intensity by a Michael addition of cysteine to the maleimide appended to a chromenoquinoline. Cell permeability and live cell imaging of thiols are also demonstrated. |
Ray Winstone
A strong character actor known for his multi-dimensional portrayals of hard men on the wrong side of the law, Ray Winstone burst onto the scene with a riveting performance in the British-made "Scum" (...
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Russell Crowe was left with bruised ribs on the set of Noah after fellow Hollywood hardman Ray Winstone repeatedly elbowed him in the chest. The pair stars in the upcoming Biblical epic and Crowe has previously told how he developed hypothermia during the tough shoot as he was filming in freezing water for hours at a time.
Now it has emerged it was not the only health issue Crowe suffered during filming, as British actor Winstone took joy in striking him in the ribs during a fight scene.
Crowe tells British magazine Event, "He's acting royalty, that man. All the way back to Quadrophenia and Scum. We did this fight sequence where Ray is lying on top of me - and there's a bit of weight to Ray - and every time we did a take, just prior to 'Action!', he would drive an elbow into my ribs. I said, 'Mate, why are you doing that?'. And he goes, 'Because you're younger and I'm old and you should know to look out for a bloke like me.' It was great."
British actor Ray Winstone has suffered a setback in his attempt to give up smoking after struggling to get to grips with an electronic cigarette. The Departed star has decided to kick his longtime addiction and opted to swap real smokes for a battery-powered device.
However, the actor was dealt a blow when he realised he didn't know how to work his e-cigarette.
Winstone tells Britain's Daily Telegraph newspaper, "I bought one of those false ones and I put the oil in the wrong end. I puffed on it and all the oil went in my mouth. It's like I was not destined to give up (smoking)."
British actor Ray Winstone was furious when he found out about his daughters' secret tattoos. The Indiana Jones and the Kingdom of the Crystal Skull star was apoplectic with rage when he discovered actress Jaime, 28, and her elder sister Lois had gone under the needle and kept the inkings hidden from their protective dad.
He tells Britain's Daily Telegraph newspaper, "They wouldn't tell me, but I found out and went berserk. I actually wanted to find the tattooist and kill him for scarring my daughters."
British actor Ray Winstone struggled with soaring temperatures while shooting biblical epic Noah and almost fell down some stairs after he was overcome on set. The film - in which Winstone stars as Noah's nemesis Tubal-Cain - was shot in New York at the height of summer and he suffered through the heat in a heavy costume and make-up.
His co-star Emma Watson describes his ordeal to Wonderland magazine, "We started filming in the summer in New York. It was so hot that Ray Winstone at one point, who wore a beard and heavy make-up, nearly fell down a flight of stairs. His make-up was literally melting off his face."
Actor Ray Winstone vowed to avoid boozing on the set of new British drama Moonfleet in Ireland after spending weeks in a drunken haze the last time he was shooting on the Emerald Isle. The Departed star plays an 18th Century smuggler in the upcoming two-part Sky TV drama, and he headed to Dublin, County Kildare, and County Wicklow to shoot scenes for the swashbuckling show.
The trip brought back memories of his last time filming in Ireland, when he starred in 2004 movie King Arthur alongside Keira Knightley, and he was determined to avoid the local bars after becoming sucked into the country's legendary drinking culture.
Winstone tells the Irish Mirror, "When I was on King Arthur, we were out all the time. I think everyone was drunk on that job for four and a half months. I actually moved out of Dublin - I was staying at the Four Seasons - and I went: 'I've got to get out of Dublin because I'm just p**sed all the time'.
"I said: 'I've got to go', so they found me a little place... I said: 'I'm going to live there, on an old farm place, I'm going to live there for the duration of filming'. And nothing changed. I was on the p**s (drinking) but the only difference was that I was looking at mountains instead of the town of Dublin... But I'm getting older now, I can't do that so much anymore, can't be out working in the morning if you do that."
Asked if he had been boozing while filming Moonfleet, the 56 year old replies, "Not this time, we haven't had the time... For this film, it was the time (that prevented drinking), but if I'd been younger, I think I would have made the time. That's probably where I made a mistake in the past, I just couldn't wait to get out and probably stay out all night, and go straight to work the next morning. But I just can't do that no more (sic), physically and mentally."
Actor Danny Dyer decided to accept a role in longrunning British soap opera Eastenders over fears his career had become a joke following a string of film flops. The Business star will join the beloved show at Christmas (13) after spending several years snubbing offers from BBC bosses to become a member of the cast.
Now he reveals his floundering film career pushed him to take the leap to the small screen, and he hopes he can turn his fortunes around like his idol Sir Michael Caine.
Dyer tells Britain's The Sun newspaper, "Back in the Eighties, Michael was known for making terrible films and now he's been knighted. I can hope!
"I did too many people favours (accepting film roles). I realised, 'F**king hell, I'm becoming a bit of a joke here.' I'm my own worst enemy. I don't blame anyone but myself."
Dyer's most recent big screen release, Run for Your Wife, which also features Ray Winstone and Girls Aloud singer Sarah Harding, was deemed a massive failure after it earned just $963 (£602) from U.K. ticket sales in February (13).
Hollywood star Sean Penn stopped traffic in London over the weekend (07-08Sep13) as he filmed scenes for new movie The Gunman. The actor spent Sunday (08Sep13) shooting footage for the upcoming thriller on the famed Tower Bridge as a low-flying helicopter zoomed overhead and passers-by crowded round to watch.
Penn stars as Martin Terrier, an international spy trying to clear his name so he can retire to be with his longtime love.
The Gunman, which also stars Idris Elba, Javier Bardem and Ray Winstone, is due in cinemas next year (14).
Ryan Gosling is undoubtedly one of the most crushed on celebrities of the 21st century. Girls' hearts exploded when they watched him kiss Rachel McAdams in the rain in The Notebook, and ever since then their opinions have not wavered. But if you take a closer look, you'll see that since the beginning of his movie career, he has steadily played psychologically unsound weirdos film after film. So what is it about the Gos that makes girls swoon, no matter how creepy he is on film? Oh yeah, it's probably because he's really, really ridiculously good-looking, with or without a pedo 'stache.
GALLERY: Ryan Gosling's Creepy Roles
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More:Why We Love Charlie's AngelsWhy You Should Know Ray WinstoneThe Detail 'The Book Thief' Trailer Leaves Out
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These actors have a history of playing bullies, ruthless killers, evil masterminds, and all-around badasses. Their distinct physical appearances (weathered, dark-haired, unsmiling) and general demeanors (quiet, menacing, and angry all the time) make them the perfect villain or antihero type. Unlike some actors who can play both the tough guy and the big, loveable goofball (we're looking at you, The Rock — you, too, Vin Diesel), these guys are just too fearsome to play mannies and tooth fairies. You might want to avoid direct eye contact, as we present to you the six most badass badasses in Hollywood.
GALLERY: 6 Most Badass Badasses in Hollywood
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More:7 Miscast SuperheroesWhy You Should Know Ray Winstone'The Bridge' Is Funner Than You Think
From Our Partners:40 Most Revealing See-Through Red Carpet Looks (Vh1)15 Stars Share Secrets of their Sex Lives (Celebuzz)
If presented with a picture of Ray Winstone, you'll probably think to yourself, "Oh yeah, that guy." He looks familiar because there's a good chance you've seen one of his movies. The character actor has been in some major films over the last 10 years, such movies as Cold Mountain, The Departed, Hugo, and Snow White and the Huntsman, but you've probably never heard of him. Well here's your chance to get to know him with six fun facts about the British chameleon, who you'll no doubt be seeing plenty more of on the big screen.
You Probably Know Him Best From Sexy Beast
His most prominent role was in Sexy Beast, in which Winstone played the lead, Gal Dove, opposite villain Ben Kingsley. Winstone's performance in Sexy Beast as a loveable but hapless retired ex-con is solid, but he was unerstandably upstaged by Kingsley's rapid-talking, short-tempered psychopath, a role that garnered Kingsley an Oscar nomination.
Or Maybe The Departed
Martin Scorsese's wildly successful The Departed put Winstone on the map once again as tough guy Mr. French. His character is one of the most memorable in a stellar ensemble cast that includes Jack Nicholson, Leonardo DiCaprio, and Matt Damon. To audiences, he's the guy who slams Billy's (DiCaprio) arm cast on the table so hard it breaks, while Billy screams in pain, and as the guy who wryly repeats the film's infamous line, "What is it, your period?" when Billy orders a cranberry juice.
He Played a Dwarf
In a departure from his tough-guy roles, Winstone played one of the dwarves in 2012's Snow White and the Huntsman. Perhaps it's his physical stature, or just his incredible range as an actor, but he really made his character, Gort, come to life, and he gave him that rough-and-tumble edge that he gives all of his characters. So I guess his dwarf was a tough guy after all.
Scorsese Seems to Love Him
After his turn in The Departed, Scorsese decided to cast Winstone in Hugo, in which he plays the title character's alcoholic uncle Claude. Though this was a smaller role for the British actor, we feel safe betting that the legendary director will seek him out again in the future.
He Does Action Movies Like The Sweeney
Even at the age of 56, he still gets down and dirty in gritty action movies like 2012's The Sweeney, in which he plays Detective Inspector Jack Regan, who leads the London Metropolitan Police department's Flying Squad, aka the armed police. Not only does Winstone beat people up and partake in car chases, but he also gets raunchy with Hayley Atwell's character. Not too shabby.
His Voice
Winstone has the kind of gritty voice and Cockney accent that lends well to the screen, so much so that it's often just his voice. Winstone has done several voice-over roles, including Rango, The Chronicles of Narnia: The Lion, The Witch, and the Wardrobe, and Beowulf. So even if his face doesn't look familiar, you've probably at least heard him on screen.
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More:Star Watch: 5 New Stars on the Rise'Mr. and Mrs. Smith' Is More Than Tabloid FodderWhat Would Jason Bourne Do?
From Our Partners:40 Most Revealing See-Through Red Carpet Looks (Vh1)15 Stars Share Secrets of their Sex Lives (Celebuzz)
Title
Featured as a loan shark in Anjelica Huston's 1967 Dublin-set drama "Agnes Browne"
Cast in the fourth Indiana Jones film series, "Indiana Jones and the Kingdom of the Crystal Skull"
Portrayed a working-class father who, along with his wife, must cope with the accidental death of their young son in the British telefilm "Our Boy" (screened at Toronto International Film Festival)
Starred in "Births, Marriages and Deaths," a four-part BBC TV series
Played recurring role of a gangster in the British series "A Fairly Secret Army"
Cast in Anthony Minghella's ensemble "Breaking and Entering"
Portrayed the title character in Robert Zemeckis' big-budget film version of "Beowulf"
Acted in "My Father, The Liar," a Bob Hoskins-directed segment of the omnibus film "Tube Tales"
Played leading role as a family patriarch in "The War Zone," an incest themed drama marking Tim Roth's directorial debut; screened at both the Sundance and Cannes Film Festivals
Appeared in the romantic comedy "Martha, Meet Frank, Daniel and Laurence" (released in the USA as "The Very Thought of You" in 1999); film starred Monica Potter, Joseph Fiennes, Rufus Sewall and Tom Hollander
Cast as one of the eight dwarfs in "Snow White and the Huntsman" opposite Kristen Stewart and Charlize Theron
Played a CIA officer covering up a murder in the film adaptation of "Edge of Darkness"
Appeared in "Ladies and Gentlemen, the Fabulous Stains," starring Diane Lane as a teenage punk star
Was in the ensemble of the drama "Last Orders"
Voiced Mr. Beaver in "The Chronicles of Narnia: The Lion, the Witch, and the Wardrobe," based on the children's novel by C.S. Lewis
Starred in Patrick Marber's play "Dealer's Choice"; transferred to the West End
Discovered by director Alan Clarke and hired to play reform school terror Carlin in the BBC telefilm "Scum" (shelved by censors for content)
Appeared in Ken Loach's "Ladybird, Ladybird"
Returned to the stage in the Royal Court production of "Some Voice"
Cast in Martin Scorsese's mob drama, "The Departed"
Had title role in the British TV series "Fox"
Starred in the BBC sitcom "Get Real"
Had first real romantic lead opposite Kerry Fox in "Fanny and Elvis"
Starred in "The Proposition," an Australian western written by musician Nick Cave
Reprised his role for Clarke's feature remake of "Scum"
Was a championship boxer, losing only eight of 88 bouts
Starred alongside Robert Carlyle as a career criminal who betrays his cohorts in "Face," helmed by Antonia Bird
Starred in Jez Butterworth's stage play "The Night Heron" at London's Royal Court Theatre
Starred as Will Scarlett in the British TV series "Robin of Sherwood"
Played Teague in the drama "Cold Mountain"
Appeared in "King Arthur" with Clive Owen and Keira Knightley
Portrayed rocker Kevin in "Quadrophenia," a Mods vs Rockers tale inspired by The Who's album of the same name
Starred in "Sexy Beast"; screened at Sundance in 2001
Starred in "Tank Malling" as titular investigative reporter
Attended drama school; was asked to leave because of an incident involving his sabotaging of the headmistress' car
Cast in Martin Scorsese’s family adventure "Hugo"
Made a a triumphant return to form with a starring role as the raging Raymond in Gary Oldman's "Nil By Mouth"
Appeared in the Donmar Warehouse production of "To the Green Fields and Beyond," directed by Sam Mendes
Initial collaboration with Kathy Burke, starring in the stage play "Mr. Thomas," written and directed by Burke
Summary
A strong character actor known for his multi-dimensional portrayals of hard men on the wrong side of the law, Ray Winstone burst onto the scene with a riveting performance in the British-made "Scum" (1979), only to spend the ensuing decade wallowing in lesser roles unworthy of his talents. Forced into bankruptcy and on the outs with acting by the end of the 1980s, Winstone re-emerged with an acclaimed performance in friend Kathy Burke's stage play, "Mr. Thomas," which not only helped relaunch his career, but also invigorated his confidence. Ever since that play, Winstone developed into a highly-sought performer who - with age and experience - gravitated towards more complex characters, portraying often violent men with a strong degree of sympathy, as he did playing an abusive alcoholic in his breakthrough performance, "Nil By Mouth" (1997). But it was his turn in "Sexy Beast" (2001), as a reticent ex-con beset by a rabid ex-colleague trying to recruit him for a job, which earned Winstone some of the highest praise of his career. From there, he entered into the realm of the high-profile Hollywood feature, appearing in "King Arthur" (2004) and "The Departed" (2006), before co-starring in perhaps one of the most anticipated summer movies of all time, "Indiana Jones and the Kingdom of the Crystal Skull" (2008). Acclaimed projects like "Hugo" (2011) and "Great Expectations" (PBS, 2012) only solidified Winstone's reputation as one of the most prolific and acclaimed actors of his generation to cross the Atlantic.
Name
Role
Comments
Elaine Winstone
Wife
Married c. 1978; separated briefly in the early 1990s when Winstone declared bankruptcy
Education
Name
Edmonton County School
Corona Stage Academy
Notes
Winstone on the aftermath of his intense and startlingly realistic portrayal of a violent husband in Gary Oldman's "Nil By Mouth": "Well, I didn't emerge unscathed. That's the truth of it. I mean, 'Nil By Mouth' is a very harrowing film. But it wasn't harrowing to make. We had a ball doing it. Lots of laughs. It was only when the filming was over that I started asking myself was there something in me that was like the character? Was I capable of showing that kind of rage myself? It can be quite frightening when you start worrying about stuff like that. But it soon passes. You get offered another role and start getting into that." – quoted in Loaded, December 1997
"You know directing is a hard game and life is too sweet for all that aggravation. When I finish a film I go home. Sit in an editing suite for three months? Sod that. I've been paid, thank you very much, see you at the premiere." – Winstone on following in the footsteps of actor-directors Gary Oldman and Tim Roth, quoted in The London Times, Jan. 8, 1999
Winstone on his character on the BBC's "Births, Marriages and Deaths": "Even though he's the baddie, I play him as the goodie. I think it's more interesting to play it the opposite way. Even Hitler had someone who loved him" – quoted in Inside Soap, Feb. 19-March 5, 1999 |
Space enthusiasts in certain regions of the world will get free seats to a potentially once-in-a-lifetime event on the celestial stage later this month.
On July 27, lucky stargazers will see the longest total lunar eclipse of the 21st century ― also known as a blood moon. The nearly two-hour total eclipse will be visible to people in parts of Africa, the Middle East and Asia, according to NASA.
Blood moons are not unusual occurrences. Still, these dramatic celestial events have inspired both awe and alarm throughout the centuries ― including among some fringe segments of American Christianity that take the appearance of blood moons to be a sign that the apocalypse is drawing nearer. |
1. Field of Invention
This invention relates to abrasion resistive packaging, such as packaging to protect a photoreceptor of a print device.
2. Description of Related Art
In current printing applications, print cartridges are incorporated in printing devices. The print cartridges contain a printing material, such as toner. Typically, the print cartridges are replaceable, and the print cartridges are discarded when they run out of toner, and a new print cartridge is inserted into the print device. The disposability of the print cartridges requires that new print cartridges be shipped. |
/*
* Copyright (c) 2002-2020 Gargoyle Software Inc.
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*/
package com.gargoylesoftware.htmlunit.svg;
import java.util.Map;
import org.apache.commons.lang3.StringUtils;
import com.gargoylesoftware.htmlunit.SgmlPage;
import com.gargoylesoftware.htmlunit.html.DomAttr;
import com.gargoylesoftware.htmlunit.html.ScriptElement;
import com.gargoylesoftware.htmlunit.html.ScriptElementSupport;
/**
* Wrapper for the SVG element {@code script}.
*
* @author Ahmed Ashour
*/
public class SvgScript extends SvgElement implements ScriptElement {
/** The tag represented by this element. */
public static final String TAG_NAME = "script";
private boolean executed_;
/**
* Creates a new instance.
*
* @param namespaceURI the URI that identifies an XML namespace
* @param qualifiedName the qualified name of the element type to instantiate
* @param page the page that contains this element
* @param attributes the initial attributes
*/
SvgScript(final String namespaceURI, final String qualifiedName, final SgmlPage page,
final Map<String, DomAttr> attributes) {
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Read More About
There’s nothing quite as revitalizing as a cold drink on a hot summer afternoon. These days, however, restaurant guests are looking for more than just refreshment from their cold beverages. They are seeking fewer calories, healthful options, or, perhaps, a jolt of energy.
Cold beverages, particularly carbonated ones, have been part and parcel of quick-service restaurants from the time the first units opened. Coca-Cola, for instance, has been served at White Castle since 1921, the year the business began.
Fizzy drinks, as a group, are still the most popular beverage option at limited-service restaurants, but noncarbonated drinks are picking up steam. Iced teas and coffees, various waters, lemonade, and juices have been growing quickly.
“There is absolutely more consumer interest in a wider array of beverages, and restaurant operators have realized that,” says Maeve Webster, research director at Datassential, a food industry market research firm and consultant with offices in Chicago and Los Angeles.
This is partly an aspect of the overall customization bent, which focuses on giving diners more options to meet their wants and needs.
“The marketplace is splintering,” says Gary Hemphill, senior vice president of information services at Beverage Marketing Corp. (BMC), a New York–based research and consulting firm. “People want more variety now and that means more beverage choices.”
This trend has been developing for the past few decades, but has become increasingly notable in recent years. According to BMC statistics, carbonated drink volume has declined seven consecutive years as consumers gravitate to noncarbonated choices.
“These are often items that have a healthier image, whether or not they really are, including teas, bottled waters, and functional products like energy drinks,” Hemphill says.
The BMC annual report for 2011 found that major carbonated brands made up half of the top 10 liquid refreshment beverages and bottled waters took three more spots. The other two were PepsiCo’s Gatorade energy drink and Tropicana fruit brands.
Energy drinks, which appeal to young males, were the fastest-growing beverage category, with annual volume jumping 14.4 percent. Coffees and teas also showed strong gains.
“[Quick-service] restaurant operators understand what is going on in the marketplace, with people looking to make different beverage choices,” Webster says. Offering a variety of drinks “increases owners’ flexibility and gives them the opportunity to compete better.”
Excepting carbonated beverages, the beverage offered most at limited-service restaurants is tea, particularly iced tea, which is on the menu at 63.2 percent of quick serves, according to Datassential. That is followed by various waters, which are on 57.5 percent of menus.
The water total may be underreported since many restaurants don’t list water on their menus if it comes from the tap or from a tab at the fountain dispenser.
Various brands of bottled water are in 46.6 percent of quick serves, while penetration is 5.5 percent for spring water, 4.3 percent for vitaminwater, and 3.1 percent for sparkling water.
The vitaminwater brand showed the biggest compounded annual growth of any beverage at fast feeders over the past five years, rising more than 27 percent per year. The next two are green tea and San Pellegrino mineral water, both at about 16 percent a year.
An old favorite, lemonade, is on the menu at 54.4 percent of limited-service units, while coffee is on 51.6 percent and orange juice is on 51.1 percent.
Juices, mostly orange and apple, appeared increasingly on menus in recent years as more quick serves added breakfast or replaced carbonated drinks on children’s menus.
“The push to get kids to move away from sodas and eat healthier led to the boost in juice offerings, even if they may not have less sugar,” Webster says. “It’s all about feeling better about what you are ordering.”
Offering a wide range of beverages also “is a way for [quick serves] to differentiate themselves from the competition,” Hemphill says. “Historically, [quick serves] have lagged a little in trends, but if an operator can figure out a way to move faster, there is opportunity.”
Not surprisingly, limited-service restaurants have been adding noncarbonated cold beverages at a rapid pace. According to statistics from MenuMonitor, the menu-tracking database created by restaurant market research and consulting firm Technomic Inc., there were more than 200 new cold beverages recently added at quick serves.
Iced teas made up the largest chunk of those additions, followed by iced coffee and waters.
“There have been a lot of innovations in tea because it has such a healthy halo,” Hemphill says. “It’s also a base for innovation, like green tea, that appeals to the sophisticated tea drinker but also for those seeking a healthier option.”
An increasing number of quick serves offer or have added fresh-brewed iced and sweet teas to meet consumers’ growing demand for a fresher, better-tasting product.
At the same time, iced and chilled coffee, espresso, and related beverages have grown steadily in the wake of aggressive marketing by coffee chains, such as Starbucks, and the addition of these types of drinks at McDonald’s and other extended-menu fast feeders.
“Americans had traditionally consumed coffee hot, but the cold coffee hurdle has been leapt,” Hemphill explains. “Most Americans are now comfortable in drinking coffee cold. So now it’s a year-round product, hot more often in winter, cold more often in summer.”
Iced coffees carry fairly high margins, he adds, and while some of the products may be labor intensive and time consuming, restaurants can do well with these items if they become part of the core strategy and generate strong repeat purchases.
While fountain drinks are a long-time staple at limited-service eateries, a number of outlets, including pizza parlors, sub shops, and fast-casual restaurants, also feature refrigerated cases that contain bottled or canned cold drinks.
The cans and bottles—glass or plastic—in fast-casual refrigerators, for instance, are often drinks not available at the fountain, including upscale carbonated beverages, flavored waters, teas, vitaminwater, and even beer.
As some mainline quick serves try to compete with fast casuals, they are considering adding their own refrigerated cases. Wendy’s is testing several ideas at its new prototype units, including a refrigerated case that includes some regular items (bottled water, milk and chocolate milk, and packaged apple juice) as well as nontraditional ones, such as canned NOS energy drinks.
The units are also trying out several iced coffees and Coca-Cola’s Freestyle dispensing machines, which offer Coke’s Dasani still water and other brands in a variety of flavors.
Wendy’s continues to measure customer feedback, sales, and costs for all these offerings, says company spokesman Denny Lynch.
Firehouse Subs is already sold on the customization potential of the Freestyle dispensers. The chain last year completed installation of the machines in all 500 of its restaurants.
“There are so many possible drink permutations,” says Don Fox, CEO of the Jacksonville, Florida–based company. “The Dasani water, for instance, has seven different flavors and those can be mixed any way the customer wants.”
The Freestyle offers more than 120 drink options, and that “certainly adds value,” Fox notes. “It’s all about segmentation and satisfying the consumers.”
Even with all of the beverage possibilities, Firehouse would not have added the machines if Coca-Cola did not include one thing not typical for the beverage company: a noncarbonated cherry syrup drink for making the chain’s cherry limeade.
Cherry limeade makes up 21 percent of the chain’s beverage sales.
“When our first restaurant opened in 1994, the cherry limeade was hand mixed,” Fox says. “Later we went to a mix [for the cherry drink’s base], but the founders weren’t really happy with it, so it was never sold outside Jacksonville.”
Within the past four years, however, the cherry base was deemed good enough to go system-wide. Guests squeeze lime wedges into the cherry drink to make limeade.
“We know it’s expensive to do that, but we build that into our cost of doing business,” Fox says. “It adds a quality halo to our beverage offerings.”
The Freestyle has helped Firehouse attract more dine-in business, particularly among families, and boosted the average ticket from $10.25–$10.50 to $11.25–$11.50.
One chain that combines a coffee house with a fast-casual bakery-café is Cosi. The company resulted from the 1999 merger of Xando Coffee and Bar with Cosi Sandwich Bar and provides guests a range of cold beverages, from coffees to specialty lemonades.
“We think it’s important to our guests to give them the combinations they want,” explains Keith Stewart, marketing director of the Deerfield, Illinois–based chain.
The company has seen an increase in customer demand for water products, but not at the expense of other beverages. “It’s additive,” Stewart says, “particularly with drinks like smartwater and vitaminwater,” which include electrolytes, minerals, vitamins, and herbs.
Cosi also has made a point of creating proprietary cold teas and coffees, including Ginger Green Tea, which the company will be premiering this year. And then there are the lemonades: Strawberry Pomegranate and Mango Pomegranate.
This year, Habanero Watermelon Lemonade, a limited-time offer, will return. The sweet drink, which has a hint of heat, arrives with four big pieces of watermelon on a skewer.
“We have so much produce on our menu that it’s easy for us to have strawberries to garnish a beverage or to add watermelon to our order,” Stewart says.
At Quiznos, beverages “are a very integral part of our offerings,” says Zach Calkins, vice president of culinary creations. “It’s a natural fit to combo” a drink with food.
Tea and noncarbonated bottled beverages, particularly waters, are popular with salads.
Last year, Quiznos, with about 2,300 U.S. locations, relaunched its tea offerings with three new blends: unsweetened, black tea infused with raspberry, and green tea with lemon, lime, and honey. Sweet tea is available at locations in the South.
The Denver-based company is also upgrading its lemonade. A new honey lemonade was tested last year in six markets and is now rolling out system-wide. Franchisees can choose this variety or the traditional raspberry lemonade.
“It’s optional,” Calkins says. “Markets like Salt Lake City and Albuquerque love this new lemonade, while markets in the South want the raspberry lemonade.”
Quiznos also offers a wide range of Pepsi’s Sobe bottled beverages. While some varieties, like green tea, consistently do well, the company regularly switches flavors in and out.
“We rely on our partnership with Pepsi to see where consumers are and what they want,” Calkins says. “It depends on what is popular in a particular area. They may tell us that a drink is really moving and recommend we put that in our cooler.”
The idea of having many beverages available gives customers plenty of choices, so there is less chance for drinks to result in a veto vote.
“By having all these options, we have not seen a downtick in our carbonated drinks at the expense of more people choosing other beverages,” Calkins explains. “You’ve got to zig and zag with consumers and try to stay ahead of them and what they crave.” |
Introduction {#Sec1}
============
Human-caused degradation of the natural environment is increasing, and a major driver of such degradation is artificial light at night (ALAN)^[@CR1],[@CR2]^. Over the last 100 years, since lighting technologies were developed and urbanization has progressed^[@CR3]^, ALAN has disrupted the natural nocturnal environment, worldwide. Presently, 23% of the earth's land mass experiences ALAN^[@CR4]^, and the level of light pollution is growing approximately 2% a year^[@CR5]^. Because most terrestrial biota have been exposed to regular cycles of sunlight and darkness throughout evolutionary history, disruption of the nocturnal environment by ALAN has ecological impacts on the biota^[@CR6]^.
In just a few decades, there has been a broad range of studies on the impacts of ALAN. For example, ALAN can alter foraging behaviour^[@CR7]--[@CR9]^, migratory behaviour^[@CR10],[@CR11]^, physiology^[@CR12],[@CR13]^ and mortality rates^[@CR14]^. More recently, some studies have found that population dynamics^[@CR15]^ and species interactions^[@CR16]^ can also be altered by ALAN. Whereas it is clear that ALAN can have significant effects on wildlife, its impacts may be complex. For example, many kinds of nocturnal invertebrates, such as beetles, flies, and moths, are attracted to artificial light ^[@CR17],[@CR18]^, which may have significant implications for populations and communities of these groups^[@CR19],[@CR20]^. In addition, however, attracted invertebrates are a food source for nocturnal predators of invertebrates, such as geckos, anurans, bats, and birds^[@CR21]--[@CR23]^. Although such phenomena are well documented^[@CR21],[@CR23]^, few studies quantify the effect of increased food availablity on predators, although they may be among the strongest impacts of ALAN. If, for example, mesopredators are attracted to areas with ALAN, and then consume other groups, this could be an important impact on community dynamics, given the impact of mesopredator release in other systems^[@CR24]^.
Furthermore, the effect of increased food availability on predators of invertebrates caused by ALAN may be influenced by various environmental factors, because the amount of invertebrates attracted to ALAN probably varies with weather and environment. For example, increasing temperature or rainfall may increase the number of invertebrates attracted to ALAN^[@CR1],[@CR6]^. On the other hand, increasing wind speed and ambient light, such as moon light, may decrease the effect of artificial light on invertebrate activity^[@CR1],[@CR6]^. It is likely that these effects on invertebrate activity flow on to influence predation success. This chain of reasoning has not been examined, but to better predict the impacts of ALAN on predators of nocturnal invertebrates, it appears we may need to understand the influence of a variety of environmental variables on predation success.
Although many previous studies have examined the effects of ALAN on native species, few have examined interactions between ALAN and invasive species^[@CR25]^. While both ALAN and invasive species are global issues causing biodiversity loss and degradation of ecosystem function, these issues have been considered separately^[@CR25]^. They may interact, however, because invasive species often proliferate in urban areas, which are a major source of ALAN. There are many reasons why invasive species inhabit disturbed environments^[@CR26]^, and ALAN may be a contributing factor. For example, the abundance of invasive house geckos was higher in artificially lit environments^[@CR27]^, and they may be more willing to use artificially lit environments to obtain food resources than are native geckos, suggesting ALAN might contribute to their invasion success, globally^[@CR28]^. Revealing the potential impact on invasive species of ALAN could provide important insights for the management of invasive species.
Cane toads (*Rhinella marina*) are a tropical invasive species, originally native to south America^[@CR29],[@CR30]^. Originally introduced to control agricultural pests^[@CR31]^, they have been introduced to the Carribean, most Pacific Islands, several Japanese Islands, and to Papua New Guinea and Australia. Famously, cane toads produce highly toxic secretions stored in their parotoid glands, which are used as anti-predator defences^[@CR30]^. It has been well documented in Australia that when native predators, including snakes, lizards, crocodiles, and marsupials attempt to consume toads, they are often poisoned^[@CR31]--[@CR36]^. Thus toads typically have negative impacts on the native biota, and require management globally. Toads feed on nocturnal invertebrates, and ALAN provides an artificially large food resource for toads^[@CR37],[@CR38]^. Although ALAN may have a positive effect on the invasion success and proliferation of toads, environmental factors influencing the food intake of toads have not been investigated. Revealing environmental factors associated with the indirect effects of ALAN on toads could contribute to efficient management of invasive cane toads.
Here, we experimentally quantified the influence of ALAN on food intake in toads. In addition, we determined the effect of four environmental factors: ambient light, temperature, rainfall and wind speed on food intake by toads in the field. We constructed field enclosures supplied with artificial light for toads in northeast Australia. The toads were allowed to feed freely overnight, after which they were euthanised, and we measured the mass and taxonomic composition of their gut contents, and categorized them as 'flying' or 'non-flying'. We hypothesized that the mass of the gut contents of toads would increase with increasing temperature and rainfall, and with decreasing wind speed. We based these predictions on the likely impact of these environmental variables on invertebrate activity^[@CR1],[@CR6]^. Similarly, we hypothesized that the mass of toad gut contents would increase with decreasing lunar phase, and with ambient light pollution levels. We based these predictions on the likely impact of light sources (i.e., the moon and ALAN) on invertebrate activity in the vicinity of our artificial light, and assumed that toads would eat more if more invertebrates were available.
Material and methods {#Sec2}
====================
Experimental design {#Sec3}
-------------------
We constructed six outdoor experimental enclosures in rural areas vegetated with open eucalypt forest (mainly popular gum \[*Eucalyptus platyphylla*\]) with a grassy understorey around Townsville, Queensland, Australia (Fig. [1](#Fig1){ref-type="fig"}). Three enclosures were set along Hervey's Range road and the others were set along the Bruce Highway. The distance between these sites were 5--15 km (Fig. [1](#Fig1){ref-type="fig"}). We drove four iron piles \[star pickets\] into the ground at the corners and wrapped these with UV stable plastic sheeting as walls (Fig. [2](#Fig2){ref-type="fig"}, Supplementary Fig. [S1](#MOESM1){ref-type="media"}). Each enclosure measured 4 \* 4 m, with walls 1.2 m high, and we provided a plant pot as a refuge. Light globes (100 W, Fluorescent Light Bulb (A Type) EFA25ED/21-A101H, Asahi Electric CO., LTD. Osaka, Japan.) were placed 1.5 m high at the centre of each enclosure, and car batteries (which lasted all night without recharge) were used as a power supply for the lights (Fig. [2](#Fig2){ref-type="fig"}, Supplementary Fig. [S1](#MOESM1){ref-type="media"}). This light bulb has three peaks in the spectrum (blue \[400--450 nm\], green \[500--600 nm\] and red \[600--650 nm\]) to simulate daylight. We collected toads from Townsville and kept them without food for 40 h to ensure they had empty guts. We provided toads with water before each trial, to ensure they were fully hydrated. We then added five, randomly selected toads to each enclosure before sunset, and toads were allowed to feed overnight within the enclosure. The next morning, all of them were humanely euthanised using an overdose of buffered MS-222 (tricaine methanesulfonate) in a bath, and dissected in the laboratory at James Cook University. We recorded the mass of prey from each toad's gut, and calculated the average gut content mass per trial (per night and per enclosure). Because toads in a trial were non-independent, we used average gut content mass per trial, as our measure of 'predation success'. We conducted each trial for six days with different toads each day (applying a light-on treatment and light-off control, alternately) at each enclosure from December 2017 to April 2018. We also recorded light pollution levels at each enclosure, once, at the dark-moon phase, using a light meter (LUX METER FT3424, HIOKI E.E. CORPORATION, Nagano, Japan). Light pollution levels were as follows: site 1: 0.00 Lx, site 2: 0.01 Lx, site 3: 0.22 Lx, site 4: 0.00 Lx, site 5: 0.01 Lx, site 6: 3.65 Lx. We categorized them as follows: 0.00 Lx: no light pollution, 0.01 Lx: low levels of light pollution, 0.22 Lx: moderate levels of light pollution, 3.65 Lx: high levels of light pollution. When the lights were on, light intensities on the floor of the enclosures were as follows: site 1: 7.34 Lx, site 2: 7.59 Lx, site 3: 7.57 Lx, site 4: 7.30 Lx, site 5: 7.81 Lx, site 6: 7.73 Lx.Figure 1A map of study area. The urban area (Townsville, Queensland, Australia) is shown in grey. The 6 experimental enclosure sites are shown as black circles. Roads are shown as light lines, and coastlines as heavier lines.Figure 2Overview of the enclosure experiment. We constructed six outdoor experimental enclosures in open eucalypt forest, and put 5 toads in each enclosure. The following day, we dissected them and recorded the mass of prey in each of their guts.
The size of individual toads that went into the enclosures varied, and we thought it possible that toad body size may influence the amount they consumed. We tested for a relationship between gut content mass per individual and snout-vent length (SVL) using a linear regression, and there was no significant relationship between these variables, so toad body size is not reported further (p \> 0.05 Supplementary Fig. [S2](#MOESM1){ref-type="media"}. Supplementary Table [S1](#MOESM1){ref-type="media"}).
Although we did not measure the influx of insects to the light, we assumed that the number of insects falling to the ground and available to toads was a measure of this variable. This seems a reasonable assumption because insect researchers often evaluate the abundance of insects using captured fallen insects attracted to light traps^[@CR39]^. They also use the number of fallen insects attracted to light to forecast pest outbreaks for agriculture^[@CR40]^.
We used available public weather data from the Australian Government Bureau of Meteorology to obtain temperature, rainfall and wind speed at each site^[@CR41]^, and lunar phase from 'timeanddate.com'^[@CR42]^, which we used as covariates, potentially influencing mean toad gut content mass.
Statistical analysis {#Sec4}
--------------------
To examine the relationships between mean mass of toad gut contents in the experimental enclosures, and various environmental factors, we used the 'lme4' package to conduct generalized linear mixed modelling (GLMM). The error distribution was identified as a Gaussian distribution. We used average gut content mass of all the toads in a trial as the response variable, and we used the experimental artificial light treatment (light-on vs light-off), light pollution level, temperature, rain fall, wind speed and lunar phase as explanatory variables. We also examined interactions between the experimental artificial light treatment and the light pollution level, the experimental artificial light treatment and lunar phase, and the light pollution level and lunar phase, to look for interactions between the impact of artificial light, and natural light. Enclosure number was included as a random effect. We standardized numeric explanatory variables (we subtracted the mean from each data point and divided by the standard deviation to scale the data to a mean of 0 and a variance of 1). We conducted model comparison using the 'dredge' function in the 'MuMIn' package to evaluate the relative importance of each explanatory variable. Additionally we tested whether percentage of flying invertabrates in gut contents of toads increased when lights were on using Welch Two Sample t-test. All statistical analysis was performed in R V 3.6.0^[@CR43]^.
Results {#Sec5}
=======
Experimental trials {#Sec6}
-------------------
We conducted 37 trials (site 1, 2, 3, 5 & 6: 6 trials, site 4: 7 trials) (Supplementary Table [S2](#MOESM1){ref-type="media"}) and we collected gut contents from 171 toads (site 1: 29 toads, site 2: 28 toads, site 3: 28 toads, site 4: 32 toads, site 5: 27 toads, site 6: 27 toads).
Variables influencing mean food intake per experimental trial {#Sec7}
-------------------------------------------------------------
Model comparisons showed that the experimental artificial light treatment (light-on vs light-off), ambient light pollution levels, lunar phase, and the interactions between experimental artificial light treatment and ambient light pollution level, and between the experimental artificial light treatment and lunar phase were selected in all models with delta AIC \< 2 (Table [1](#Tab1){ref-type="table"}). The light-on treatment increased mean gut content mass of invasive toads (Fig. [3a](#Fig3){ref-type="fig"}), but the impact of the experimental artificial light treatment was influenced negatively (i.e., mean gut contents were reduced) by both increased light pollution levels at each site (Fig. [3b](#Fig3){ref-type="fig"}), and light lunar phases (gut contents were least when the moon was full) (Fig. [3c](#Fig3){ref-type="fig"}). In addition, mean gut contents of invasive toads were likely to increase with increasing temperature (Fig. [3d](#Fig3){ref-type="fig"}). Rainfall and wind speed were selected in several models (Table [1](#Tab1){ref-type="table"}), and mean gut contents of invasive toads were likely to increase slightly with increasing rainfall (Fig. [3e](#Fig3){ref-type="fig"}) and wind speed (Fig. [3f](#Fig3){ref-type="fig"}). When lights were on, percentage of flying taxa consumed by toads increased significantly (Fig. [4](#Fig4){ref-type="fig"}, p \< 0.05).Table 1The result of model comparison of the generalized linear mixed models (GLMM) used to examine the relationships between gut contents of toads and various explanatory variables (experimental artificial light treatment \[light-on vs light-off\], ambient light pollution level, temperature, rain fall, wind speed, lunar phase, an interaction between the experimental artificial light treatment and ambient light pollution levels, an interaction between experimental artificial light treatment and lunar phase, and an interaction between present light pollution level and lunar phase).Models No.(Intercept)Experimental artificial light treatment (Light-on vs Light-off)Light pollution levelLunar phaseRainfallTemperatureWind speedInteraction between experimental artificial light and light pollution levelInteraction between experimental artificial light and lunar phaseInteraction between light pollution level and lunar phasedfLogLikAICDeltaWeight2001.521.41−0.84−0.61NANANA−0.75−0.69NA8−63.85143.710.000.142241.501.69−0.82−0.700.490.57NA−0.80−0.59NA10−62.13144.250.550.102161.531.52−0.84−0.58NA0.34NA−0.77−0.70NA9−63.36144.731.020.082321.541.47−0.87−0.66NANA0.31−0.74−0.76NA9−63.53145.061.350.072481.551.62−0.87−0.63NA0.400.37−0.76−0.78NA10−62.60145.201.490.06Enclosure number was fitted as a random effect. A Gaussian distribution was identified as the error distribution. The model comparison was performed by dredge function in MuMIn package in R 3.6.0 (R Development Core Team 2019).Figure 3(**a**) Relationship between average toad gut content masses in experimental enclosures, and experimental light treatment (comparing all periods when the light was on versus all periods when the light was off). (**b**) The influence of ambient light pollution on average toad gut content masses in experimental enclosures when an artificial lights were on, and during dark controls. Gut contents masses when artificial lights were on are shown as white circles and a light line, and light-off treatment as black circles and heavier line. (**c**) The influence of lunar phase on average toad gut content masses in experimental enclosures when an artificial lights were on, and during dark controls. Mean gut content masses collected when lights were on are shown as white circles, and a light line, whereas mean gut content masses during light-off controls are shown as black circles and heavier line. (**d**) The influence of temperature on average toad gut content masses in experimental enclosures. (**e**) The influence of rainfall on average toad gut content masses in experimental enclosures. (**f**) The influence of wind speed on average toad gut content masses in experimental enclosures.Figure 4Percentage of flying invertebrates in gut contents of toads when lights were on and off.
Discussion {#Sec8}
==========
We found that the presence of artificial light in our experiment greatly increased the mass of gut contents of invasive toads, and that this effect was reduced when there was more ambient light, either from urban light pollution or natural moonlight. We also found that temperature, rainfall and wind speed had relatively weak effects on toad gut contents compared to light over the summer period of our study, and were not likely to be important drivers influencing the ecological impact of ALAN on invasive toads. These results, taken together, suggest that the food intake of invasive toads was more strongly influenced by artificial light sources than by weather effects, and that the effect of artificial light was reduced by other light sources, including natural light and ambient artificial light pollution. Moreover, flying invertabrates, such as Coleoptera, contributed strongly to the increase in gut content mass of toads in light treatments.
Lunar phase changes gradually over the synodic month, hence the impact of ALAN on invasive toads should vary cyclically corresponding to lunar phase. Although ALAN clearly provides an important food resource for invasive toads^[@CR37],[@CR38]^, no one has examined the impact of lunar phase on foraging success. Lunar phase influences the attraction of biting midges (*Culicoides brevitarsis*) to artificial light, because lunar light dilutes the effect of artificial light, essentially competing with it in terms of attractiveness^[@CR6]^. Our results were consistent with the possibility that bright lunar phases reduced the attraction of invertebrates to the experimental artificial light, which, in turn, lead to variation in the amount toads ate.
As with lunar illumination, we also found that the impact of ALAN was influenced by light pollution levels at each site. Our experimental light treatments were less effective at providing food for toads closer to urban centres, and thus the impact of our experimental lights, in terms of food provision, was largest in the light-naïve areas located furthest from the city. There are two plausible reasons for this effect. One is that ambient light pollution competed with the effect of our experimental artificial light, such that light pollution diluted the impact of the experimental artificial light^[@CR6]^. Another reason for our observation could be that ambient light pollution, and a plethora of artificial light closer to urban centers has already degraded the invertebrate fauna at those sites. Although there is little direct experimental evidence, there is some suggestion in the literature that ambient light pollution causes declines in invertebrate populations; there are a few correlative studies reporting invertebrate population decline in association with ALAN, and species of invertebrates attracted to light have declined greatly compared to species that are not attracted to light^[@CR19],[@CR44]^. Finally, moth populations in the UK and Ireland have declined as a result of ALAN^[@CR20]^. In our tropical study area, there are abundant nocturnal invertebrates, and there was no indication of lower food intake in ALAN-effected areas in our study when our experimental lights were off, providing weak evidence that ALAN has not depleted invertebrate populations in our study area very much. While our study did not address the reason why ambient light pollution levels influenced the impact of our experimental lights, we suggest it was related to competition between light types in attractiveness^[@CR6]^, rather than depleted invertebrate populations in our study area, although this assertion deserves further experimental examination. Possibly, invertebrates around urban areas have adapted to artificial light and have reduced flight-to-light behaviour^[@CR45]^, which could also decrease numbers in urban areas.
Invasive species often inhabit environments characterised by anthropogenic disturbances, from which they may benefit, including from the presence of artificial light^[@CR26]^. Invasive toads are well known to consume invertebrates attracted to artificial light around buildings, and artificial light might facilitate their invasion^[@CR38]^. Our study indicated that the impact of experimental lighting on invasive toads varied depending on the light pollution level at the site. When artificial light was located in urban or peri-urban locations, the impact of experimental ALAN per light bulb seemed relatively weak. We think it most likely that this effect was due to dilution of the effect of the experimental ALAN by ambient light pollution. When the artificial light was located in peri-urban or rural areas, the impact of ALAN was relatively large. Hence, to avoid providing food resources to toads from artificial light, management of artificial light in peri-urban and rural areas, such as highway lights or scattered buildings, may be important. Additionally, light management approaches should consider the lunar cycle; light use during dark lunar phases may be most beneficial to toads, whereas the impact of light during brighter lunar phases could be relatively small.
Cage traps using ultraviolet light as a lure, which attracts invertebrates, capture toads^[@CR46]^. Our results suggest that trapping may be more effective during darker lunar phases (corroborated by^[@CR47]^), and in urban areas shaded from ALAN, or in peri-urban and rural areas. Considering the spatio-temporal pattern of the impact of ALAN may contribute to better management of invasive amphibians, especially if lights are used to attract insect food.
We placed all our experimental enclosures in similar habitat (open savannah woodland). Invertebrate diversity and mass may, however, vary with local environmental conditions. Future studies, should examine similarity in the invertebrate fauna among areas, and conduct this experiment at more sites, perhaps comparing different habitat types. This experiment should be repeated at other urban centres to determine if the urban effect is consistent among cities. In addition, future studies should examine the contribution of artificial light to growth rate and reproductive success of toads, to determine how ALAN influences fitness in these invasive animals.
In our experiments, the enhancement of food intake caused by experimental ALAN on invasive toads was reduced by natural light (lunar phase), and existing ambient light pollution levels. To avoid providing substantial food resources to toads from artificial lights, management of artificial light in peri-urban and rural areas, and during dark lunar phases may be advisable. On the contrary, to effectively capture toads, trapping using lights as lures at such times and places should be more successful. Considering spatio-temporal patterns in the impact of ALAN may contribute to management strategy of invasive species that benefit from it.
Ethical statement {#Sec9}
-----------------
All procedures in this study were approved by Animal Ethics Committee at James Cook University (permit number A2520). All procedures undertaken in this study were in accordance with approved guidelines.
Supplementary information
=========================
{#Sec10}
Supplementary information.
**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
=========================
is available for this paper at 10.1038/s41598-020-63503-9.
We thank members of the Vertebrate Ecology Lab James Cook University who gave us constructive comments and supports. Especially Ms. Ayano Fushida, who helped us to get land use permissions. We are grateful to The Atkinson family, Paul Verrall, the Parkside Group and Townsville City for giving us permissions to use their property. This study could not have been conducted without their kindness and support. This study was financially supported by Tokyo University of Agriculture and Technology.
H.K. designed the study, collected field data, carried out statistical analysis and draughted the manuscript. S.K. helped to draft the manuscript. L.S. helped to design the study, carry out statistical analysis, and draft the manuscript.
All data analyzed in this study are included in Supplementary Table [S2](#MOESM1){ref-type="media"}.
The authors declare no competing interests.
|
Anthelmintic activity of continuous low doses of fenbendazole into the rumen of sheep.
Fenbendazole (FBZ) was continuously infused for 30 days into the rumen of 103 lambs which had mature or developing benzimidazole-susceptible or thiabendazole-resistant Haemonchus contortus and susceptible Trichostrongylus colubriformis infections. Ovicidal, larvicidal and adulticidal activities were exhibited against benzimidazole-susceptible and benzimidazole-resistant H. contortus worms by FBZ at a dose level of greater than or equal to 0.2 mg kg-1 body weight day-1. Reasonably consistent high level efficacy against H. contortus was obtained with dose levels greater than 0.4 mg kg-1. Excellent control of susceptible T. colubriformis worms was achieved with the lowest dose tested of 0.4 mg kg-1 day-1. The intraruminal infusion critical study method is a tool to determine the feasibility of incorporating a candidate anthelmintic compound in a continuous sustained-release rumen device formulation. The anthelmintic profile of FBZ obtained by low-level intraruminal administration suggests that it would be a potential candidate. |
Leptospirosis disease burden estimation and surveillance networking in India.
Although leptospirosis is known to have occurred in India since the early years of the 20th century, no accurate data on disease burden exist. During the past two decades, leptospirosis cases have been reported with increasing frequency from different parts of the country. Several large outbreaks have occurred. In the year 2000, the Indian Council of Medical Research set up a Task Force on Leptospirosis. The Task Force conducted a multicentric study on disease burden due to leptospirosis. As part of the study, 3,682 patients with acute febrile illness, from 13 different centers in India, were investigated for the presence of current leptospiral infection using the Lepto-dipstick test. Of these patients, 469 (12.7%) were found to have leptospiral infection. The positivity rate ranged from 3.27% in the central zone to 28.16% in the southern zone. Fever, body aches and chills were the common symptoms observed. Urinary abnormalities, such as oliguria, yellow discoloration of urine and hematuria were found in 20%-40% of patients. Distribution of serogroups was studied based on microscopic agglutination test (MAT) titers. The southern zone had all the eleven serogroups in the panel, the eastern zone had nine, the northern zone eight, and the central and western zones had five circulating serogroups each. Among various risk factors studied, rat infestation of houses had the strongest association with leptospiral infection. Many other factors related to the environment, personal and occupational habits, etc, also had significant associations. The study had a few drawbacks. The Task Force has decided to continue the study with modified protocols to generate more accurate and detailed information about disease burden. |
[Therapy options for psoriasis in childhood and adolescence].
Up to 30% of all psoriatic patients show their first symptoms during childhood and adolescence. In 1/4 of these children, psoriatic lesions appear within the first two years of life. The treatment of pediatric psoriasis differs considerably in several ways from that of adults. Not only the age and intensity but also physical development, prognostic criteria and social background should be considered. Standard procedures, clinical trials of high quality and therapeutic guidelines for psoriasis in childhood are still lacking. This review surveys the therapeutic management of pediatric and juvenile psoriasis. Current topical and systemic therapy options are critically reviewed. Prevention as well as enhancement of quality of life are also considered. |
Case: 14-31117 Document: 00513113924 Page: 1 Date Filed: 07/13/2015
IN THE UNITED STATES COURT OF APPEALS
FOR THE FIFTH CIRCUIT
No. 14-31117 United States Court of Appeals
Fifth Circuit
FILED
In the Matter of: TORRANCE TREMAYNE GREEN, July 13, 2015
Lyle W. Cayce
Debtor Clerk
--------------------------------
RIVERBEND CONDOMINIUM ASSOCIATION,
Appellant
v.
TORRANCE TREMAYNE GREEN,
Appellee
Appeal from the United States District Court
for the Eastern District of Louisiana
Before KING, SMITH, and ELROD, Circuit Judges.
PER CURIAM:
In this Chapter 13 bankruptcy case, the bankruptcy court held that the
privilege created by La. Rev. Stat. § 9:1123.115(1) (2014) on a Louisiana
condominium for all unpaid sums assessed by the condominium association
against the condominium owner is a statutory lien (as distinguished from a
security interest) and is therefore subject to bifurcation under 11 U.S.C.
§ 1322(b)(2). The district court affirmed. For the reasons given by the district
Case: 14-31117 Document: 00513113924 Page: 2 Date Filed: 07/13/2015
No. 14-31117
court in its Order and Reasons attached hereto, we affirm the district court’s
affirmance of the bankruptcy court’s order.
AFFIRMED.
2
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|
Adolescence and the diet-dieting disparity: healthy food choice or risky health behaviour?
Food choice in schoolchildren was examined in relation to dieting and measures of eating psychopathology. It was predicted that dieters would make healthier food choices compared to non-dieters and that measures of eating psychopathology would be associated with food choice. A cross-sectional questionnaire design incorporating an established adapted recall method was used to assess patterns of food consumption. Questionnaires were administered in 13 state secondary schools. Measures included a food frequency questionnaire, the Children's Eating Attitudes Test (CHEAT), body satisfaction ratings, dietary restraint, and questions about dieting status. The sample consisted of 574 females and 445 males aged 11-16 years. Females made significantly more healthy food choices compared to males. Females reported dieting more than males (35% vs. 18%, respectively), and female dieters made more healthy food choices than female non-dieters. Almost a fifth (19%) of the entire sample reported skipping breakfast, with female dieters being three times more likely to do so than non-dieters. There were small but significant associations between reported food consumption and measures of eating attitudes, body dissatisfaction and restraint. For females who scored in the at-risk range on the CHEAT (8.7%), these associations were more substantial. Female dieters appear to make more healthy food choices than non-dieters and so may be tuning into healthy eating messages more effectively. Vulnerable females may use 'healthy eating' to hide risky weight reduction behaviours. Further studies are required to examine the nutritional impact of moderate and extreme dieting in this age group. |
Attitude similarity and satisfaction of family members of schizophrenics with services of a professional.
Examined a hypothesis that satisfaction with professionals among families of schizophrenics varies as a function of how similar the professionals' attitudes about schizophrenia are to the family members' attitudes. Twenty-eight family members of individuals diagnosed by DSM-III criteria as having schizophrenia completed a questionnaire that assessed their attitudes with regard to causes and treatments of schizophrenia. Ss then were mailed a completed questionnaire and were asked to indicate how satisfied they would be working with a person who held the attitudes expressed in the questionnaire. In the attitude-similar condition, the questionnaire was 90% in agreement with their own attitudes, and in the attitude-discrepant condition, the questionnaire was 10% in agreement. Responses were received from 21 family members. Results supported the hypothesis; family members in the attitude-similar condition reported that they would be more satisfied with the professional than did family members in the attitude-discrepant condition. Implications for work with families of schizophrenics are discussed. |
STORY: Lucasfilm's Kathleen Kennedy on 'Star Wars,' 'Lincoln' and Secret J.J. Abrams Meetings
"They're talking to us," Mark Hamill, who played the orphan-turned-Jedi hero, tells Entertainment Tonight. "George [Lucas] wanted to know whether we'd be interested. He did say that if we didn't want to do it, they wouldn't cast another actor in our parts; they would write us out. I can tell you right away that we haven't signed any contracts. We're in the stage where they want us to go in and meet with Michael Arndt, who is the writer, and Kathleen Kennedy, who is going to run Lucasfilm. Both have had meetings set that were postponed -- on their end, not mine. They're more busy than I am."
Hamill says he has no indication of what the films will be about but wants all of his surviving co-stars to be involved, from Carrie Fisher to Billy Dee Williams and Tony Daniels, who played the robot C-3PO. He also thinks his character will follow in the footsteps of his mentor, Obi-Wan Kenobi, played by the late Alec Guinness in the original trilogy.
PHOTOS: 'Star Wars' Actors, Then and Now
"I'm assuming, because I haven't talked to the writers, that these movies would be about our offspring -- like my character would be sort of in the Obi-Wan range [as] an influential character. … When I found out [while making the original trilogy] that ultimate good news/bad news joke – the good news is there's a real attractive, hot girl in the universe; the bad news is she's your sister – I thought, 'Well, I'm going to wind up like Sir Alec. I'm going to be a lonely old hermit living out in some kind of desert igloo with a couple of robots.'"
Lucasfilm and Disney are planning a new trilogy of films, as well as spinoff movies that focus on individual characters. It was reported earlier this month that the studio was prepping films about Han Solo, the iconic space trafficker played by Harrison Ford, and bounty hunter Boba Fett. Lawrence Kasdan and Simon Kinberg are working on two spinoff films.
Hamill most recently appeared the film Sushi Girl and has made a career of voice acting, most notably voicing The Joker in various Batman cartoons and video games. |
package io.buoyant.namerd.storage
import com.twitter.conversions.DurationOps._
import com.twitter.finagle.Dtab
import com.twitter.finagle.util.DefaultTimer
import com.twitter.io.Buf
import com.twitter.util._
import io.buoyant.namerd.DtabStore.{DtabNamespaceAlreadyExistsException, DtabNamespaceDoesNotExistException, DtabVersionMismatchException}
import io.buoyant.namerd.{DtabStore, Ns, VersionedDtab}
import java.nio.ByteBuffer
/**
* A toy DtabStore that stores all state in memory.
*/
class InMemoryDtabStore(namespaces: Map[String, Dtab]) extends DtabStore {
private[this] val dtabStatesMu = new {}
private[InMemoryDtabStore]type DtabState = Option[VersionedDtab]
private[InMemoryDtabStore]type DtabStateVar = Var[DtabState] with Updatable[DtabState]
private[this] var dtabStates: Map[String, DtabStateVar] =
namespaces.mapValues { dtab =>
Var[DtabState](Some(VersionedDtab(dtab, InMemoryDtabStore.InitialVersion)))
// mapValues produces a view. We force it so that only one Var is created per-namespace.
}.view.force
private[this] def get(ns: String): DtabStateVar =
dtabStatesMu.synchronized {
dtabStates.get(ns) match {
case Some(state) => state
case None =>
val state = Var[DtabState](None)
dtabStates += (ns -> state)
state
}
}
private[this] lazy val keys = Var.async[Set[Ns]](Set.empty) { update =>
@volatile var stopping = false
def loop(): Future[Unit] = {
if (stopping) Future.Unit
else {
dtabStatesMu.synchronized {
val keySet = dtabStates.filter {
case (key, value) => value.sample.isDefined
}.keySet
update.update(keySet)
}
Future.sleep(1.second)(DefaultTimer).before(loop())
}
}
loop()
Closable.make { _ =>
stopping = true
Future.Unit
}
}
def list(): Activity[Set[Ns]] = Activity(keys.map(Activity.Ok(_)))
def create(ns: String, dtab: Dtab): Future[Unit] = {
val state = get(ns)
dtabStatesMu.synchronized {
state.sample match {
case Some(_) =>
Future.exception(new DtabNamespaceAlreadyExistsException(ns))
case None =>
state.update(Some(VersionedDtab(dtab, InMemoryDtabStore.InitialVersion)))
Future.Unit
}
}
}
def delete(ns: String): Future[Unit] = {
val state = get(ns)
dtabStatesMu.synchronized {
state.sample match {
case Some(_) =>
state.update(None)
Future.Unit
case None =>
Future.exception(new DtabNamespaceDoesNotExistException(ns))
}
}
}
def update(ns: String, dtab: Dtab, version: Buf): Future[Unit] = {
val state = get(ns)
dtabStatesMu.synchronized {
state.sample match {
case Some(VersionedDtab(_, currentVersion)) if version == currentVersion =>
state.update(Some(VersionedDtab(dtab, InMemoryDtabStore.nextVersion(version))))
Future.Unit
case Some(VersionedDtab(_, currentVersion)) =>
Future.exception(new DtabVersionMismatchException)
case None =>
Future.exception(new DtabNamespaceDoesNotExistException(ns))
}
}
}
override def put(ns: String, dtab: Dtab): Future[Unit] = {
val state = get(ns)
dtabStatesMu.synchronized {
val version = state.sample.map(_.version)
val next = version.map(InMemoryDtabStore.nextVersion).getOrElse(InMemoryDtabStore.InitialVersion)
state.update(Some(VersionedDtab(dtab, next)))
Future.Unit
}
}
def observe(ns: String): Activity[Option[VersionedDtab]] =
Activity(get(ns).map(Activity.Ok(_)))
}
object InMemoryDtabStore {
def InitialVersion: Buf = version(1)
def version(n: Long): Buf = {
val bb = ByteBuffer.allocate(8)
bb.putLong(n)
bb.rewind()
Buf.ByteBuffer.Owned(bb)
}
def nextVersion(buf: Buf): Buf = {
val bb = Buf.ByteBuffer.Owned.extract(buf)
version(bb.getLong + 1)
}
}
|
Cultivation of plant cells in aqueous two-phase polymer systems.
Suspension cultures ofNicotiana tabacum have been successfully grown in aqueous, two-phase systems comprised of polyethylene glycol (PEG) and dextran in a modified LS medium. Aqueous two-phase systems may be advantageous for plant tissue cultivation since cells can be immobilized in one phase while secondary products are collected and withdrawn in the other phase, thus enhancing productivity. Culture growth rate was compared in a variety of two-phase systems, covering a range of both polymer molecular weight and concentration. Systems exhibiting relatively higher phase miscibility yielded increased growth rates as compared to less miscible phase formulations. The highest observed growth rate occurred in 3% PEG 20000/5% crude dextran and approached growth rates and cell densities of cultures grown in standard LS medium. |
Academic dissertation to be presented with the assent of the Doctoral Training Committee of Technology and Natural Sciences of the University of Oulu for public defence in Auditorium IT116, Linnanmaa, on 27 May 2016, at 12 noon
Abstract
To date, plant endophytic bacteria have mainly been studied in roots of crop plants. However, shoot-associated endophytes are less diverse than root-associated ones. Hence, endophytic bacteria of plant shoots evolved different traits, than root colonizers, especially with types of host tissues infected and patterns of growth and development. This study found Methylobacterium extorquens colonized pine seedlings similarly to stem-colonizing rhizobia of other plants. M. extorquens DSM13060 was isolated from meristematic cells in shoot tip cultures of Scots pine (Pinus sylvestris L.). M. extorquens infected the plant stem through epidermis or stomatal apertures, forming infection pockets in the root and stem epidermis, or cortex. Post-infection, thread-like infection structures passed through the endoderm, invading vascular tissues. This led to systemic colonization of above and below ground-parts, observed in in vitro grown Scots pine.
A novel mechanism enabling development of endophyte-host symbiosis is discovered within the M. extorquens – Scots pine model. This mechanism involves ability of M. extorquens to produce polyhydroxybutyrates (PHB) to protect itself from host-induced oxidative stress during infection. Upon initial colonization on the host surface, M. extorquens DSM13060 consumes methanol as a carbon source, using it to biosynthesize PHB. PHB are then degraded, upon host infection, by PHB depolymerases (PhaZ) to yield methyl-esterified 3-hydroxybutyrate oligomers. These oligomers have substantial antioxidant activity towards host-induced oxidative stress, enabling the bacterium to bypass host defenses and colonize further tissues. The bacteria can also store PHBs for future protection. The capacity for PHB production and, thus, protection from oxidative stress, is discovered in a wide taxonomic range of bacteria.
This study also shows meristematic endophytes are important in growth and development of their hosts. Unlike many bacterial root endophytes, M. extorquens DSM13060 does not induce plant growth through hormones. However, this bacterium can colonize the interior of living host cells, where it aggregates around the nucleus of the host plant. M. extorquens DSM13060 genome encodes nucleomodulins, eukaryotic-like transcription factors, which may intervene in host transcription and metabolism. |
NIT denied stipend, claims student
A full time student of PhD mathematics at the Dr BR Ambedkar National Institute of Technology (NIT) said she had been denied stipend in the form of teacher assistantship as per the guidelines of the ministry of human resource development, even though she had gained admission in the course following high court directions.
The Punjab and Haryana high court had directed NIT Jalandhar to admit six PhD students, who were initially denied admission on unjustified grounds, in the mathematics program.
In June 2013, NIT had invited applications for the PhD course and declared the merit list after the result was announced in July. The interviews were also conducted but the result of PhD mathematics was not declared.
According to the RTI filed by one of the students, Isha Garg in December, it was found the result was delayed as it had not been signed by one of the committee members.
Garg filed a case against the institute in the high court after which admissions were invited. However, she said she was denied stipend along with the course.
“The institute is not providing the stipend despite the fact that the students are awarded scholarship-cum-teaching assistantship as per the guidelines of the ministry of human resource development. As per the recommendations of departmental admission committees, all the admissions in PhD full time for 2013-14 were made with stipend,” Garg said.
However, the institute said the students were misleading the media. MK Jha, dean of academics said, “The institute has only 31 teaching assistantship scholarships allotted for 13 different teaching departments for the academic year 2013-14 which have already been distributed.”
He added, “Out of 31, 50% scholarships are given to the reserved category students while the other 50% are distributed among the 13 departments. Each department gets maximum two scholarships.”
Jha said since there was a delay in admissions to the mathematics department, scholarships were distributed to other departments.
He added that Garg had been given admission to the PhD mathematics course without teaching assistantship as per the judgment of the high court. “She is approaching the press and other people in the institute to create a bad environment,” Jha added.
Isha’s father-in-law Ashok Kumar said this was a false claim by the institute as the institute had given stipend to 32 PhD students in the year 2013-14, out of which 20 were from the general category, a fact for which they had proof. |
Wednesday, 23 December 2015
According to Nielsen, Vietnam consumers is the motivation for economic development as they are willing to spend more and are also living in the lands of the potential opportunities. By 2020, Vietnam middle class will grow double, from 12 million people in 2014 increased to 33 million people in 2020.
Vietnam is among the top countries with the most optimistic consumers in the world, with more income and more spending. The percentage of increasing in per capita income rose in 2012 by 44% compared to 2010. The average growth rate of the monthly spending per person in 2012 increased by 32% compared to 2010. Therefore, Vietnam people have a strong desire for a better life, demanding about quality when 73% of people are willing to pay for higher quality.
Health is an important issue while there are 39% see health as the most concerning problem in life. Vietnam consumer’s monthly savings is to prepare for future problems, while 34% goes for the future of children, 12% is for health and 11% savings for house purchasing.
Consumers in Vietnam are also having more opportunities for shopping than ever. Modern trade channels are gaining significant role when 42% of consumers buy groceries at the supermarket more often. However, the utility factor is gradually becoming a way of life and developing quickly because of the accordance with the youth and officer with 23% of students and 36% of officer go shopping in the supermarket, convenient shop.
However, grocery store is still the dominant shopping channel in the market, while over 80% of sales of fast moving consumer goods coming from grocery stores, with 1,3 million stores across the country.
Technology offers more opportunities to help Vietnamese consumers connect. Smartphone is booming in Vietnam when nearly 1 in 2 Vietnamese people owning a smartphone, most of rural consumers watch TV daily. Online sales channel has also been in the market with 28% of Vietnamese consumers prefer online shopping.
ANT Consulting is here to assist you from the outset; providing intelligence, information, management or support and administrative services that assist market entrance, and ensure efficient business start-up operation. Our services are as following:
We strive to save your cost by guiding you towards economical solutions that comply with local legislation and procedures. We support you through early logistic solutions and carry you through as your business grows. We aim to bridge the gap between international best practices and local cultures and assist foreign companies and organizations entering Vietnam market to overcome commercial and regulatory issues. |
Q:
How can I search for an integer after a string in a document using Python?
I have a document.txt that has a line in it that says something like "randomtext here location 34 randomtexthere".
I know how to replace a word with another word but what if I want to replace the random integer after the word "location"? And maybe give an error if there is no integer after the word.
I can't specify the exact number I want to replace because that number can change. So I'm looking for a way to find the number after "location" and change it to the number I specify.
I'm currently working with something like this:
def replaceid():
source = "C:/mypath/document.txt"
oldtext = "oldtexthere"
newtext = "newtexthere"
with fileinput.FileInput(source, inplace=True, backup='.bak') as file:
for line in file:
print(line.replace(oldtext, newtext), end='')
A:
I can't specify the exact number I want to replace because that number can change
This says you want a regular expression to describe the pattern "a number" without writing any specific number, and to say that it must be found after 'location'".
It might look like this:
import re
s = "randomtext here location 34 randomtexthere"
pattern = r'(?<=location )\d+' # match a number
# i.e. a digit (\d) then any more digits (+)
# Only if it comes after 'location '
# (but don't match that word)
if re.search(pattern, s): # Search for the pattern in the string
print(re.sub(pattern, '200', s)) # replace the pattern match with new number
else:
print("Number not found") # or print an error message
And in your case, do that re.search for each line in the file.
|
/*******************************************************************************
* Copyright 2019 Viridian Software Limited
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
******************************************************************************/
using System;
using System.Collections.Generic;
using System.Linq;
using System.Text;
using System.Threading.Tasks;
using Microsoft.Xna.Framework.Content.Pipeline;
using Microsoft.Xna.Framework.Content.Pipeline.Serialization.Compiler;
using monogame.Files;
namespace monogame_pipeline_ext
{
[ContentTypeWriter]
class mini2DxFileWriter : ContentTypeWriter<mini2DxFileContent>
{
public override string GetRuntimeReader(TargetPlatform targetPlatform)
{
return typeof(mini2DxFileReader).AssemblyQualifiedName;
}
public override string GetRuntimeType(TargetPlatform targetPlatform)
{
return typeof(mini2DxFileContent).AssemblyQualifiedName;
}
protected override void Write(ContentWriter output, mini2DxFileContent value)
{
output.Write(value.content);
}
}
}
|
Introduction {#S1}
============
IFN-γ is primarily produced by innate cells, including natural killer (NK) and natural killer T (NKT) cells, non-cytotoxic innate lymphoid cells ^[@R1]^, and adaptive immune cells, including CD4^+^ T helper (Th) 1 and CD8^+^ cytotoxic T lymphocytes (CTL) cells. ^[@R2]^ IFN-γ activates macrophages to produce pro-inflammatory cytokines^[@R3]^, but can also counteract inflammatory and immunostimulatory pathways^[@R4]^. Transgenic mice engineered to express IFN-γ in airway epithelial cells were found to present with increased inflammation and emphysema^[@R5]^ but also with reduced eosinophilia and airway reactivity^[@R6]^. However, because airway epithelial cells do not express IFN-γ the findings in these transgenic mice may not be physiologically relevant.
For clinical applications, IFN-γ has beneficial effects when administered as prophylactic treatment of lupus nephritis^[@R7]^ and in cases of rheumatoid arthritis.^[@R8]^ IFN-γ signaling inhibits neutrophil accumulation in the lung^[@R9]^ or suppresses neutrophil production in the bone marrow.^[@R10]^ These anti-inflammatory responses are mediated by induction of cytokine decoy receptors, IL-1Rα and IL-18BP.^[@R2]^ Further, IFN-γ tempers the development of erythrocytes and eosinophilic granulocytes ^[@R11]^, and inhibits Th2 cell function. ^[@R12]^
Because chronic inflammation promotes chronic lung diseases^[@R13]^, identifying the intracellular factors that mediate the anti-inflammatory action of IFN-γ can be of great importance. Our previous studies have shown that IFN-γ causes cell death in airway epithelial cells by activating STAT1^[@R14]^, inducing expression of the BH3-only protein, Bik^[@R15]^, and suppression of Bmf expression to induce autophagy.^[@R16]^ Bik and Bmf are Bcl-2 family members that share only the Bcl-2 homology region 3 (BH3) such as Noxa, Puma, Bim, Bid, Bad, Bid, Bnip-3L, and Hrk. This group of proteins is believed to sense cell death signals that emanate from internal stresses such as DNA damage^[@R17]^ or CAP-independent translation^[@R18]^ or from external stimuli, such as IFN-γ^[@R15]^ or other cytokines.^[@R19]^
We found that in airway epithelial cells IFN-γ dramatically induced the BH3-only protein, Noxa, but that Noxa did not induce cell death, yet inhibited inflammation in response to allergen. Noxa required the interaction with phosphorylated HSP27 via a covalent disulfide bond to suppress the nuclear translocation and activation of NF-κB by inhibiting degradation of ubiquitylated κBa. Furthermore, inducible expression of Noxa in airway epithelia of adult mice suppressed allergen-induced inflammation *in vivo*. However, the cross-linking Cys25 was not necessary when the N-terminal peptide was used to block IκBα degradation and inflammation. Therefore, these studies identify the anti-inflammatory mediator of IFN-γ to be Noxa cross-linked to the non-Bcl-2 protein, pHSP27 that renders N-terminal region of Noxa functional.
Results {#S2}
=======
IFN-γ rapidly induces Noxa expression to suppress inflammation {#S3}
--------------------------------------------------------------
Noxa mRNA levels were dramatically induced by 25-50 ng/ml IFN-γ treatment over 24-48 h in primary HAECs from non-diseased individuals ([Fig. S1A](#SD1){ref-type="supplementary-material"}). Induction occurred within 1 h of IFN-γ treatment both for Noxa mRNA ([Fig. 1A](#F1){ref-type="fig"}), and protein levels ([Fig. 1B](#F1){ref-type="fig"}), while Hrk, Bad, or Puma showed no change in expression (data not shown). This rapid induction by IFN-γ was consistently observed in HAECs from 14 individuals ([Fig. 1C](#F1){ref-type="fig"}). As expected, Noxa protein and mRNA were undetectable in MAECs from *noxa*^-/-^ mice but Noxa expression was increased by IFN-γ in wild-type MAECs ([Fig. S1B](#SD1){ref-type="supplementary-material"}). IFN-γ failed to upregulate Noxa expression in MAECs from *STAT1^-/-^* mice ([Fig. S1B](#SD1){ref-type="supplementary-material"}). However, unlike the DNA damage-induced Noxa expression ^[@R20]^, IFN-γ-induced Noxa expression was independent of p53 ([Fig. S1C](#SD1){ref-type="supplementary-material"}).
Noxa deficiency causes increased inflammation {#S4}
---------------------------------------------
While Noxa mRNA and protein levels were induced robustly by IFN-γ, *noxa*^+/+^ and *noxa*^-/-^ airway cells were both susceptible to IFN-γ-induced cell death ([Fig. S1D](#SD1){ref-type="supplementary-material"}). However, we observed that *noxa*^-/-^ compared with *noxa*^+/+^ mice developed increased inflammation following intranasal instillation with house dust mite allergen for 5 consecutive days. The numbers of total cells ([Fig. 1D](#F1){ref-type="fig"}) eosinophils and macrophage, but not neutrophils and lymphocytes ([Fig. 1E](#F1){ref-type="fig"}) recovered by bronchoalveolar lavage (BAL) were significantly higher in *noxa*^-/-^ compared with *noxa*^+/+^ mice. In addition, when sensitized with ovalbumin (OVA) injection on days 1 and 7 and challenged with OVA aerosols for 5 d, mucous cell numbers were higher ([Fig. S2A](#SD1){ref-type="supplementary-material"}) and inflammatory cells were more evident in *noxa*^−/−^ compared with *noxa*^+/+^ mice ([Fig. S2B](#SD1){ref-type="supplementary-material"}). These observations suggested that Noxa may play a role in blocking allergen-induced inflammation, but not in the cell death process of hyperplastic airway epithelial cells. Previous studies have shown that Noxa expression sensitizes cells to apoptosis ^[@R21]^. To determine whether Noxa sensitizes airway epithelial cells, we first treated HAECs with increasing H~2~O~2~ concentrations and found that 45 μM affects cell viability slightly ([Fig. S2C](#SD1){ref-type="supplementary-material"}). However, when combined with increasing multiplicity of infection (MOI) of Ad-Noxa, cell viability was progressively reduced compared to the Ad-GFP controls ([Fig. S2D](#SD1){ref-type="supplementary-material"}).
Because expression of many pro-inflammatory genes are regulated by NF-κB including IL-8,^[@R22]^ we investigated whether Noxa suppresses the synthesis of inflammatory chemokines. The TNFα-induced IL-8 secretion from human airway epithelial cells was significantly reduced when Noxa was expressed using an adenoviral expression vector (Ad-Noxa) compared to Ad-GFP-infected controls ([Fig. 2A](#F2){ref-type="fig"}). The possible role of Noxa in affecting NF-κB activation was tested using the A549-NF-κB-luc cells that are stably transfected with a luciferase reporter gene driven by a promoter containing several NF-κB response elements. As expected, TNFα-induced luciferase activity was inhibited when Noxa was expressed in a dose-dependent manner ([Fig. 2B](#F2){ref-type="fig"}); no cell death was detected by Ad-Noxa even at a MOI of 300 (data not shown). Further, suppression of Noxa expression using shRNA enhanced IFN-γ-induced NF-κB activity in cells treated with TNFα for 30 min ([Fig. 2C](#F2){ref-type="fig"}). Further, merely expressing Noxa or expressing Noxa in the presence of IFN-γ treatment showed a similar reduction in A549-NF-κB-luc cells, showing that IFN-γ had no further impact on Noxa-mediated suppression of NF-κB activity ([Fig. S2F](#SD1){ref-type="supplementary-material"}). Together, these findings suggest that the anti-inflammatory effect of IFN-γ is mediated by Noxa. We next analyzed the effects of IFN-y or Noxa on TNFα-induced change in sub-cellular localization of NF-κB. While NF-κB was localized to the nucleus 30 min after TNFα treatment, it remained localized to the cytosol in cells that were pretreated with IFN-γ for 24 h ([Fig. 2D](#F2){ref-type="fig"}). Similarly, direct expression of Noxa using adenoviral vectors suppressed TNFα-induced nuclear translocation of NF-κB as shown by immunofluorescence ([Fig. 2E](#F2){ref-type="fig"}). In addition, IFN-γ was delayed in suppressing nuclear translocation of NF-κB in *noxa^-/-^* MAECs ([Fig. 2F](#F2){ref-type="fig"}), confirming that IFN-γ requires Noxa to delay NF-κB activation. These findings were further confirmed by immunoblotting of nuclear and cytoplasmic extracts that showed nuclear NF-κB being significantly reduced in cells pretreated with IFN-γ compared to non-treated controls ([Fig. S2F](#SD1){ref-type="supplementary-material"}).
Noxa blocks the degradation of ubiquitylated IκB-α {#S5}
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In non-stimulated cells, the inhibitory IκBα protein sequesters NF-κB to the cytoplasm and inflammatory stimuli activate IKKα and IKKβ to phosphorylate IκBα, which leads to its ubiquitylation and proteasomal degradation, releasing NF-κB to translocate to the nucleus.^[@R23],\ [@R24]^ Over 0, 15, and 30 min of TNFα treatment, IκBα levels were reduced in the cytosolic extracts of *noxa^-/-^* but not *noxa*^+/+^ MAECs ([Fig. S2G](#SD1){ref-type="supplementary-material"}), suggesting that Noxa stabilizes IκBα. TNFα-induced nuclear translocation of NF-κB was also significantly reduced following overexpression of Noxa using Ad-Noxa compared to cells infected with Ad-GFP ([Fig. 2G](#F2){ref-type="fig"}), suggesting that Noxa expression is sufficient to stabilize IκBα. Interestingly, after 10 min of TNF-α treatment the levels of phosphorylated IκBα were similar in HAECs infected with Ad-Noxa and Ad-GFP as control ([Fig. 2H](#F2){ref-type="fig"}). Lysine-48 (K48)-linked polyubiquitin chains are well established as the canonical signal for proteasomal degradation ^[@R25]^. Interestingly, the levels of IκBα with homotypic K48-linked ubiquitin chains were increased in HAECs infected with Ad-Noxa and expressed Noxa compared with Ad-GFP-infected controls ([Fig. 2I](#F2){ref-type="fig"}). This finding suggests that Noxa blocks the proteasomal degradation of IκBα that is already destined for degradation.
Noxa is cross-linked to phosphorylated HSP27 {#S6}
--------------------------------------------
Because Noxa is known to inactivate Mcl-1 and thereby sensitize cells to apoptotic death^[@R26],\ [@R27]^ we tested the hypothesis that Noxa may interact with other protein(s) to gain anti-inflammatory properties. Noxa antibodies consistently detected a cross-reacting protein of approximately 32 kDa in size only in IFN-γ-treated HAECs ([Fig. 3A](#F3){ref-type="fig"}). Peptide mass fingerprint analysis of the cross-reacting the 32 kDa band excised following immunoprecipitation repeatedly revealed a high score for HSP27 ([Table S1](#SD1){ref-type="supplementary-material"}). This observation was confirmed by immunoblotting of anti-Noxa immunoprecipitated proteins with an antibody to HSP27 phosphorylated at Ser~82~ ([Fig. 3B](#F3){ref-type="fig"}). Interestingly, Mcl-1 and Bcl-x~L~, proteins known to interact with Noxa, ^[@R27]^ were not detected in the immunoprecipitates ([Fig. 3B](#F3){ref-type="fig"}). Immunoprecipitation with p-S~82~HSP27 antibodies confirmed that Noxa forms a complex with phosphorylated HSP27 (pHSP27) ([Fig. 3C](#F3){ref-type="fig"}). The interaction between Noxa and pHSP27 was further verified by pull-down assays from extracts prepared from AALEB cells using recombinant, purified GST-Noxa protein and detecting pHSP27 protein by Western blot analysis ([Fig. 3D](#F3){ref-type="fig"}). Blocking the phosphorylation of expressed HSP27 using the p38MAPK inhibitor, SB203580, reduced the levels of immunoprecipitated pHSP27-Noxa complex ([Fig. 3E](#F3){ref-type="fig"}), further supporting that pHSP27 rather than total HSP27 needs to be present to form the Noxa/pHSP27 interaction. Interestingly, merely overexpressing Noxa by infecting cells with Ad-Noxa in the absence of IFN-γ also resulted in the appearance of the 32 kDa Noxa-pHSP27 complex ([Fig. S3A](#SD1){ref-type="supplementary-material"}), suggesting that IFN-γ was not inducing a cross linking enzyme to facilitate this complex formation. The idea that Noxa and p-HSP27 are linked by disulfide bond(s) was confirmed by the absence of the p-HSP27-GST-Noxa complex in pull-down products from cell extracts treated with the reducing reagent, DTT that cleaves disulfide bonds ([Fig. S3B](#SD1){ref-type="supplementary-material"}).
To identify the amino acids within Noxa that are responsible for the Noxa-HSP27 complex, we generated various mutant GST-Noxa proteins that were tested in pull-down assays. Deletions of 10 amino acids from the N-terminus (Noxa-Δ5′) or 14 amino acids from the C-terminus (Noxa-Δ3′), abrogated the interactions of Noxa and pHSP27 ([Fig. S3C](#SD1){ref-type="supplementary-material"}). Because 293T cells express no detectable levels of endogenous HSP27, these cells were co-transfected with an HSP27-expression vector along with wild-type Noxa, Noxa-2CS, and Noxa-3KR. Mutations of cysteines 25 and 51 to serines (Noxa-2CS) also disrupted the interactions while mutation of lysines 35, 38, and 41 to argnines (Noxa-3KR) did not ([Fig. 3F](#F3){ref-type="fig"}). Further mutagenesis experiments demonstrated that only Cys~25~ residue was essential for the formation of Noxa-phospho-HSP27 complex ([Fig. 3F](#F3){ref-type="fig"}) confirming the hypothesis that Noxa and HSP27 are linked by an intermolecular disulfide bond.
Because HSP27 contains only one cysteine residue at position 137, the role of this residue was investigated by comparing wild-type and C137A mutant HSP27 constructs expressed in 293T cells that were treated with IFN-γ to induce Noxa. Although expression levels of pHSP27 were equal in cells transfected with either construct, immunoprecipitation with Noxa antibodies showed that the formation of Noxa-pHSP27 was impaired in cells transfected with the C137A mutant and was accompanied by the loss of interactions with IκBα/NF-κB complex ([Fig. 3G](#F3){ref-type="fig"}). These studies demonstrated that an intermolecular disulfide bond between Cys~25~ in Noxa and Cys~137~ in HSP27 cross-links Noxa to pHSP27 to allow the formation of a complex with IκBα and NF-κB.
HSP27 is essential for Noxa-κBα-NF-κB interaction {#S7}
-------------------------------------------------
Suppression of HSP27 in AALEB cells by stably expressing shHSP27 did not affect IFN-γ-induced Noxa expression ([Fig. S3D](#SD1){ref-type="supplementary-material"}). These cells were used to investigate the contribution of pHSP27 in blocking nuclear translocation of NF-κB. As shown by immunofluorescence staining IFN-γ blocked nuclear translocation of NF-κB in shCtrl but not in shHSP27 cells ([Fig. 3H](#F3){ref-type="fig"}). In addition, when Noxa or HSP27 expression in AALEB cells was reduced using shNoxa or shHSP27, IFN-γ no longer suppressed secretion of IL-8 ([Fig. S3E](#SD1){ref-type="supplementary-material"}) or IL-6 ([Fig. S3F](#SD1){ref-type="supplementary-material"}). Therefore, we proceeded to determine whether the interaction of Noxa with IκBα/NF-κB would be disrupted by reducing HSP27 levels. Although NF-κB and κBα were equally expressed in shCtrl and shHSP27 cells, the interactions between Noxa and NF-κB or κBα were abolished in shHSP27 cells ([Fig. 3I](#F3){ref-type="fig"}). Immunoprecipitation with NF-κB (p65) antibodies from shHSP27 cell extracts showed that the interaction of NF-κB with IκBα was essentially completely disrupted when cells were treated with TNFα, suggesting that IκBα degradation occurred faster when HSP27 was suppressed ([Fig. 3I](#F3){ref-type="fig"}). Further, the NF-κB---Noxa interaction was disrupted in shHSP27 cells but not in shCtrl cells ([Fig. 3I](#F3){ref-type="fig"}) and TNFα-induced degradation of IκBα was enhanced in shHSP27 compared with shCtrl cells ([Fig. 3J](#F3){ref-type="fig"}), suggesting that pHSP27 also is crucial in stabilizing IκBα. Therefore, Noxa requires the presence of pHSP27 to interact with the IκBα/NF-κB complex and the cross-linking of pHSP27 and Noxa appears to play a critical role in stabilizing IκBα.
Inducible Expression of Noxa in AECs protects from allergic inflammation and mucous cell hyperplasia {#S8}
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Constitutive expression of HSP27 has been detected in the lungs of mice ^[@R28]^ but the presence phosphorylated HSP27 in various tissues and cell types have not been studied. Because the cross-linking of Noxa to pHSP27 may be specific to airway epithelia, we compared pHSP27 levels in various tissues and cell types. Phospho-HSP27 was detected in MAECs and in lung tissues but not in murine embryo fibroblasts, thymus, and liver tissues ([Fig. 4A](#F4){ref-type="fig"}). To investigate the anti-inflammatory and possibly the therapeutic role of Noxa expression in airway epithelial cells *in vivo*, we generated a conditional inducible transgenic (Noxa^Ind^) mouse using the tetO-CCSP promoter system. Immunofluorescence analyses showed induced levels of Noxa in the bronchial epithelial cells of three founder Noxa^Ind^ mouse lines compared with wild-type littermates ([Fig. 4B](#F4){ref-type="fig"}). These mice expressed Noxa mRNA and protein in the lung tissues 24 h post doxycycline (dox)-diet ([Fig. 4C](#F4){ref-type="fig"}). These transgenic mice and littermate controls were instilled with house dust mite (HDM) extract for 5 consecutive days, given the dox-diet on days 6 and 7, and euthanized on day 8. The number of total inflammatory cells in the BAL fluid was reduced in Noxa^Ind^ mice compared to littermate controls and these reduced numbers were due to reduced BAL eosinophils and lymphocytes ([Fig. 4D](#F4){ref-type="fig"}). The no dox, no HDM, dox-fed but not HDM mice controls showed only macrophages and no inflammation (data not shown). Transgenic expression of Noxa also resulted in a 3-fold reduced number of mucous cells per mm basal lamina (BL) compared with littermate controls ([Fig. 4E](#F4){ref-type="fig"}). Immunofluorescence analysis showed that expressed Noxa was co-localized with NF-κB in the cytosol resulting in the lower percentage of airway epithelial cells with nuclear NF-κB in Noxa^Ind^ mice ([Fig. 4F](#F4){ref-type="fig"}). Further, pHSP27 was co-localized with induced Noxa ([Fig. S4A](#SD1){ref-type="supplementary-material"}) and NF-κB ([Fig. S4B](#SD1){ref-type="supplementary-material"}) in airway epithelial cells of Noxa^Ind^ mice.
The N-terminal Noxa peptide stabilizes IκBα and is anti-inflammatory {#S9}
--------------------------------------------------------------------
We further tested whether specific regions of the Noxa protein may act as anti-inflammatory by using Noxa-derived peptides. Based on our findings that Cys25 constitutes the cross-linking amino acid, and because the human and murine Noxa proteins share a high homology, except that the murine Noxa contains the duplicate sequence ([Fig. S5A](#SD1){ref-type="supplementary-material"}), we selected four regions that are 15 amino acids in length and span the following functional regions of the human Noxa protein. Peptide NoxaA represents the N-terminus, NoxaB contains Cys25, NoxaC comprises the BH3 domain, and NoxaD represents the C-terminal end of the protein ([Fig. S5B](#SD1){ref-type="supplementary-material"}). To facilitate uptake into cells, the peptides were synthesized with the HIV-derived TAT sequence on their N-termini. When A549 cells were treated with 10 ng/ml TNFα, NF-κB-induced luciferase activity, was reduced by NoxaA and NoxaD peptides but not by NoxaB or NoxaC ([Fig. 5A](#F5){ref-type="fig"}). However, when nuclear localization of NF-κB was investigated in TNFα-treated MAECs by immunofluorsence, only NoxaA but not NoxaD or the control TAT peptide affected nuclear localization ([Fig. 5B](#F5){ref-type="fig"}).
To examine the anti-inflammatory effect *in vivo*, *noxa^-/-^* mice were intranasally instilled with 50 μg house dust mite allergen for 5 consecutive days and then instilled with NoxaA peptide on days 6 and 7. The number of inflammatory cells in the BAL fluid mice was significantly reduced by NoxaA ([Fig. 5C](#F5){ref-type="fig"}) and this reduction was due to reduced numbers of eosinophils ([Fig. 5D](#F5){ref-type="fig"}). The number of neutrophils, macrophages, and lymphocytes were not affected (data not shown). After 10 min of TNF-α treatment the levels of IκBα with homotypic K48-linked ubiquitin chains were increased in AALEB cells treated with NoxaA compared to Ctrl peptide ([Fig. 5E](#F5){ref-type="fig"}).
Discussion {#S10}
==========
The present studies show that IFN-γ through STAT1 activation rapidly induces Noxa which is cross-linked with a non-Bcl-2 family member, pHSP27, and suppresses the canonical NF-κB signaling pathway. Therefore, these findings define the mediator by which IFN-γ acts as anti-inflammatory and are the first to show that a Bcl-2 family member could inhibit inflammation by reducing NF-κB activation.
Members of the extrinsic apoptotic machinery, including the TNFR1 interactors, TRADD, FADD, and RIPK1 ^[@R29]^ are known to be required for optimal NF-κB activation. The present study adds a new paradigm by showing that a member of the intrinsic apoptotic machinery affects the immune response by directly blocking NF-κB activation. It is well-established that proteins of the Bcl-2 family interact with each other to control the permeabilization of the mitochondrial outer membrane (MOM) and thereby regulate apoptosis. However, only a limited number of studies have explored their interaction with non-Bcl-2 family members and their roles in cellular processes other than those related to cell death. For example, Bad effects insulin secretion and metabolism ^[@R30]^ and BID, contrary to Noxa, by interacting with NOD1, NOD2, and the IκB kinase (IKK) complex facilitates NF-κB activation.^[@R31]^
Noxa is induced rapidly also by hypoxia via hypoxia-inducible factor (HIF)-1α^[@R32]^ by DNA damage,^[@R17]^ by ER stress inducing agents.^[@R33]^ Furthermore, anticancer agents, including the proteasome inhibitor, bortezomib, or ubiquitylation of Mcl-1, induce Noxa expression.^[@R35]^ All these studies used fibroblasts, chronic lymphocytic leukemia, melanoma, neuroblastoma, osteosarcoma, and lung cancer cells and investigated expressed Noxa interacting with the anti-apoptotic Mcl-1 to regulate cell death by affecting Mcl-1 degradation.^[@R25],[@R36]^ However, although Mcl-1 was present in airway epithelial cells, the presence of pHSP27 caused the IFN-γ-induced Noxa to prefer the cross-linking with pHSP27 and not Mcl-1. Ser~13~ phosphorylation alters Noxa structure and blocks the interaction site with Mcl-1.^[@R34]^ Whether pHSP27 phosphorylates Noxa or just forces the N-terminal region to be exposed for interaction with IκBα is unclear. While the phosphorylation and ubiquitylation process remained unaffected, Noxa delayed the degradation IκBα after it was already tagged by the K48 ubiquitin chain. Small molecules, called ubistatins, block the binding of ubiquitylated substrates to the proteasome by targeting the ubiquitin-ubiquitin interface of K48-linked chains.^[@R35]^ Whether the N-terminus of Noxa interacts with the IκBα-specific proteins or the ubiquitin-ubiquitin interface or blocks the interaction of ubiquitylated IκBα to the 19S proteasome before being shuttled for degradation needs further investigation.
The airway epithelium is constantly exposed to the elements of the outer world and therefore has to continuously regulate inflammation. We show that Noxa is rapidly induced within hours and this rapid response allows the fine-tuning or unnecessary enhancement of inflammation. Given that Noxa expression in airway epithelium causes a significant difference in inflammation reveals that this protein contributes to the anti-inflammatory protective role of the airway epithelium. Because many pathways that are not necessarily associated with inflammation, including autophagy, regulators of ROS also play a role in regulating inflammation the induction of Noxa may be one of many mechanisms by which the airway epithelium dampens inflammation. Noxa expression can either sensitize airway cells when cells are damaged or inhibit inflammation. The present studies also suggest that the underlying mechanisms of Noxa-induced cell death in airway epithelial cells need further investigation, because Noxa-induced cell death may not only depend on enhanced degradation of Mcl-1 but also on blocking NF-κB activation that directly regulates expression of the anti-apoptotic Bcl-2.
Both the whole Noxa protein when cross-linked with pHSP27 and the peptide comprising the N-terminal region without the cross-linking Cys25 equally delayed the proteasomal degradation of ubiquitylated IκBα. Therefore, the role of pHSP27 is likely to expose the N-terminal region of Noxa to form a complex with IκBα and NF-κB. HSP27 has vastly different functions, including reducing growth or proliferation and increasing differentiation, and protecting against apoptosis.^[@R36]^ This diverse function of HSP27 may depend on its ability as a chaperone protein to interact with other proteins that are present in various cell types or conditions. Further, HSP27 can be phosphorylated at three serine residues, resulting in the redistribution of the large oligomer into smaller tetrameric units, and its dephosphorylation favors the formation of large oligomers, the dimer of HSP27 being the building block for multimeric complexes that can be up to 1000 kDa.^[@R37]^ It is possible that depending on the phosphorylation state, HSP27 interacts with different proteins to ultimately mediate different outcomes. For example, in prostate cancer cells, HSP27-eIF4E interaction defines the chaperoning role of HSP27 to decrease eIF4E ubiquitylation and proteasomal degradation to protect the protein synthesis initiation process and survival.^[@R38]^ Similarly, hic-5 interacts with HSP27 and blocks the anti-apoptotic role of HSP27.^[@R39]^
Our finding that pHSP27 has an anti-inflammatory role is consistent with the report that HSP27 deficiency in mice augments neutrophil infiltration in wounds.^[@R40]^ In other studies, HSP27 can enhance NF-κB activity by interacting with IKK ^[@R41]^ or by interacting with polyubiquitin chains.^[@R42]^ However, these studies focused on analyzing the presence or absence of HSP27 and did not investigate the phosphorylation state of HSP27. Our studies demonstrate a novel observation that Noxa expression being highly induced in airway epithelial cells may define the anti-inflammatory function of pHSP27.
The finding that pHSP27 is primarily detected in lung tissues or airway epithelial cells would suggest that the anti-inflammatory role of Noxa is restricted to AECs. Consistent with this hypothesis, inducible Noxa expression in airway epithelial cells of transgenic mice was effective in suppressing inflammation. Delivering the NoxaA peptide directly to the airways may be a useful tool to temper inflammatory responses by prolonging the half-life of IκBα. Therefore, developing therapeutic vectors that deliver Noxa proteins or peptides to the airway epithelium or molecules that specifically induce Noxa expression in airway cells would represent novel anti-inflammatory tools to control chronic inflammation. Noxa as treatment may be effective particularly in diseases that are associated with high levels of pHSP27, including COPD,^[@R43]^ asthma,^[@R44]^ and cancer.^[@R45]^ IFN-γ has been used to treat chronic inflammatory diseases, but as a pleiotropic cytokine, it has many effects. By identifying Noxa as the protein that mediates the anti-inflammatory role of IFN-γ this study may have uncovered a means to harness the anti-inflammatory benefits of IFN-γ and minimize the other effects of IFN-γ This would place Noxa in a unique position among anti-inflammatory therapeutic agents, especially when prolonged treatments are expected in chronic inflammatory diseases, such as asthma and COPD.
Materials and Methods {#S11}
=====================
Animals {#S12}
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All mouse studies were performed at the Lovelace Respiratory Research Institute (LRRI), a facility approved by the Association for the Assessment and Accreditation for Laboratory Animal Care International using protocols, pre-approved by the Institutional Animal Care and Use Committee (IACUC), and the Environmental Safety and Health department (ES&H). *Noxa*^-/-^ on C57Bl/6 background mice were provided by Dr. A. Strasser (Walter and Eliza Hall Institute, Melbourne, Australia) and *p53*^-/+^ breeders were purchased from The Jackson Laboratory (Ben Harbor, ME) and were bred at LRRI.^[@R17]^ Mice were housed in isolated cages under specific pathogen-free conditions for the described studies.
The conditional and airway specific overexpression of Noxa was achieved by mating two lines of transgenic mice, the CCSP--reverse tetracyclineresponsive transactivator (rtTA) mice, bearing the rtTA under the control of the CCSP gene promoter (Perl et al 2009), and the tetracycline operator (TetO)~7~--Noxa mice, containing TetO and minimal cytomegalovirus (CMV) promoter and the Noxa transgene. (TetO)~7~-Noxa mice were generated at the M.D. Anderson Genetically Engineered Mouse Facility following standard methods and Institutional Animal Care and Use Committee-approved protocols and bred with CCSP-rtTA mice at LRRI. The transgene plasmid was cut with HindIII and NheI, and murine Noxa cDNA was separated from the TG-1 vector. Purified murine Noxa cDNA was injected into the pronuclei of zygotes collected from superovulated (C57BL/6) female mice, and injected zygotes were transferred to pseudopregnant ICR recipient females. Founder animals were identified by polymerase chain reaction amplification of 2.5 ul of tail DNA segments digested overnight in NaOH at 55°C. Oligonucleotides were as follows: a, 5′-AGGGATCCAT GTGTATTGTA TGTGGGCTC TAACCTGGC-3′ b, 5′-TGCAGCTAGG TGAGCGTCCA CAGGACCCTG AGTGGT-3′. To conditionally express murine Noxa in the lung, transgenic mice were fed with doxycycline-containing diet. Founder animals (C57Bl/6J) were bred to C57Bl/6J × C57Bl/6J animals to evaluate germline transmission. Six lines that transmitted the Noxa sequence were analyzed by q-PCR for expression of Noxa in lung and tracheal tissue. On the basis of these results, three murine lines with expression of Noxa in the airway epithelia were chosen for colony expansion and line 2 was maintained by breeding with wild-type C57Bl/6 mice and using the wild-type littermates as controls for each experiment.
Exposures {#S13}
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At 6-10 weeks of age, mice were entered into the experimental protocols. Mice were instilled with HDM extracts for 5 consecutive days and lung tissues were analyzed 24 or 72 h post the last challenge. HDM (Greer Laboratories, Lenoir, NC) was from *Dermatophagoides Pteronyssinus*, (lot \#248041), as 21.5 mg protein per 103.3 mg dry weight in a freeze-dried form, was resuspended in sterile phosphate buffered saline for a final concentration of 1μg/μl and stored in frozen aliquots at -20°C. Sensitization and exposure of mice to ovalbumin was as described previously.^[@R46]^ Bronchoalveolar lavage and preparation of lung tissues for histopathological examination and staining with Alcian blue/hematoxylin and eosin (H&E) was as described.^[@R46]^
Cells {#S14}
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Primary human airway epithelial cells (HAECs) (Cambrex Bio Science Walkersville, Inc.), murine airway epithelial cells (MAECs), AALEB cells, A549 cells stably transfected with multiple copies of the NF-κB response element driving a luciferase reporter construct (A549-NF-κB-luc cell line) (Panomics, Inc., CA.), and 293T cells were cultured as described previously.^[@R14]^ AALEB cells are immortalized HAECs that have been well characterized ^[@R47]^. Cells were maintained in bronchial epithelial growth medium BEGM (Lonza) supplemented with growth factors (BEGM Singlequots, Lonza) as described previously ^[@R14]^. Adenoviral expression vectors for Noxa were provided by Dr. G. Shore (McGill University, Montreal, Canada), and cells were infected as previously described ^[@R48]^. The A549-NF-κB-luc cell line was purchased from Panomics, Inc., CA. and grown in DMEM (Invitrogen) supplemented with 10% fetal bovine serum (FBS), 1mM sodium pyruvate, (Invitrogen), penicillin/streptomycin (Invitrogen) and hygromycin. The 293T cells were cultured in DMEM with 10% FBS. Transfections were carried out with the TransIT-2020 Transfection Reagent (Mirus Bio) according to manufacturer\'s protocol. Cell viability was determined by trypan blue exclusion.
Mouse airway epithelial cells (MAECs) were isolated essentially as described previously ^[@R49]^ by incubation in pronase solution (DMEM, 1.4 mg/ml pronase and 0.1 mg/ml DNase) overnight at 4°C to dissociate airway epithelial cells from the basal lamina. Cells were collected by gently rocking trachea in DMEM/Ham H12 media (Invitrogen) followed by centrifugation at 400g for 10 min at 4°C. MAECs were grown in media described previously.^[@R50]^
Generation of Expression Constructs {#S15}
-----------------------------------
The GST-tagged recombinant proteins of the full length Noxa (pGEX-Noxa), 5′ or 3′ truncated versions (pGEX-NoxaΔ5′ or pGEX-NoxaΔ3′), C25/51S mutant (pGEX-Noxa-2CS), and C-terminal K35/38/41R mutant (pGEX-Noxa-3KR) were expressed in pGEX-5X-1 Gene Fusion System (GE Health). The constructs were generated by amplifying the desired coding regions with appropriate mutations using PCR and inserting the products into the BamHI and EcoRI sites of pGEX-5X1 vector. The primers for generating NOXA full-length and truncated constructs were: NOXA (BamHI)- 5′-tcc gga ctc gga tcc cca tgc ct-3′ NOXA (EcoRI)- 5′-ccg tcg act gca gaa ttc tca gg-3′ NOXA-5′deletion (BamHI)-5′-cgg atc ccc caa ccg agc ccc gcg cgg gct cca gc-3′ NOXA-3′deletion (EcoRI) -- 5′-cag aat tct cac tgc cgg aag ttc agt ttg tct cc-3′. Primers for generating pGEX-Noxa-2CS were: pGEX-NOXA-BamHI-F (5′-aag gtc gtg gga tcc cca tgc ctg gg-3′), NOXA C25S-F (5′-ctg gaa gtc gag tct gct act caa ctc-3′), NOXA C25S-R (5′-gag ttg agt agc aga ctc gac ttc cag-3′), NOXA-C51S-EcoRI-R (5′-cga ccc ggg aat tct cag gtt cct gag gag aag agt ttg g-3′). After generating products PCR1 and PCR2 using primers pGEX-NOXA-BamHI-F / NOXA C25S-R, and NOXA C25S-F / NOXA-C51S-EcoRI-R, these products were purified and used as the templates to amplify PCR3 product using pGEX-NOXA-BamHI-F and NOXA-C51S-EcoRI-R primers. PCR3 was digested with BamHI+EcoRI, and cloned into pGEX-5X1. pGEX-Noxa-3KR was constructed using the following primers: pGEX-NOXA-BamHI-F, NOXA-K35R-R (5′-ctg ccg gaa gtt cag gcg gtc tcc aaa tct-3′), NOXA-K41R-R (5′-gat atc aga ttc aga agg cgc tgc cgg aag ttc ag-3′), NOXA-K48R-EcoRI-R: (5′-cgg gaa ttc tca ggt tcc tga gca gaa gag gcg gga tat cag att cag-3′). To express Noxa and its mutant proteins in mammalian cells, Noxa-WT, Noxa-2C and Noxa-3KR were sub-cloned into the BamHI and EcoRI sites of pcDβA vector. pcDβA-Noxa-C25S and pcDβA-C51S constructs were generated using pGEX-NOXA-BamHI-F/NOXA-EcoRI-R (5′-cga ccc ggg aat tct cag gtt cct gag cag aag agt ttg g-3′) to amplify pGEX-Noxa-2C and pGEX-NOXA-BamHI-F / NOXA-C51S-EcoRI-R to amplify Noxa-WT. The PCR products were digested with BamHI+EcoRI and sub-cloned into the pcDβA vector, where expression of cloned sequences is driven by the CMV enhancer. All constructs were verified by sequencing.
Immunofluorescence {#S16}
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Cells were seeded onto 2- or 4-well chamber slides (Labtek), fixed with 3.5% paraformaldehyde, permeabilized with 0.1% Triton X-100, and incubated in blocking buffer (3% BSA, 1% normal goat serum in PBS). After incubation with the relevant primary antibody cells were stained with either anti-rabbit Alexa647 or mouse Alexa555 (Invitrogen), mounted with glass coverslips using Fluoromount-G (Southern Biotech) and immunofluorescence visualized using Axioplan 2 (Carl Zeiss) with a Plan-Aprochromal 63×/1.4 oil objective and a charge-coupled device camera (SensiCam; PCO) using an acquisition and processing software Slidebook 5.0 (Intelligent Imaging Innovation, CO).
GST Pull-down Assays {#S17}
--------------------
Expression constructs were transformed into ECOS-21 bacterial cells (Yeastern Biotech) and induced using 1mM IPTG (Sigma) for 4 h at 37°C (GE Health, manufacturer\'s protocol). Cells were lysed by repeated freeze-thawing and sonication. Expression was determined via Western blot analysis using an anti-Noxa Mouse mAb (114C307, Calbiochem). Fusion proteins were affinity-purified on glutathione-Sepharose beads (Pharmacia) and quantified. For pull-down assays, lysates of non-treated and IFN-γ-treated cells were incubated for 2 h with GST fusion proteins noncovalently immobilized on glutathione-Sepharose beads. Beads were washed in cell lysis buffer (50 mM Tris (pH 7.5), 150 mM NaCl, 0.5% Triton X-100, 1 mM PMSF, 0.07 trypsin inhibitor units/ml of aprotinin, and 1 μg/ml each of leupeptin, pepstatin, antipain, and chymostatin (Sigma)). Bound proteins were solubilized in sample buffer, resolved by SDS-PAGE, and subjected to anti-HSP27 immunoblotting.
Preparation of Cytoplasmic and Nuclear Extracts {#S18}
-----------------------------------------------
Briefly, cells were lysed in 100 μl lysis buffer (10 mM Tris-HCl, pH8.0; 60 mM KCl; 1 mM EDTA; 1 mM DTT, protease Inhibitors cocktail, 0.5% NP-40), and nuclei centrifuged at 2000g. Nuclear extract was obtained by incubating nuclei in nuclear extraction buffer (20 mM Tris-HCl; 420 mM NaCl; 0.2 mM EDTA; 25% glycerol; 1.5 mM MgCl~2~; 1 mM DTT and 0.1 mM PMSF) and centrifugation at 10,000g.^[@R15]^
Immunoblotting {#S19}
--------------
Western blot analysis was performed as described previously ^[@R15]^. Briefly, equal amount of proteins were resolved by SDS-PAGE and transferred to PVDF membranes (Immobilon-P, Millipore Corp). Membranes were incubated with optimal concentrations of relevant primary antibody and incubated with horseradish peroxidase (HRP)-conjugated anti-mouse or -rabbit secondary antibody (Sigma), washed 3×5 min in TBS-T and visualized by Western Lightning Plus-ECL according to manufacturer\'s protocol (Perkin Elmer). The antibodies used were mouse Noxa (114C307) (Calbiochem), rabbit anti-Noxa (FL-54), anti-κBα (C-21) and mouse anti-NF-κB p65 (F-6) (Santa Cruz Biotechnology), rabbit anti-Lamin A/C and mouse HSP27 (Cell Signaling Technology), rabbit anti-p-Ser ^15,\ 78,\ or\ 82^ HSP27 (Stressgen), anti-K48-linkage Specific Polyubiquitin mAB (Cell Signaling), mouse anti-β-Actin, and anti-β-tubulin (Sigma).
Immunoprecipitation {#S20}
-------------------
The Crosslink IP Kit (Thermo Fisher Scientific) was used to cross-link 10 μg of anti-Noxa, anti-NF-κB and anti-κBα (Santa Cruz) or HSP27 (Stressgen) antibodies to Sepharose protein A beads using disuccinmidyl suberate according to manufacturer\'s protocol. The associated proteins were immunoprecipitated by gentle mixing equal amounts of protein lysates with the antibody-crosslinked beads at 4°C overnight. After 6 washes, bead-bound proteins were eluted and analyzed by immunoblotting.
Retroviral silencing with shRNA {#S21}
-------------------------------
Retroviral silencing vector encoding shHSP27 or shNoxa and the corresponding control vector (shCtrl) were purchased from Origene Technologies, Inc. The suppressing effect of the shRNA was first established in AALEB cells and the subsequent amplification, purification, and packaging of the retroviral particles using Phoenix cells (Orbigen, Inc.) were performed as specified by the manufacturer.
Luciferase assay {#S22}
----------------
A549 /NF-κB-luc cell line (Panomics Corp.) was used to monitor the activity of NF-κB transcription factor in a cell based assay (R/D Biosystems, Minneapolis, MN). Cells were lysed by rocking for 15 min in passive lysis buffer (Promega Corp., Madison, WI) and luciferase activity was detected with the Luciferase Assay system (Promega) using a Fluoroskan Ascent detector (Labsystems) according to the manufacturer\'s protocol.
Luminex Cytokine Assay {#S23}
----------------------
The cytokines in cell culture media were quantified by Luminex instrument (Luminex Corp.) using Multiplex Fluorescent Bead-Based Luminex Cytokine Assays (EMD Millipore).
MALDI-TOF {#S24}
---------
To identify interacting proteins, Noxa was immunoprecipitated with antibodies cross-linked to Sepharose protein A beads. The immunoprecipitate was fractionated on a SDS-PAGE and the 32 kDa band along with blank controls excised, eluted, and subjected to tryptic digestion. Samples were dissolved in methanol, mixed at a 1:1 ratio (v/v) with 2,5-dihydrobenzoic acid (20 mg/ml in 70% methanol in water) as matrix. Survey scans were acquired from *m*/*z* 500--4,000. Sequence analysis of the tryptic peptides was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (ABI 4700 MALDI /TOF Mass Spectrometer) running 4000 Series Explorer. Precursors for MS/MS were selected on the basis of signal intensity with up to 20 peptides per spot being chosen for MS/MS analysis. Peptide sequences were identified by searching MASCOT® database using GPS Explorer Version 3.5 software (Applied Biosystems). Both MS and MS/MS spectra were processed by the software. For MS spectra, an S/N threshold of 30 was used, while for MS/MS spectra, a threshold of 20 was used to detect peaks.
Real-time PCR Analysis {#S25}
----------------------
Total RNA was isolated from HAECs, MAECs and AALEB cells using RNeasy Micro Kit (QIAGEN). The mRNA levels of Noxa, IL-1β, IL-6, Bcl-2, Bcl-x~L~ were quantified by ABI HT 7900 Real Time PCR system using TaqMan One-step RT-PCR Gene Expression kit (Life Technologies). The mRNA levels of KC from MAECs were quantified using High Capacity RNA-to-cDNA Kit (Life Technologies) and QuantiTect SYBR Green PCR Kit (QIAGEN).
Statistical Analysis {#S26}
--------------------
Grouped results from at least three different experiments were expressed as means ± SEM. Results (grouped by time point and treatment) were analyzed using two-way analysis of variance. In the event that significant main effects were detected (*P* \< 0.05), Fisher\'s least significant difference test was used to differentiate between groups. A *P*-value of 0.05 was considered to indicate statistical significance. Data were analyzed using statistical analysis software (Statistical Analysis Software Institute).
Supplementary Material {#S27}
======================
######
**Figure S1. (A)** Primary normal human airway epithelial cells (HAECs) were treated with 0, 25, or 50 ng/ml IFN-γ for 24 and 48 h and analyzed for Noxa mRNA levels by qRT-PCR. **(B)** Induction of Noxa mRNA in MAECs from wild-type, *noxa^-/-^* and *STAT1^-/-^* mice treated with 50 ng/ml IFN-γ for 24 h. **(C)** IFNγ induces Noxa independent of p53. MAECs from *p53^-/-^* mice were treated with 50 ng/ml of IFN-γ for 48 h or left untreated and mRNA analyzed by qRT-PCR. **(D)** Susceptibility of *noxa^+/+^* and *noxa^-/-^* MAECs to 50 ng/ml IFN-γ treatment over 96 and 120 h. Error bar indicates ± SEM (n=3 wells/group) \* *P* \< 0.05.
**Figure S2. (A)** Mucous cells/mm basal lamina were higher after exposure to ovalbumin in *noxa^-/-^*compared with *noxa^+/+^* mice. **(B)** Perivascular inflammation in *noxa^+/+^* and *noxa^-/-^* mice exposed to allergen for 5 as scored by a person unaware of slide identities. Mice were injected IP with OVA/Alum on days 1 and 7 and exposed to OVA aerosols at 2 mg/m^[@R3]^ for 5 d (n=6 mice/group). **(C)** AALEB cells were treated with increasing concentrations of H~2~O~2~ and cell counts were determined. Error bars indicate ± SEM, \* *P* \< 0.05. **(D)** AALEB cells infected with Ad-Noxa or Ad-GFP at either 0, 20, 30, or 40 MOI and treated 24 h later with 45 μM H~2~O~2~ (n= 3 wells per group) **(E)** A549-NF-κB-luc were infected with either Ad-GFP or Ad-Noxa at 100 MOI for 16 h and or treated with 50 ng/ml human recombinant IFN-γ or vehicle for 15 h. Subsequently cells were treated with 10 ng/ml TNFα for 6 h and analyzed for luciferase activity. Luciferase values were corrected for total protein. (n= 3 wells per group) **(F)** AALEB cells treated with vehicle or IFN-γ were treated with TNFα for 30 min and following Western blotting were probed for NF-κB, IκB, Noxa, β-tubulin, and lamin A/C. **(G)** Cytosolic extracts prepared from *noxa^+/+^* and *noxa^-/-^*MAECs treated with TNFα for 0, 15 and 30 min were analyzed by Western blotting. The extracts were probed for NF-κB (p-65), IκB, and β-actin, and the relative fold-change of cytosolic IκBα was quantified over the respective β-actin levels. Error bar indicates ± SEM (n=3 independent experiments with 3 wells in each experiment) \*denotes *P* \< 0.05, \*\*\* denotes *P* \< 0.001.
**Figure S3: (A)** AALEB cells infected with Ad-Noxa or Ad-GFP (40 MOI) for 24 h and then treated with IFN-γ or nothing as control were subjected to immunoblot analyses using anti-Noxa and anti- p-S~82~HSP27 antibodies. **(B)** GST-Noxa-coated beads incubated with extracts from IFN-γ-treated AALEB cells in the presence or absence of 5 mM DTT for 6h. The pull-down products were analyzed by Western blotting using antibodies to Noxa and GST. **(C)** GST or GST-Noxa proteins bound to glutathione-sepharose beads were used to pull down interacting proteins from AALEB cell lysates and analyzed by Western blotting using antibodies to p-S~82~HSP27, Noxa, and β-actin. **(D)** shHSP27 and shCtrl cells treated with IFN-γ and tested for Noxa expression by Western blotting using antibodies to Noxa and β-actin. **(E+F)** Multiplex bead-based Luminex assays of cytokines in shControl, shNoxa and shHSP27 AALEB cells. AALEB cells stably transfected with shCtrl, shNoxa, or shHSP27 were pretreated with IFN-γ for 24 h and either treated with TNFα (20 ng/ml) or were left untreated for 2 h. Culture media supernatants from at least 3 wells per group were subjected to Multiplex Bead-based Luminex assays for IL-8 **(E)** and IL-6 **(F)**. Error bar indicates ± SEM \*\*\* *P* \< 0.001.
**Figure S4. Co-localization of Noxa, NF-κB and HSP27 *in vivo*. (A)** Immunostaining with Noxa (red) and pS~82~Hsp27 (green) antibodies of the airway epithelium from *Noxa^WT^*and *Noxa^Ind^* mice following HDM challenge and dox-mediated Noxa induction. **(B)** Immunostaining with NF-κB (green) and pS~82~Hsp27 (red) antibodies of the airway epithelium from *Noxa^WT^*and *Noxa^Ind^* mice.
**Figure S5: (A)** The amino acid sequence of Noxa is highly conserved for mouse and human. Murine Noxa appears to have a duplicate of the human sequence. Especially, the N-terminal sequence and the BH3 domain are conserved and represented twice in the murine Noxa. **(B)** Amino acid sequences of NoxaA, NoxaB, NoxaC, and NoxaD peptides. **(C)** HAECs were treated with 45 μM H~2~O~2~ and 1.0 μM Noxa C peptide and cell counts were determined after 24 h. Error bars indicate ± SEM.
**Table S1.** Peptide mass fingerprint analysis by Matrix Assisted Laser Desorption Ionization-Time of Flight mass spectrometry (MALDI-TOF). Protein extracts from AALEB cells treated with IFN-γ for 48 h were immunoprecipitated using Noxa antibodies, fractionated by PAGE. After elution from the gel, the 32 kDa band was subjected to protease treatment and MALDI-TOF analysis. These are data related to [Figure 2](#F2){ref-type="fig"}.
The authors thank Dr. Ram H. Nagaraj for providing HSP27 WT and C137A expression constructs and Lois K. Herrera for technical assistance with Luminex assays and quantification of inflammation in lung tissues. These studies were supported by grants from the National Institutes of Health (HL068111 and ES015482).
**Author Contributions:** CZ performed most of the experiments and drafted parts of the paper, JJ conducted the peptide, HDM, and ubiquitylation studies, HC performed the immunofluorescence studies, MW provided strategies to generate various mutation constructs, JX propagated the adenoviral constructs, YM helped with the mouse studies, YT designed the studies and wrote the manuscript for review by all co-authors.
**Disclosure/Conflict of Interest:** The authors have no conflicting financial interests.
{#F1}
{#F2}
{#F3}
{#F4}
{#F5}
[^1]: Present address: Department of Oncology, Johns Hopkins Bayview Medical Center, Baltimore, MD 21224, USA
[^2]: Present address: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University Miami, FL 33199, USA
[^3]: These authors contributed equally.
|
2012 European Athletics Championships – Men's 800 metres
The men's 800 metres at the 2012 European Athletics Championships was held at the Helsinki Olympic Stadium on 27, 28 and 29 June.
Medalists
Records
Schedule
Results
Round 1
First 4 in each heat (Q) and 4 best performers (q) advance to the Semifinals.
Semifinals
First 2 in each heat (Q) and 2 best performers (q) advance to the Final.
Final
References
Round 1 Results
Semifinal Results
Final Results
800
Category:800 metres at the European Athletics Championships |
SP&M Article Archive
School Planning & Management's vast database of articles is a valuable tool for anyone who plans, designs, equips, maintains and operates pK-12 schools nationwide. Popular topics include facilities, safety & security, technology, business, finance and the learning environment. Articles are displayed in chronological order, beginning with the most recent.
Even the most thoughtfully designed and perfectly installed access control strategies can often easily be compromised by staff who do not do their part to support them. While staff development is called for, making access control a reality in deed as well as word is must be a leadership priority.
In recent years, more research has come to light in support of the impact that facility design has on student performance. These studies reveal clear evidence that the physical characteristics of a classroom impact learning, and furthermore, that a link exists between well-designed school facilities and increased academic achievement.
Charter schools are not for everyone and are meticulously designed for their student populations. As conservative school choice activists argue for greater funding for charter schools, like public schools, they differ in performance and student outcomes based on zip codes.
Technology has become an integral part of K-12 classrooms. Here are some examples of how districts across the country use technology—both software and hardware—to create authentic learning experiences for students. |
In 1977, the Du Toit family purchased Die Pastorie (The Parsonage)-one of the most recognised properties in Riebeek Kasteel, from the Dutch Reformed Church. Thirty-three years later, Pieter and Annalene du Toit transformed this landmark property into one of the Riebeek Valley’s most luxurious overnight accommodation options, the Kloovenburg Pastorie.
This historic property has been affectionately restored and transformed into a beautiful villa, offering guests to the Riebeek Valley three sumptuous air-conditioned en-suite bedrooms and one super luxurious suite with en-suite bathroom and private lounge area. Along with the luxurious accommodation, the Kloovenburg Pastorie also has relaxing public spaces, including a well-appointed lounge, dining room, kitchen and a sparkling pool with loungers to relax on. The décor in this classic Victorian-styled home is an eclectic mix of French and Victorian. |
Is hemifacial spasm a phenomenon of the central nervous system? --The role of desflurane on the lateral spread response.
A signature EMG feature of hemifacial spasm (HFS) is the lateral spread response (LSR). Desflurane is a common anesthetic with potent effects on synaptic transmission. We tested the hypothesis that the LSR is mediated by corticobulbar components by comparing the LSR during total intravenous anesthesia (TIVA) or TIVA plus desflurane during microvascular decompression (MVD) surgery. 22 HFS patients undergoing MVD surgery participated in this prospective study. The LSR data was recorded from the o. oculi, o. oris and mentalis muscles prior to opening dura. LSR onset latencies and amplitudes were determined under TIVA and TIVA/desflurane (0.5 and 1MAC). Facial muscle LSRs and EEG were analyzed. Desflurane (1MAC) significantly decreased the LSR amplitude in all 3 facial muscles (p<0.01). Pooled LSR data from all facial muscles showed desflurane inhibited the LSR amplitude by 43% compared to TIVA (p<0.001). No effects on the latency of the LSR or on EEG state were observed. LSR inhibition by desflurane suggests a central mechanism involvement in the genesis of this signature HFS response. This study demonstrates that facial nerve vascular compression and plastic changes within the CNS are part of the pathophysiology of HFS. |
651 F.2d 176
18 ERC 2128, 11 Envtl. L. Rep. 20,857
ROHM & HAAS COMPANY, Appellant,v.UNITED STATES ENVIRONMENTAL PROTECTION AGENCY, and Walter C.Barber, and Mobil Oil Corporation, Appellees.
No. 81-1757.
United States Court of Appeals,Third Circuit.
Argued May 22, 1981.Decided May 26, 1981.
James J. Binns, Philadelphia, Pa., Patrick M. Raher, David J. Hayes, David A. Kikel, Washington, D.C., for appellant Rohm and Haas Company; Robert P. Vogel, Regulatory Counsel, Rohm and Haas Company, Philadelphia, Pa., of counsel.
David Richman, Pepper, Hamilton & Scheetz, Philadelphia, Pa., A. Duncan Whitaker, Mark D. Wegener, Ray A. Jacobsen, Jr., Howrey & Simon, Harold Himmelman, Cynthia A. Lewis, Beveridge & Diamond, Washington, D.C., for intervenor-defendant Mobil Oil Corporation; Thomas J. Winans, Deborah E. Lynch, Mobil Oil Corp., New York City, of counsel.
Before GIBBONS, GARTH and SLOVITER, Circuit Judges.
OPINION OF THE COURT
PER CURIAM.
1
Rohm & Haas Company appeals from a judgment in favor of the defendants in its action against the Environmental Protection Agency et al., in which Mobil Oil Corporation intervened as a defendant. Rohm & Haas sought an injunction against the issuance to Mobil of an Experimental Use Permit (EUP) for experimental use of Mobil's product Tackle as a pesticide for soybeans. Rohm & Haas contends, and the defendants do not dispute, that the Environmental Protection Agency, in approving experimental use of Tackle, relied on information in the agency's file with respect to Rohm & Haas's product Blazer, which like Tackle contains the active ingredient acifluorfen. Such reliance, Rohm & Haas contends:
2
(1) violates Section 5 of the Federal Fungicide and Rodenticide Act, 7 U.S.C. § 136c in that EUP's may not be issued in reliance on data submitted by anyone but the applicant; and
3
(2) violates restrictions on the use of submitted data in Section 3(c)(1)(D) of the Federal Fungicide and Rodenticide Act, 7 U.S.C. 136a(c)(1)(D).
4
Rohm & Haas also contends that the agency should have permitted additional time for public comments in response to its May 5, 1981 Federal Register Notice of Mobil's application for the EUP.
5
Upon filing its notice of appeal Rohm & Haas moved for an injunction pending appeal, and alternatively for accelerated disposition of the appeal after oral argument, on the briefs filed with the trial court. All parties agreed to a disposition of the appeal on the submissions to date. We heard oral argument on the merits of the appeal on May 22, 1981.
6
We affirm the judgment appealed from, essentially for the reasons set forth in the comprehensive opinion of the trial court.
|
Q:
Inno setup: how to replace a string in XML file?
The following (in quote) is the content of a XML file which is part of my package.
I'd like to replace the value of c:\path\myapp.exe during the installation (with the real path where the user chose to install the application.
Is that possible? How to?
<?xml version="1.0" encoding="UTF-8"?>
<launchConfiguration type="org.eclipse.ui.externaltools.ProgramLaunchConfigurationType">
<listAttribute key="org.eclipse.debug.ui.favoriteGroups">
<listEntry value="org.eclipse.ui.externaltools.launchGroup"/>
</listAttribute>
<stringAttribute key="org.eclipse.ui.externaltools.ATTR_LAUNCH_CONFIGURATION_BUILD_SCOPE" value="${none}"/>
<stringAttribute key="org.eclipse.ui.externaltools.ATTR_LOCATION" value="c:\path\myapp.exe"/>
<stringAttribute key="org.eclipse.ui.externaltools.ATTR_TOOL_ARGUMENTS" value="${resource_loc}"/>
</launchConfiguration>
A:
Your best option is to use the XML DOM to select and edit the required node as TLama suggested.
Alternatively, you can install a template file with a known string in the location you want to replace.
The file can then be read as a string, modified and written back out again using something like:
[Code]
procedure WriteAppPath;
var
FileData: String;
begin
LoadStringFromFile(ExpandConstant('{app}\app.xml'), FileData);
StringChange(FileData, 'XXXXXMARKERXXXXX', ExpandConstant('{app}'));
SaveStringToFile(ExpandConstant('{app}\app.xml'), FileData, False);
end;
See also this question about doing the same thing en masse to an INI file.
|
Ultrasensitive electrochemical immunosensor for clinical immunoassay using thionine-doped magnetic gold nanospheres as labels and horseradish peroxidase as enhancer.
A new signal amplification strategy based on thionine (TH)-doped magnetic gold nanospheres as labels and horseradish peroxidase (HRP) as enhancer holds promise to improve the sensitivity and detection limit of the immunoassay for carcinoembryonic antigen (CEA), as a model protein. This immunoassay system was fabricated on a carbon fiber microelectrode (CFME) covered with a well-ordered anti-CEA/protein A/nanogold architecture. The reverse micelle method was initially used for the preparation of TH-doped magnetic gold nanospheres (nanospheres), and the synthesized nanospheres were then labeled on HRP-bound anti-CEA as a secondary antibody (bionanospheres). Sandwich-type protocol was successfully introduced to develop a new high-efficiency electrochemical immunoassay with the labeled bionanospheres toward the reduction of H2O2. Under optimized conditions, the linear range of the proposed immunoassay without HRP as enhancer was 1.2-125 ng/mL CEA, whereas the assay sensitivity by using HRP as enhancer could be further increased to 0.01 ng/mL with the linear range from 0.01 to 160 ng/mL CEA. The developed immunoassay method showed good precision, high sensitivity, acceptable stability and reproducibility, and could be used for the detection of real samples with consistent results in comparison with those obtained by the enzyme-linked immunosorbent assay (ELISA) method. |
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"It was a dream." "The bionics enhance the width of human strength." "And then some." " What have you done to me?" " Jaime." " Why did you do this to me?" " You were going to die." "Sir." "Borned Jaime Wells Sommers, Van Horn, Iowa," "February 23rd 1983." "Mother deceased, cancer." "Father still a hawkeye." "She's was enrolled at Berkeley until last semester which is when her sister began to attend classes at the Dolton school for the deafs." "She's clean except for a sealed court record from 1998." "What's in it?" " It's sealed." " Unseal it." "I'm working on it." "I think she's a good candidate." "Well let's pretend I'm soliciting opinions, why?" "She's stable." "I've put up an old Minnesota multiphysic personality inventory." "I liked what I saw." "Plus the situation whith her sister shows loyalty." "And she's smart." "I found an old I.Q. test." " How did she do?" " A little better than you, sir." "Jae, can you train her?" "Well, the last one we screened, tested, made the psych evaluations and she was a soldier." "Look where that got us." "We've always talked about non-military applications." "Here is our chance." "Your opinion is invalid, you're too close to the subject." "There's from the guy who played house with the last one." "Let's get fresh data, I want you to sit her down." "Alright." "Yeah, I once had a wolf." "And a wolf only makes a good pet, if he thinks he's a dog." "And your girlfriend, we're keeping her here against her will." "How long until she realizes that no one can make or do anything against her will." "You're talking about killing a human." "I'm talking about killing a wolf." "You know what scares me about you?" "Your father." "He seemed normal too." "If I'm anything like my father, you just made a big mistake." "Alright, I have to get you to rehab before... rehabilitation." "I'm not the one performing human experiments and keeping people prisonner." "You rehabilitate yourself." "Booh." " I'm Ruth." " I'm pissed." "Good." "We're here to talk about our feelings." "How do you feel about me being captured against my will?" "I was speaking editorially." "Actually, we're here to talk about your feelings." "Something no one seems to have any regard for." "Curve balls will do that." "You can have all the contingency plans you like and then someone goes into something like this and then we all have to stay after school..." "And talk about our feelings." " Your feelings." " Right." "After all, feelings are what got us here in the first place." "You like to draw?" " True or false?" " I have a sister." "She's staying with your landlady." "She thinks you're skiing in Vail." "This is where you stayed." "It looks nice." "You had fun." "Except for the part where" "Will enjured his arm skiing into a tree." "Does this mean I'll be going home at some point?" "It means we have a contengency plan, should you be going home at some point." "We also have a plan, should you not?" "True or false?" "You can't teach an old dog new tricks." "You would have done the same thing." "You never met my wife, did you?" "For two years I watched her die in a hospital while they disassembled her." "And the whole time I knew all I had to do to save her was to bring her here, but saving my wife was not the mission." "Ruth said she's stable." "How long until she's combat ready?" "She's a civilian." "Everyone has to sing for their supper around here, Will." "Haven't you figured that out yet?" "How long until the rest of her implants come online?" " She likes to draw." " I don't care." "I think you'll care about this." "Who did they bury?" "I mean, did you ever see the body?" " Did you show this to anybody else?" " Just you." "Keep it that way." "I can't protect you in here." " But once you're on the outside..." " Why should I trust you?" "Because I'm the only one you can trust." "Go back to your life like none of this ever happened." " I'll work it out with them." " What about you?" "Go, now!" "Alright, so I'll have those faxed over to you by Friday afternoon." "And, we're still on for that meeting tomorrow?" "Okay, good." "Yeah?" "Mummy?" "There is a lady out there running very fast." "Like as fast as the car!" "Sweety, what did I tell you about making things up?" "I thought it was cool that a girl could do that." "That's all." " Let her go." " What the hell did you do?" "You want her, right?" "For the program, leave her alone." "I'll make her understand what's at stake," " just let me have time to..." " Time to what?" "Letting her go is not a bad idea." "If you want her loyalty, give her freedom." "Or the illusion of freedom." "Alright." "Everybody, stand down." " You're making a mistake." " Listen to me." "The accident wasn't an accident." "According to the autopsy, the driver's neck was broken an hour before the crash." "Which means someone else was driving that car." "We need to find out who." "Jaime, it's Will." "Jaime, if you're there, pick up the phone, I need to talk to you." "Jaime, please." "There's so many these things I want to say to you." "So many things," "I can't say on the phone." "There are things I need to tell you about." "Before they happen." "Nice of you to show up." "I'm sorry." "What for?" "For leaving and not telling you first." "How was skiing?" "It was fine." "Don't lie to me!" "Where were you?" "I can't tell you." "You failed me." "Coffee." "It's no smoking." "What are you?" "A forest ranger?" "Something like that." "It must be scary." "Alone in the forest, just you and the animals." "Not if they know who's in charge." "Hey!" "Wait up!" "***." "We both know you're working in the Supermax Prison." "A thousand feet below Florence." "We both know this is the place where they stick people when they outlive their usefulness." " I don't know who you are." " If you don't do exactly what I say," "I'm gonna carve your wife Barbara like ***." "Baby, it's me." "Do what he says." "How did you do it?" "Do you know what they call creatures that can live comfortably in environments considered lethal, say, for instance, a thousand feet below the Earth's surface?" " How did you do it?" " Extremophiles." "I'll do an impression of one for you, ready?" " How... did you do..." " What?" " How did I do what?" " That Sarah Corvus is still alive." "And you come all the way here to tell me that?" "Let me do another impression for you." "Impression of a man who's been stabbed in the back, stripped of his rights and thrown in a hole like a dog." "Sarah Corvus is a time bomb, we both know it." "Well, time bombs only matter to those who have time." "Good bye, Jae." "Please give my regards to Will." "Tell him Daddy says hello." "Guards?" "If I may make an observation, you seem way too innocent and sweet to be behind a bar." "And you should be out there with the rest of them." "Finally, I'm not the only person who feels that way." " What can I get you?" " Beer." " On the house." " Thank you." "Don't I know you?" "We met very briefly." "We didn't even actually meet." " Where?" " Guess." " Are you alright?" " Yeah." " Let me take a look at it." " No, it's ok." "Are you ok?" "Come on, your husband will never know." "***." "Are you alright?" "Let me help you." "Just breathe." "It's like that, the first time the ear and eye inputs come online." "It's too much information." "We have to learn how to focus it." "And turn it off on our will." "You're a fast healer." "The intrasites are doing their job." "Who are you?" "Who are you!" "Tell everyone Sarah Corvus says hello." "Yo?" "You're looking for something?" "You need something?" "Uh?" "Come here, baby." "I got what you need." "Please." "Please don't." "Don't." " Are you ok?" " Tell me what you put in my head?" " Jaime." " I almost killed a man." "I didn't even know what I was doing." "What did you put in my head?" "Microscopic chips have been implanted in your cerebral cortex." "My father developped a technology for the military." "The program was meant to help amputees in the Gulf." "Of course he saw the combat application immediately." "You made me into a soldier!" "You're hardwired for very highly specialized warfare, yes." "I was gonna kill him." "I would have..." "But you didn't, you're still in control." " And with a proper training..." " Training?" "Jaime, we're the only ones that can protect you." " Let me protect you." " How can you protect me if you're scared at me?" "I never meant for any of this to touch you, I didn't." "I just..." "I couldn't bare to lose you." "That isn't even me." "Yes, it is." " Hey." " Hey." "I have to get back to Becca." " I can't keep leaving her like this." " Jaime." "What do you people do anyway?" " It's complicated." " Try me." "The world is further along than everyone wants to admit." "Technology is at a point where science-fiction isn't fiction anymore." "We keep that technology from getting into the wrong hands." "Who gets to decide right from wrong?" "What about Sarah Corvus?" "Where does she figure in all this?" "Where did you hear that name?" "Where did you hear that name, Jaime?" "Will?" "Will?" " Sorry." " Just hold on, ok?" " Where is she?" " I don't know." "I need everyone." "Time out." "The intrasites in our blood can filter out any impurities in our lungs." " Fringe benefit of being a freak." " What do you want from me?" "Honestly, I'm not sure..." " Jogging partner?" " Who are you?" "Without being too melodramatic about the whole thing, I'm Sarah Corvus... the first bionic woman." "Tada!" "So what did they replace?" "I figured the eyes and the ears." "What else?" "Me, they did both arms, both legs, only one eye." "Anthros wasn't sure about the optical interface." "Neither was his son." "So I did the other one myself." "Part of my chest too." "I'm cutting away all the parts of me that are weak." "Time in." "You only have one bionic arm." "You should really do something about that." "You gotta have to do a little better than that." "How am I doing now?" "Not bad." "Not bad at all." "We have a 33 year old male, caucasian, a gunshot victim, wound to shoulder." "Request assistance from Mercy General." "Will gonna make it?" "Miss Sommers." " Just wanted to get a look at you." " Who are you?" "You have 50 million dollars worth of my property inside you, so I guess you could say I'm your landlord." "What do you want from me?" "I don't know, maybe you died 3 days ago and you just haven't realized that yet." "Is that a threat?" "There's no free agents, Miss Sommers." "Sooner or later you're gonna have to make a choice, it goes something like this, heads you lose, tails you die." "Welcome to the game." "Hey!" "If we do this, whatever this is, we do it on my terms." "If that's not okay with you," "I know what I'm capable of now." "So you send whoever you send, and I'll bury one guy after the next." "You understand me?" "By the way," "Sarah Corvus says hello." "Tell Jae we have a candidate." "What are you doing?" "I haven't seen the moon in a 1023 days." "It hasn't changed, let's go." "We have work to do." "To be continued..." |
Author and political commentator on Fiji affairs, Rajendra Prasad, who authored Tears in Paradise – Suffering and Struggles of Indians in Fiji 1879-2004.
Corruption was the fastest growing industry during the
era of democratic rule in Fiji. It is not to claim that it has vanished but it
is being addressed. Much maligned Prime Minister Bainimarama and
Attorney-General Aiyaz Khaiyum have declared their assets, which gives
startling comparison to the wealth of leaders who were Prime Ministers of Fiji
except Rabuka who had the harvest but was not astute enough to hold it in his
granary. All others, except Rabuka, are multimillionaires. It clearly shows
that there is prestige, power and unlimited wealth that draw many, not through
genuine desire to serve, but to take advantage through such placement. Some say
Rabuka chose a different lifestyle and either misunderstood or underestimated
the treachery in Fiji politics. Once a hero to his people, following the
military coup of May 14, 1987 but today he is shunned and no political party
needs him or wants him. His plight is no different to George Speight except
that he is serving his sentence and Rabuka will remain a prisoner of his conscience
for the rest of his life.
In
the build up to the 2014 elections, racial attacks through the media or other
public forums, a common feature in the past elections, was demonstrably absent.
However, the Internet is being extensively used, sometimes savagely, where the
Blogs and Facebook sites give opportunity to people to rant and rave to their
hearts content. What is good about this
medium is that Internet is an even playing field where everyone can contribute
on issues of common interest. The voices of the weak cannot be stifled. Undoubtedly,
the political parties are also using this medium to their best advantage. But on the ground and in public, racial
comments and open display of racial hostility is not visible. Credit must go to
the Bainimarama Government for facilitating this remarkable change and for the
first time, equality and dignity of every citizen of Fiji is not only being
seen but felt across the nation. It has not only given dignity to Fijian
citizenship but also raised sense of patriotism in Fijians as never before.
FRANK BAINIMARAMA- credited with implementing policies to stem out racism and divisive politics, the fruits of which are evident in Fiji as witnessed by the Author.
It has contributed to a demonstrable change, as the two
dominant communities’ live in harmony and go about their day to day business
without rancour or bitterness. Go to the towns, markets or sports arenas, the
people of Fiji are one happy lot who relate well with one another. There is
happy and respectful exchange of greetings and hearty banter, followed by
laughter that is an evolving as Fiji Way, replacing the meaningless Pacific
Way. Letters to editor columns carry the same spirit and not the nasty
‘snarling’ of the past. Indo-Fijians
follow the Fiji Sevens team with same fervour as the iTaukei, including
Indo-Fijian women. Bollywood has also infiltrated the iTaukei hearts and minds,
drawing them to the TV screens and rigid following of their favourite
programmes. Go through the iTaukei settlements and it is not unusual to hear
the Bollywood beats echoing, as they do from Indo-Fijian homes. This medium is
also enhancing race relations, which is also transforming hearts and minds of
Fiji’s peoples, as they realize and accept they are one people and Fiji is
their home.
There
has also been a physical transformation, which cannot go unnoticed. ITaukei
girls, with their frail features and straightened hairs, adjusting to modern
fashion trends, are easily mistaken for Indo-Fijians. The effect of the roti
and curry across the nation is palpable.
Those muscular features
of the iTaukei are diminishing and the Policemen in sulu, without the bulging
calf muscles, look starved. On the Indo-Fijian front, the kava has contributed
to the diminishing physique. Indeed, there is physical harmony among the
peoples of Fiji that cannot be apprehended. However, Fiji can only become the
utopia of our dreams if there is political harmony. This can come about when
advocates of racism are disabled in the interests of the nation. Racism has
favoured a few who benefit from the spoils. Racism does not build but destroys
nations. Fiji has suffered too much from it for too long. Those closure of the
racial ‘kennels’ has brought about perceptible change that needs to be nurtured
with care, caution and thoughtfulness.
Indeed,
democracy in Fiji was a label without the basic ingredients of equality,
justice and dignity. Democracy that is reconfigured to pursue racial
discrimination is not democracy but tyranny. Both form and
content comprise its inseparable limbs. Worldwide such autocratic democracies
abound and it usually entails the tyranny of the aristocracy, propped by the Armed forces, against the
majority. Fiji has had a parting of ways between the two on December 5, 2006
and a new era in Fiji politics began, much to the disgust of the ruling elite
who had a long reign, using it to restore it to power whenever it was lost, as
in 1987 and 2000. With this detachment, a new era in Fiji politics began,
which will culminate in first democratic elections on September 17, 2014. The
field is open and those deposed in 2006 and their associates are back with
their ideologies and banners to retake what they considered to be their birth
right. Truth, morals, ethics and principles will become the immediate
casualties, as victory at any cost becomes the name of the game.
What
amused and also saddened me was the sheer lack of remorse and moral conscience
of some of the leaders, convicted for abuse of office or violation of taxation
laws, as they campaigned for their political parties. They moved around defiant
and dismissive of their past when common decency expected them to leave the
public domain. Indeed, the fodder of deceit and lies are
aplenty and the simple and gullible sometimes fail to distinguish between the
grain and chaff.
An unholy alliance, and marriage of convenience, where political enemies become friends for political expediency? [Fiji Sun Photo]
Sometimes, it is beyond the bizarre, as one person, a recent
arrival to the mainland from Vanua Levu told me that the Government was wrong
in fining Chaudhry F$2 million, as he was paying the farmers evicted from their
leased land $28,000 each from the funds he held in Australia! He genuinely
grieved that now the poor farmers cannot be helped because the Government had
taken all the money in fines. I was gobsmacked by the naivety of the person
whose seriousness in his belief was inscrutable. Will this election be won on
deceit and lies or will it be won on truth and understanding? Only time will
tell. God Bless Fiji!
[About the Author: Rajendra
Prasad is the author of Tears in
Paradise – Suffering and Struggles of Indians in Fiji 1879-2004), former Ba
Town Clerk and an analyst on Fiji’s struggling efforts to seek an appropriate
form of democracy.] |
Issue
Filter design sifts deadly prions from blood supply
08/01/2004
BY STEVE SMITH
EAST HILLS, N.Y.—For the second time this summer, a major advance has been unveiled in the battle against infectious prions associated with Mad Cow Disease, Creutzfeldt-Jakob Disease (vCJD). The latest, announced last month by Pall Corp. (www.pall.com), is a proprietary filter technology that's said to reduce deadly prions from the blood supply before it is used for transfusions.
Earlier this summer, Serologicals Corp. (Atlanta, Ga.; www.serologicals) was granted a patent on its proprietary purification process that clears the Mad Cow prions from bovine-based pharmaceuticals. More than 60 percent of pharmaceuticals on the market have involved bovine-based products in their development or manufacture.
Pall Corp.'s Leukotrap affinity prion reduction filter is designed to offer a multi-targeted approach to blood safety by reducing leukocytes and infectious prions that are cell or non-cell associated. Tests indicate the filter reduces deadly Mad Cow Disease prions from the blood supply before it is used for transfusions.
Click here to enlarge image
Prion transmission via blood transfusion, though reduced in recent years, remains a concern for the public blood supply—particularly overseas. In December 2003, a case of vCJD was identified in a person who received a blood transfusion six years earlier from a donor who later died of the disease. In announcing its breakthrough to the International Society for Blood Transfusion annual meeting, Pall Corp. officials noted that since vCJD has an unknown and lengthy incubation period that is asymptomatic, there is no way to know how many have transmitted the disease via transfusion.
The Leukotrap affinity prion reduction filter, however, is designed to offer a multi-targeted approach to blood safety by reducing leukocytes and infectious prions that are cell or non-cell associated. According to the company, about 60 percent of prions in blood resides in cell-associated leukocytes and about 40 percent in non-cell associated plasma. Pall says its research indicates that the Leukotrap filter has an affinity to all types of prions, including aggregated, denatured and normal.
"We are moving this technology forward rapidly," reports Pall Corp. chairman and CEO Eric Krasnoff. "Blood centers and hospitals will soon be able to combine both prion and leukocyte reduction in a single, simple step."
Pall says it will also investigate broadening the technology to help identify Mad Cow Disease in cattle before it reaches the food supply.
With hopes of introducing the Leukotrap filter to hospitals by early next year, Pall says it expects that its technology will meet the requirements of the Council of Europe and will be ready for operational trials in Europe, where vCJD is most prevalent.
Because a majority of blood transfusions in the industrialized world is leukocyte-reduced, Pall is hopeful that its filtration development can swiftly fit into routine operating practice already in use in blood centers around the world.
Meanwhile, testing on the filter continues. With support from the New York Institute of Basic Research, Pall is studying the Leukotrap filter using Western blot assay, bioassay and animal models of prion disease to validate reduction of the infectious prions. Additional results on the animal model research are expected in the coming months. |
Dobutamine cardiovascular magnetic resonance for the detection of myocardial ischemia with the use of myocardial tagging.
The purpose of this study was to assess the value of high-dose dobutamine cardiovascular magnetic resonance (CMR) with myocardial tagging for the detection of wall motion abnormalities as a measure of myocardial ischemia in patients with known or suspected coronary artery disease. Two hundred eleven consecutive patients with chest pain underwent dobutamine-CMR 4 days after antianginal medication was stopped. Dobutamine-CMR was performed at rest and during increasing doses of dobutamine. Cine-images were acquired during breath-hold with and without myocardial tagging at 3 short-axis levels. Regional wall motion was assessed in a 16-segment short-axis model. Patients with new wall motion abnormalities (NWMA) were examined by coronary angiography. Dobutamine-CMR was successfully performed in 194 patients. Dobutamine-CMR without tagging detected NWMA in 58 patients, whereas NWMA were detected in 68 patients with tagging (P=0.002, McNemar). Coronary angiography showed coronary artery disease in 65 (96%) of these 68 patients. All but 3 of the 65 patients needed revascularization. In the 112 patients with a negative dobutamine-CMR study, without baseline wall motion abnormalities, the cardiovascular occurrence-free survival rate was 98.2% during the mean follow-up period of 17.3 months (range, 7 to 31). Dobutamine-CMR with myocardial tagging detected more NWMA compared with dobutamine-CMR without tagging and reliably separated patients with a normal life expectancy from those at increased risk of major adverse cardiac events. |
Q:
Using an IP-Address in URL to HTML Linked Resources (CSS, ...)
A well-known technique is to link resources (CSS, JavaScript, ...) with a separate DNS name for various reasons. Like this:
GET http://stackoverflow.com/
GET http://cdn.sstatic.net/stackoverflow/all.css
(Two different domain names)
Instead:
GET ...
GET http://92.60.242.2/stackoverflow/all.css
(One DNS lookup)
This means that two DNS lookups are required. Couldn't we just use an IP address instead of cdn.sstatic.net in order to save one DNS lookup?
Please assume that it is possible to use an IP host from the point of view of the server. Assume, that there is a dedicated resource serving server with a dedicated IP.
A:
Content delivery networks usually employ some sort of load balancing, often implemented at the DNS level (e.g. the name cdn.sstatic.net resolves to different IP addresses, based on the geographical location of the requester). Hard-coding the IP address would be counter-productive, as the request will always go to the same server (which might still be a load balancer in front of several backend servers, but all of them will be in the same location).
|
Q:
A simple C++ framework for Win32 Windows Applications?
Is there a simple/small framework (Other than .NET) which allows you to create windowed applications with C++ under Win32. Just like a little DLL I can include with my app.
It should have basic functions like creating a window , buttons , text edits and handling them.
A:
WTL is a set of lightweight templates that make writing Win32 windowing code quite easy (to the extend C++/Win32 can be easy).
A:
I would recommand Qt. It's an intuitive and user friendly framework. In addition it is cross platform if one day you want to deploy your app anywhere else.
Qt can be used through Visual Studio or through the QtCreator IDE installed with the framework (as well as QtDesigner [GUI editor]).
A:
Take a look at Win32++
|
In this case, Plaintiff has not provided any evidence which shows that when MERS assigned the mortgage to Plaintiff, it also transferred the interest in the underlying note. According to the mortgage assignment contract, MERS held legal title to the mortgage. There is no language in the agreement which transfers interest in the note to MERS. Because MERS did not hold title to the underlying note, it could not transfer any rights to the underlying note when it assigned the mortgage to Plaintiff. See LPP Mortgage Ltd v. Sabine Properties No. 103648/10,2010 N.Y. Misc. LEXIS 4216, at*7 (Sup. Ct. N.Y. Co. Sept. 1, 2010); Lamy , 824 N.Y.S.2d at 769 (Sup. Ct. Suffolk Co. 2006); HSBC Bank USA v. Miller, 26 Misc. 3d 407,411,889 N.Y.S.2d 430,433 (Sup. Ct. Sullivan Co. 2009). Without a transfer of title to the underlying note, Plaintiff cannot foreclose on the property based on default payment and lacks standing under CPLR 5 321 1 (a)(3)
[…]
Therefore, it is
ORDERED that Defendant’s motion to dismiss is granted; and it is further
ORDERED that this action is dismissed; and it is further
ORDERED that the clerk of the court directed to enter judgment accordingly.
NY SUPREME COURT: FINAL DISPOSITION
Here, there are no allegations or evidence that MERS was the owner of the note such that it could assign it to LPP. Thus, the assignment from MERS was insufficient to confer ownership of the note to LPP and it has no standing to bring this action. Kluge v. F umz ~1, 45 AD2d at 538 (holding that the assignment of a mortgage without transfer of the debt is a nullity); Johnson v. Melnikoff, 20 Misc3d 1142(A), “2 (Sup Ct Kings Co. 2008), n. 2, afr, 65 AD3d 519 (2d Dept 20 1 Oj(noting that assignments by MERS which did not include the underlying debt were a legal nullity); m e Elect ro pic Registration Svstem v, Coakley, 41 AD3d 674 (2d Dept 2007)(holding that MERS had standing to bring foreclosure proceeding based on evidence that MERS was the lawful holder of the promissory note and the mortgage).
Thus, even assuming arguendo that the language of the assignment from MERS to LPP could be interpreted as purporting to assign not only the mortgage but also the note, such assignment is invalid since based on the record, MERS lacked an ownership interest in the note. $ee LaSalle Bank Nat. Ass’n v. Lamv, 12 Misc3d 1191(A), “3 (Sup Ct Suffolk Co. 2006) (noting that “the mortgage is merely an incident of and collateral security for the debt and an assignment of the mortgage does not pass ownership of the debt itself ’); |
Q:
Is it important to model heteroscedasticity during multiple regression?
Given a multiple linear regression (eg. using a GLS procedure) between a response variable and several predictive variables with different, heteroscedastic relationships with the response variable and among them. How important it is to introduce in the model estimations of the different heteroscedasticities among model variables? e.g. between response and predictor 1, or among predictors one and 2...
A:
If I understand your question correctly, then you are asking how important it is to take heteroskedascticity into account when modelling in a multivariate linear regression setting.
I will use the following model for reference:
$$ y = X \beta + \varepsilon $$
where $y$ is $(n \times 1)$, $X$ is $(n \times k)$, and $\beta$ is $(k \times 1)$. So you have $k$ parameters including the constant and $n$ observations and $\varepsilon$ is the residual with same dimensions as $y$.
This representation is equivalent to:
$$y_i = \beta_0 + \beta_1 x_{i,1} + ... + \beta_{k-1} x_{i,k-1} + \varepsilon_i$$
So for ordinary least squares to be the best linear unbiased estimator (BLUE) you need the Gauss-Markov (GM) assumptions to hold:
$\mathit{E}(\varepsilon_i) = 0$ i.e. residuals have zero mean
$\mathit{Var}(\varepsilon_i) = \sigma^2 < \infty$ i.e. constant bounded residual variance
$\mathit{Cov}(\varepsilon_i,\varepsilon_j) = 0$ for $i \neq j$ i.e. homoskedascticity
You also need:
$X'X$ is full rank i.e. no multicollinearity
In the case conditions 2 or/and 3 are invalid OLS is still a consistent estimator, and furthermore your estimate for $\beta$ will be unbiased, thus valid. However you will not be able to test the significance of $\beta$ (i.e. t-test) as your standard errors will be incorrect. If this is important for you, then you need to either use GLS/FGLS (which will give a different estimate for $\beta$) or use a post-correction model e.g. HAC (heteroskedascticity-consistent standard errors).
GLS is a simple extension to OLS:
The estimate for OLS is:
$$\hat{\beta} = (X'X)^{-1}X'y$$
For GLS:
$$\hat{\beta} = (X'\Omega^{-1}X)^{-1}X'\Omega^{-1}y$$
where $\Omega$ characterises your heteroskedascticity structure i.e. $\mathit{E}(\varepsilon\varepsilon') = \Omega$
Typically, we do not know $\Omega$ so we must estimate it using an FGLS (Feasable GLS) procedure which is a multi-step process:
Estimate $\varepsilon$ using OLS
$$ \hat{\varepsilon} = y - X\hat{\beta}_{OLS}$$
Calculate $\hat{\Omega}_{OLS}$ i.e. $\hat{\Omega}_{OLS} = \frac{\hat{\varepsilon}\hat{\varepsilon}'}{n-1}$
Use $\hat{\Omega}_{OLS}$ to calculate $\hat{\beta}_{FGLS1}$
Repeat step 1 and 2 using $\hat{\beta}_{FGLS1}$ instead of $\hat{\beta}_{OLS}$ to obtain $\hat{\Omega}_{FGLS1}$
Finally use $\hat{\Omega}_{FGLS1}$ with the GLS procedure to calculate a final estimate for $\beta$
To answer your question, importance depends on whether you want to test significance of parameters or not and how big your sample size is. With large samples ($n > 200$) the efficiency gains between OLS and GLS will start to become marginal.
|
<file_state xmlns="http://oval.mitre.org/XMLSchema/oval-definitions-5#unix" id="oval:org.mitre.oval:ste:1704" version="1">
<oexec datatype="boolean" operation="equals">true</oexec>
</file_state>
|
/**
* Copyright 2018 LinkedIn Corporation. All rights reserved. Licensed under the BSD-2 Clause license.
* See LICENSE in the project root for license information.
*/
package com.linkedin.nn.distance
import breeze.linalg.norm
import com.linkedin.nn.distance.DistanceMetric.DistanceMetric
import com.linkedin.nn.utils.VectorUtils
import org.apache.spark.ml.linalg.Vector
object L2Distance extends Distance {
override val metric: DistanceMetric = DistanceMetric.l2
/**
* Compute distance between x and y
* @param x input vector
* @param y input vector
* @return l2 distance between x and y
*/
override def compute(x: Vector, y: Vector): Double = {
// TODO What are the performance implications here? Can we do better using direct computation rather than using breeze
norm(VectorUtils.toBreeze(x) - VectorUtils.toBreeze(y), 2.0)
}
}
|
Q:
Check if a Python list item contains a string inside another string
I have a list:
my_list = ['abc-123', 'def-456', 'ghi-789', 'abc-456']
and want to search for items that contain the string 'abc'. How can I do that?
if 'abc' in my_list:
would check if 'abc' exists in the list but it is a part of 'abc-123' and 'abc-456', 'abc' does not exist on its own. So how can I get all items that contain 'abc' ?
A:
If you only want to check for the presence of abc in any string in the list, you could try
some_list = ['abc-123', 'def-456', 'ghi-789', 'abc-456']
if any("abc" in s for s in some_list):
# whatever
If you really want to get all the items containing abc, use
matching = [s for s in some_list if "abc" in s]
A:
Just throwing this out there: if you happen to need to match against more than one string, for example abc and def, you can combine two comprehensions as follows:
matchers = ['abc','def']
matching = [s for s in my_list if any(xs in s for xs in matchers)]
Output:
['abc-123', 'def-456', 'abc-456']
A:
Use filter to get at the elements that have abc.
>>> lst = ['abc-123', 'def-456', 'ghi-789', 'abc-456']
>>> print filter(lambda x: 'abc' in x, lst)
['abc-123', 'abc-456']
You can also use a list comprehension.
>>> [x for x in lst if 'abc' in x]
By the way, don't use the word list as a variable name since it is already used for the list type.
|
Q:
The main thread randomly doesn't reach end (trying to sum natural numbers in concurrent threads)
I have the following code to find the sum of natural numbers from 1 to 5000. It's a simple exercise to practice concurrency.
public static void main(String[] args) throws InterruptedException {
final int[] threadNb = new int[] {5};
final Integer[] result = new Integer[1];
result[0] = 0;
List<Thread> threads = new LinkedList<>();
IntStream.range(0, threadNb[0]).forEach(e -> {
threads.add(new Thread(() -> {
int sum = 0;
int idx = e * 1000 + 1;
while (!Thread.interrupted()) {
if (idx <= (e + 1) * 1000) {
sum += idx++;
} else {
synchronized(result) {
result[0] += sum;
System.err.println("sum found (job " + e + "); sum=" + sum + "; result[0]=" + result[0] + "; idx=" + idx);
Thread.currentThread().interrupt();
}
}
}
synchronized(result) {
System.err.println("Job " + e + " done. threadNb = " + threadNb[0]);
threadNb[0]--;
System.err.println("threadNb = " + threadNb[0]);
}
}));
});
threads.forEach(Thread::start);
//noinspection StatementWithEmptyBody
while(threadNb[0] > 0);
System.out.println("begin result");
System.out.println(result[0]);
System.out.println("end result");
}
Sometimes, when I run the code, the last 3 System.out.println() are not displayed. If I put a statement in the while(threadNb[0] > 0), like another System.out.println(), my problem never happen again.
Can anyone explain me this behaviour?
Thanks in advance for any help
A:
Nothing about how the threadNb variable is declared tells the JVM that it needs to make updates to it visible to other threads. At what point updates to your variable become visible to other threads is entirely up to the JVM implementation, it can make them visible or not depending on circumstances. Also, the JIT is free to re-order or optimize away code if it thinks it can get away with it, and it bases its decisions on the visibility rules. So it's hard to say exactly what happens here because the behavior is left unspecified by the Java language specs, but definitely you're having a problem where your worker threads' updates are usually not getting seen by the main thread.
If you replace the arrays with AtomicInteger then the updates are guaranteed to become visible to other threads. (Volatile works too, but AtomicInteger is preferred. In order to use volatile you have to make the variable an instance or class member.) If you save the updated values in a local variable then you don't need synchronization:
import java.util.*;
import java.util.stream.*;
import java.util.concurrent.atomic.*;
public class SumNumbers {
public static void main(String[] args) throws InterruptedException {
AtomicInteger threadNb = new AtomicInteger(5);
AtomicInteger result = new AtomicInteger(0);
List<Thread> threads = new LinkedList<>();
IntStream.range(0, threadNb.intValue()).forEach(e -> {
threads.add(new Thread(() -> {
int sum = 0;
int idx = e * 1000 + 1;
while (!Thread.currentThread().isInterrupted()) {
if (idx <= (e + 1) * 1000) {
sum += idx++;
} else {
int r = result.addAndGet(sum);
System.out.println("sum found (job " + e + "); sum="
+ sum + "; result=" + r
+ "; idx=" + idx);
Thread.currentThread().interrupt();
}
}
System.out.println("Job " + e + " done.");
int threadNbVal = threadNb.decrementAndGet();
System.out.println("Job " + e + " done, threadNb = " + threadNbVal);
}));
});
threads.forEach(Thread::start);
//noinspection StatementWithEmptyBody
while(threadNb.intValue() > 0);
System.out.println("result=" + result.intValue());
}
}
where you can see the updates become visible.
Busy waiting is not preferred since it wastes CPU cycles. You do see it in lock-free programming, but it is not a good thing here. Thread#join will work or you can use a CountdownLatch.
Be aware that using Thread#interrupted() clears the interrupted flag. Usually it's used when you're about to throw InterruptedException, otherwise it's better to use Thread.currentThread().isInterrupted(). It doesn't hurt anything in this specific case because the while loop test is the only thing using the flag, so whether it gets cleared is irrelevant.
|
Baldwin Ford, Kentucky
Baldwin Ford is a rural unincorporated community in northeast Caldwell County, Kentucky, United States.
References
Category:Unincorporated communities in Caldwell County, Kentucky
Category:Unincorporated communities in Kentucky |
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Winnipeg Roofing Company Now Open Seven Days A Week To Meet Growing Demand
Winnipeg roofers Racka Roofing are now open seven days a week to meet a growing homeowner and commercial demand for roofing services in the South Manitoba area.
Winnipeg, Manitoba (PRWEB) October 24, 2012
In response to an overwhelming demand in the Winnipeg area, Racka Roofing is available for roof installations, roofing repair and roofing quotes seven days a week. The company has now staffed their team to enable roofing services to customers who may have job commitments that inhibit their available time for home improvements. The company plans to work seven days a week repairing both residential and commercial roofs from weather damage, and poorly executed contracting jobs.
In today's economy, consumers might be working up to seven days a week, which leaves them a narrow window for free time. The company understands their customers' professional lives often take precedent. For this reason, Racka is pleased to offer more availability with the same top quality and customer service.
Because of professional commitments, many homeowners put off home improvements. Replacing or repairing a roof is essential in keeping or increasing the value of the home, and sometimes replacing or repairing a roof can come at an inconvenient time for the homeowner. Luckily for these homeowners, Racka is now open seven days a week to help customers at the most convenient time for them.
Racka Roofing is a veteran in the roofing industry. With more than thirty years in the business, and highly skilled and qualified roofers, Racka has provided thousands of residential homeowners and commercial developers with professionally designed roofs, and high quality roofing services. Racka's commitment to courtesy and expertise has made them a leader in the roofing and contracting industry. Learn more about Winnipeg roofing at their website, http://www.racka.ca |
1. Field of the Invention
This invention relates to an optical amplifier repeater for use with an optical amplification multi-stage repeating system.
2. Description of the Related Art
In the field of very long haul optical transmission across an ocean over several thousands kilometers, development of an optical amplification multi-stage repeating system which employs a repeating system in which a plurality of optical amplifier repeaters are interposed at a plurality of stages like a chain in an optical transmission line in order to compensate for the loss involved in transmission of signal light is proceeding. An optical amplifier repeater amplifies and outputs signal light inputted thereto as it is, and allows achievement of considerable reduction in cost by reduction in number of parts in each repeater and is expected to achieve improvement in reliability comparing with a conventional a regeneration repeater which performs, after it converts an optical signal inputted thereto into an electric signal, synchronization regeneration (to re-arrange code pulses to correct time positions) and waveform regeneration (to return code pulses into pulses having a correct waveform free from a distortion) and then converts the resulted electric signal back into an optical signal to be outputted. Further, it has an advantage in that it is also possible to increase the transmission rate by improvement in terminal equipments on the opposite sides of it in future.
By the way, in an optical amplification multi-stage repeating system which employs such an optical amplifier repeater as described above, it is necessary to normally supervise the conditions of each optical amplifier repeater and each optical transmission line and, when a trouble occurs, promptly specify and repair a location where the trouble has occurred. Accordingly, it is demanded to provide an optical amplifier repeater which can achieve an increase in reliability in detection of occurrence of a trouble and specification of the trouble occurrence location and allow realization of stabilized communication.
A construction of an optical amplification multi-stage repeating system is shown in FIG. 13. The optical amplification multi-stage repeating system is constructed such that, as shown in FIG. 13, a downstream side terminal equipment 1 and an upstream side terminal equipment 2 are connected to each other by an ascending line 4 and a descending line 5 each formed from an optical fiber by way of a plurality of optical amplifier repeaters 3. Supervision of the condition of the ascending line 4 is performed by introducing part of signal light sent from the downstream side terminal equipment 1 using the ascending line 4 into the descending line 5 at each of the optical amplifier repeaters 3 and measuring the signal light at the downstream side terminal equipment 1. 0n the other hand, supervision of the condition of the descending line 5 is performed by introducing part of signal light sent from the upstream side terminal equipment 2 using the descending line 5 into the ascending line 4 at each of the optical amplifier repeaters 3 and measuring the signal light at the upstream side terminal equipment 2. It is to be noted that, in the following description, an optical transmission route for introducing signal light of the ascending line into the descending line or introducing signal light of the descending line into the ascending line will be referred to as loop back path.
Further, detection of a trouble point on an optical transmission line is performed by sending a predetermined optical pulse or the like from the downstream side terminal equipment 1 using the ascending line 4, introducing part of reflected light of the ascending line 4 into the descending line 5 at each of the optical amplifier repeaters 3 and measuring the reflected light at the downstream side terminal equipment 1. Meanwhile, detection of a trouble point of the other transmission line is performed by sending a predetermined optical pulse or the like from the upstream side terminal equipment 2 using the descending line 5, introducing part of reflected light of the descending line 5 into the ascending line 4 at each of the optical amplifier repeaters 3 and measuring the reflected light at the upstream side terminal equipment 2. It is to be noted that, in the following description, an optical transmission route for introducing reflected light of the ascending line into the descending line or introducing reflected light of the descending line into the ascending line will be referred to as return path.
A construction of the conventional optical amplifier repeater having a loop back path described above will be described with reference to FIG. 14. The optical amplifier repeater shown includes an ascending optical amplifier 6A, a descending optical amplifier 6B, a first optical coupler 7 and a second optical coupler 8. Each of the first optical coupler 7 and the second optical coupler 8 is a two-input two-output optical coupler having two input ports and two output ports.
An input side 4A of the ascending line is connected to the input side of the ascending optical amplifier 6A, and a first input port 7A of the first optical coupler 7 is connected to the output side of the ascending optical amplifier 6A. An output side 4B of the ascending line is connected to a first output port 7D of the first optical coupler 7. An input side 5A of the descending line is connected to the input side of the descending optical amplifier 6B, and a first input port 8A of the second optical coupler 8 is connected to the output side of the descending optical amplifier 6B. An output side 5B of the descending line is connected to a first output port 8D of the second optical coupler 8. A second output port 7E of the first optical coupler 7 and a second input port 8B of the second optical coupler 8 are connected to each other by a first optical transmission line 9A, and a second input port 7B of the first optical coupler 7 and a second output port 8E of the second optical coupler 8 are connected to each other by a second optical transmission line 9B.
Thus, signal light sent from the input side 4A of the ascending line is amplified by the ascending optical amplifier 6A and sent to the output side 4B of the ascending line by way of the first input port 7A and the first output port 7D of the first optical coupler 7. Meanwhile, signal light sent from the input side 5A of the descending line is amplified by the descending optical amplifier 6B and sent to the output side 5B of the descending line by way of the first input port 8A and the first output port 8D of the second optical coupler 8. Further, part of signal light inputted to the first optical coupler 7 is outputted from the second output port 7E of the first optical coupler 7 and sent to the output side 5B of the descending line by way of the first optical transmission line 9A and the second input port 8B and the first output port 8D of the second optical coupler 8. Part of signal light inputted to the second optical coupler 8 is outputted from the second output port 8E of the second optical coupler 8 and sent to the output side 4B of the ascending line by way of the second optical transmission line 9B and the second input port 7B and the first output port 7D of the first optical coupler 7. In this manner, an ascending loop back path is constituted from the first optical coupler 7, the first optical transmission line 9A and the second optical coupler 8 while a descending loop back path is constituted from the second optical coupler 8, the second optical transmission line 9B and the first optical coupler 7.
Subsequently, a construction of another conventional optical amplifier repeater having a loop back path and a return path described above will be described with reference to FIG. 15. The optical amplifier repeater shown includes an ascending optical amplifier 10A, a descending optical amplifier 10B, a first optical coupler 11, a second optical coupler 12, a third optical coupler 13 and a fourth optical coupler 14. Each of the first to fourth optical couplers 11, 12, 13 and 14 is a two-input two-output bidirectional optical coupler having two input ports and two output ports.
The input side of the ascending optical amplifier 10A is connected to an input side 4A of an ascending line, and the output side of the ascending optical amplifier 10A is connected to a first input port 11A of the first optical coupler 11. A first output port 11D of the first optical coupler 11 is connected to an output side 4B of the ascending line. The input side of the descending optical amplifier 10B is connected to an input side 5A of a descending line, and the output side of the descending optical amplifier 10B is connected to a first input port 13A of the third optical coupler 13. A first output port 13D of the third optical coupler 13 is connected to an output side 5B of the descending line.
A first input port 12A of the second optical coupler 12 is connected to a second output port 11E of the first optical coupler 11 by way of a first optical transmission line 15A, and a first output port 12D of the second optical coupler 12 is connected to a second input port 13B of the third optical coupler 13 by way of a second optical transmission line 15B. A first input port 14A of the fourth optical coupler 14 is connected to a second output port 13E of the third optical coupler 13 by way of a third optical transmission line 15C, and a first output port 14D of the fourth optical coupler 14 is connected to a second input port 11B of the first optical coupler 11 by way of a fourth optical transmission line 15D. A second input port 14B of the fourth optical coupler 14 is connected to a second input port 12B of the second optical coupler 12 by way of a fifth optical transmission line 15E.
Thus, signal light sent from the input side 4A of the ascending line is amplified by the ascending optical amplifier 10A and sent to the output side 4B of the ascending line by way of the first input port 11A and the first output port 11D of the first optical coupler 11. Part of the signal light inputted to the first optical coupler 11 is outputted from the second output port 11E of the first optical coupler 11 and sent to the output side 5B of the descending line by way of the first optical transmission line 15A, the second optical coupler 12, the second optical transmission line 15B and the third optical coupler 13. By this, a loop back path for the ascending line is constructed. Further, reflected light from the output side 4B of the ascending line is sent to the output side 5B of the descending line by way of the first optical coupler 11, the fourth optical transmission line 15D, the fourth optical coupler 14, the fifth optical transmission line 15E, the second optical coupler 12, the second optical transmission line 15B and the third optical coupler 13. By this, a return path for the ascending line is constructed.
Meanwhile, signal light sent from the input side 5A of the descending line is amplified by the descending optical amplifier 10B and sent to the output side 5B of the descending line by way of the first input port 13A and the first output port 13D of the third optical coupler 13. Part of the signal light inputted to the third optical coupler 13 is outputted from the second output port 13E of the third optical coupler 13 and sent to the output side 4B of the ascending line by way of the third optical transmission line 15C, the fourth optical coupler 14, the fourth optical transmission line 15D and the first optical coupler 11. By this, a loop back path for the descending line is constructed. Further, reflected light from the output side 5B of the descending line is sent to the output side 4B of the ascending line by way of the third optical coupler 13, the second optical transmission line 15B, the second optical coupler 12, the fifth optical transmission line 15E, the fourth optical coupler 14, the fourth optical transmission line 15D and the first optical coupler 11. By this, a return path for the descending line is formed.
Further detailed description of the loop back paths and the return paths in the second conventional optical amplifier repeater described above will be given below. For the convenience of description, the optical transmission lines in the optical amplifier repeater are divided into 16 paths with the directions taken into consideration, and reference characters from a to p are applied to them as shown in FIG. 15. In particular, a normal loop back path of the ascending line is constituted from the paths a-g-i-e. A normal loop back path of the descending line is constituted from the paths d-k-m-b. Further, a normal return path of the ascending line is constituted from the paths c-n-o-i-e. A normal return path of the descending line is constituted from the paths f-j-p-m-b.
Since the maximum transmission distance of an optical amplification multi-stage repeating system ranges over up to several thousands kilometers, it is necessary to accurately detect occurrence of a trouble as well as to specify and rapidly repair a location at which the trouble has occurred with a high degree of accuracy. However, according to the prior art shown in FIG. 14, while, for example, in the ascent, part of signal light sent from the input side 4A of the ascending line by way of the optical amplifier 6A is sent to the output side 5B of the descending line by way of the first optical coupler 7, the first optical transmission line 9A and the second optical coupler 8, since a loop (annular light transmission path) is formed from the first optical coupler 7, the first optical transmission line 9A, the second optical coupler 8 and the second optical transmission line 9B, circulation light which has circulated the loop once, twice or more is superimposed as noise with part of the signal light for supervision of a trouble. The noise (in the specification of the present application, such noise will be referred to as circulation noise) makes a factor to deteriorate the signal to noise ratio (SNR) of signal light, and detection of a trouble cannot be achieved with a high degree of accuracy. It is to be noted that this quite similarly applies to the descent.
Meanwhile, according to the second conventional optical amplifier repeater shown in FIG. 15, the loop back paths have the same problem as the conventional optical amplifier repeater of FIG. 14. In particular, referring to FIG. 15, as an abnormal loop back path of the ascending line, paths a-g-i-k-m-g-i-e are constructed while, as abnormal loop back paths of the descending line, paths d-k-m-g-i-k-m-b are constructed, and the signal to noise ratio is deteriorated by light which circulates in the abnormal loop back paths.
Further, as abnormal return paths of the ascending line, paths c-n-o-i-k-m-g-i-e (hereinafter referred to as first abnormal return path), paths c-n-l-j-p-m-g-i-e (hereinafter referred to as second abnormal return path) and further paths c-n-l-j-h-n-o-i-e (hereinafter referred to as third abnormal return path) are constructed. As abnormal return paths of the descending line, paths f-j-p-m-g-i-k-m-b (hereinafter referred to as first abnormal return path), paths f-j-h-n-o-i-k-m-b (hereinafter referred to as second abnormal return path) and further paths f-j-h-n-l-j-p-m-b (hereinafter referred to as third abnormal return path), and the signal to noise ratio is deteriorated by circulation light which circulates in those abnormal return paths.
In this manner, according to the prior art, there is a problem in that light which circulates between a plurality of optical couplers constituting loop back paths and return paths is superimposed as circulation noise with signal light or reflected light for detection of a trouble and deteriorates the signal to noise ratio (SNR) of the signal light or reflected light, resulting in failure in detection of a trouble with a high degree of accuracy. Further, the conventional optical amplifier repeaters have another problem in that the intensity of signal light is sometimes rendered unstable by a variation in optical loss caused by deterioration of an optical transmission line with respect to time or the like. |
version https://git-lfs.github.com/spec/v1
oid sha256:6d8b1e77b09afc6edaa506fbcd700175ec0faec1b8b384e1dcfdc789320a9ebb
size 20857
|
Clinical outcomes of laser in situ keratomileusis with an aberration-neutral profile centered on the corneal vertex comparing vector planning with manifest refraction planning for the treatment of myopic astigmatism.
To evaluate clinical outcomes of laser in situ keratomileusis (LASIK) with an aberration-neutral profile centered on the estimated visual axis (considering 70% of the pupil offset toward the corneal vertex) comparing vector planning with manifest refraction planning for the treatment of myopic astigmatism. Muscat Eye Laser Center, Muscat, Sultanate of Oman, Muscat, Oman. Retrospective case series. The outcomes were evaluated at a 6-month follow-up in eyes showing ocular residual astigmatism (ORA) over 0.75 diopters (D) preoperatively. Eighty-five treatments were based on manifest astigmatism (preoperative sphere -2.11 D ± 1.3 [SD], cylinder -0.90 ± 1.0 D), and 79 treatments were based on vector planning (preoperative sphere -2.46 ± 1.5 D, cylinder -0.78 ± 0.79 D). At a 6-month follow-up, 128 patients (164 eyes) were evaluated and no significant differences were observed between the 2 groups in terms of difference between corrected distance visual acuity and uncorrected distance visual acuity (UDVA) (P = .1, t test and Fisher exact test Snellen lines 1 or better, P = .4) and postoperative UDVA (P = .05, t test and Fisher exact test for UDVA 20/16 or better, P = .3). Significant differences were observed between the 2 groups in terms of achieved spherical equivalent (P = .04), corneal toricity, and ORA (P < .001, t test and Fisher exact test for ORA ≤0.75 D, P < .001). Performing LASIK for myopic astigmatism with the vector planning approach resulted in comparable visual outcomes to manifest refraction planning. |
1. Field of the Invention
This invention relates to a lightweight aerogel reflector particularly one having a reflective layer on a low-density aerogel substrate and method for manufacturing same.
2. The Prior Art
Optical systems including space-based optical system often have need for large reflectors, including mirrors. Presently available under current ULE (ultra low expansion) glass technology, a mirror substrate with a density of 2.2 gms/cc is obtainable, which can result in mirrors weighing hundreds of pounds, which limits the size of the optical system according to launch payload constraints. If a lower density mirror substrate can be fabricated, larger reflectors and optical systems could be launched and deployed in space for improved observation of the skies and of the Earth below.
There has now been discovered a method for manufacture of lightweight reflectors having a substrate density considerably below the 2.2 gms/cc of the above prior art per ULE glass technology. In fact the present invention provides reflector substrates with densities approaching a full order of magnitude below presentday ULE glass mirrors to as low as 0.01 gms/cc or as expressed herein, 10 mg/cc.
The present invention employs a reflector substrate of low density or LD. By a low density or LD substrate as used herein, is meant one with a density of 10-500 mg/cc.
Such aerogel is typlified by high porosity and thus a rough surface not apparently suitable for optical substrate applications. In fact no prior art literature was found on low-density aerogel optical substrate applications. However, the present invention provides a method for adapting LD aerogels as suitable substrates for lightweight optical applications including mirrors. |
Q:
Rails ActionMailer template updates not taking effect
I'm making changes to a Rails site that I was not involved in creating. This site has a form for new users to sign up, which generates an email to administrators who can approve the new account.
When the template for these emails is changed, the content of the generated emails does not change. How do I get changes to the email template to take effect?
I'm new to Rails, so I might be missing something obvious. I believe these are the relevant files:
app/mailers/user_mailer.rb
class UserMailer < ActionMailer::Base
default from: 'webmaster'
def new_user_notification_mailer(user, admin_email)
@user = user
mail(to: admin_email, subject: 'New User Registration')
end
end
app/workers/send_new_user_notification_worker.rb
class SendNewUserNotificationWorker
include Sidekiq::Worker
def perform(user_id)
user = User.find(user_id)
if user
User.is_admin.each do |admin|
if admin.email
UserMailer.new_user_notification_mailer(user, admin.email).deliver
end
end
end
end
end
app/views/user_mailer/new_user_notification_mailer.html.slim
doctype html
html
head
meta content='text/html; charset=UTF-8' http-equiv='Content-Type'
body
p
| New user
b #{@user.first_name} #{@user.last_name}
| has registered on the web site.
| You can
= link_to "Manage", edit_admin_user_url(@user)
| this account from admin panel.
I've been restarting the server (of the working copy) with this:
RAILS_ENV=production bash -c 'bundle exec rake assets:clean; bundle exec rake bower:resolve; bundle exec rake assets:precompile'; kill `cat tmp/pids/server.pid`; nohup bundle exec rails s -e production -p 4000 1>> log/rails.sever.log 2>> log/rails.server.err.log &
A:
You need to restart your sidekiq process also. It will re-load your rails environment and code changes for sidekiq process. After this, your changes should reflect.
|
Q:
Download from external subversion repository and merge own code
My project "A" is in my own svn repository. My project A needs a reference to an external project "B". But I need to modify the code of project B. I cannot commit code to project B since this is not my project. I want to checkout project B and merge code into project B.
What I have tried so far:
Added project B as external link into a folder named B_source. (the update command downloads the external code. This step works)
I copied with windows explorer the content of B_source into a folder named B_changes and applied the source code changes I needed. (works)
I checked out project B into a folder named B_patched. (works)
In TortoiseSVN right click on B_patched, click "merge", select "merge two different trees", set "From: B_source" and "To: B_changes" and "Working Copy: B_patched".
"Test merge" showed the message "svn/B_source path not found". I guess it's because of the external link!?
What am I doing wrong?
A:
Merging is for taking two trees in the same repository and merging them to your working copy from the same repository. You would then commit that merge to the repository.
What you are trying to do, is apply custom changes to a repository, without being able to commit those changes. You cannot do this with the "merge" command.
What you're probably looking for is a vendor branch. The idea of a vendor branch is that you keep a project in your repository (call it "vendor") that you only update by copying unmodified code from the external project, and committing those updates. You create a branch of that project wherever you want (call it "patched") in a place convenient for you to pull into your build. You apply any of your custom changes to this branch. Periodically, as the external project makes updates, you will copy those updates into "vendor", commit, and then merge "vendor" to "patched" and commit those changes.
TortoiseSVN makes this easy with a context-menu entry when you right-click and drag from one unversioned folder into a folder in your repository which you maintain. You will not use svn:exterals in this case, you will simply be committing code, where most of the changes come from the customer.
|
Anquan Boldin's time with the San Francisco 49ers is off to a great start, as the NFL named him NFC Offensive Player of the Week. Boldin caught 13 passes for 208 yards and a touchdown in his 49ers debut, keying the passing attack in the 34-28 win over the Green Bay Packers. There was plenty of praise for the performance following Sunday's game.
The 49ers head up to Seattle this week, and it will be interesting to see how Boldin follows up that performance. The 49ers faced a banged up Packers secondary, with the defense keying in on the run. Boldin would have found success even with more pressure against the pass, but it is still worth noting the context of the performance. The Seahawks have as strong a secondary as anybody in the NFL, although we do not yet know the status of Brandon Browner.
The 49ers moved Boldin all around the field, and I suspect we'll see him moving around once again on Sunday night. At some point (and possibly quite frequently), he will face off with Richard Sherman. While I know plenty of folks don't like Sherman, he is a great cornerback and this will be a fascinating matchup. Boldin has the size advantage, but Sherman will do what he can to get in Boldin's face and slow him down.
KEEP READING |
Appearance and mental retardation: some first steps in the development and application of a measure.
A measure of atypical appearance derived from components developed during the course of a study of 22-year-old mentally retarded adults was described. Hypotheses about relationships between mental retardation, biological damage, and appearance were tested and confirmed. Atypical appearance increased with severity of retardation. Mildly retarded young adults who received no mental retardation services after age 16 were more atypical in appearance than were nonretarded peers. Issues relating to the appearance measure and the results were discussed. |
8/29/2012 – OKC, OK — Debi Mangrum with No Boundaries was interviewed by KWTV News9 regarding the murder trial of Fulgencio Lopez. Lopez is accused of murdering and engaging in necrophilia with Lori Green.
Green, 39, suffered from severe addiction to crack cocaine and could often be found prostituting herself along South Robinson Ave.
Mangrum, along with other volunteers, sat in on the three-day trial in support of the memory of Green and to gain additional insights to the crime and judicial process.
Lopez was found guilty and sentenced to life with the possibility of parole.
2/1/2012 – OKC, OK — Volunteers with No Boundaries International begin one of their very first efforts on South Robinson Ave. by taking Prayer Walks along the same streets shared with pimps, prostituted women, drug dealers and ‘Johns.’ |
Described embodiments relate generally to web-based video streaming and specifically to adaptive video streaming over a content delivery network using fast network protocols.
Networked video streaming provides users with rich opportunities to upload, watch and share videos in fast-growing online video entertainment communities. Video streaming sites such as YOUTUBE™ allow content providers to upload videos and download videos from the video streaming sites. Users can easily share videos by mailing links to others, or embedding them on web pages or in blogs. Users can also rate and comment on videos, bringing new social aspects to video viewing.
Videos have various video quality levels, for example including low, medium and high. Video quality is one characteristic of a video passed through a video processing/transmission system and is often measured by the perceived degradation compared to the original video. Streaming a high quality video generally requires a high bitrate, high resolution and high requirement for network bandwidth to support video streaming.
It is challenging to stream a high quality video over a content delivery network (e.g., the Internet) with acceptable delay using existing network protocols for the web. For example, the existing network protocols Hpertext Transfer Protocol (HTTP) and Transmission Control Protocol (TCP) are not particularly designed to be latency sensitive. Because HTTP can only fetch one video resource at a time, a server delay of 500 milliseconds prevents reuse of a TCP channel for additional streaming requests. Recently improved network protocols, such as SPDY protocol, allow concurrent HTTP requests to run across a single TCP session for a variety of content delivery applications. Thus, there is a need for adaptive video streaming over a content delivery network using fast network protocols |
/*
* JBoss, Home of Professional Open Source.
*
* Copyright 2019 Red Hat, Inc., and individual contributors
* as indicated by the @author tags.
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*/
package org.wildfly.event.logger;
import java.util.Map;
import java.util.concurrent.Executor;
import java.util.function.Supplier;
/**
* A logger for various events such as access or audit logging.
* <p>
* Note that a {@linkplain #getEventSource() event source} is an arbitrary string used to differentiate logging events.
* For example a web access event may have an even source of {@code web-access}.
* </p>
*
* @author <a href="mailto:jperkins@redhat.com">James R. Perkins</a>
*/
@SuppressWarnings({"StaticMethodOnlyUsedInOneClass", "unused", "UnusedReturnValue"})
public interface EventLogger {
/**
* Creates a new logger which defaults to writing {@linkplain JsonEventFormatter JSON} to
* {@link StdoutEventWriter stdout}.
*
* @param eventSource the identifier for the source of the event this logger is used for
*
* @return a new event logger
*/
static EventLogger createLogger(final String eventSource) {
return new StandardEventLogger(eventSource, StdoutEventWriter.of(JsonEventFormatter.builder().build()));
}
/**
* Creates a new event logger.
*
* @param eventSource the identifier for the source of the event this logger is used for
* @param writer the writer this logger will write to
*
* @return a new event logger
*/
static EventLogger createLogger(final String eventSource, final EventWriter writer) {
return new StandardEventLogger(eventSource, writer);
}
/**
* Creates a new asynchronous logger which defaults to writing {@linkplain JsonEventFormatter JSON} to
* {@link StdoutEventWriter stdout}.
*
* @param eventSource the identifier for the source of the event this logger is used for
* @param executor the executor to execute the threads in
*
* @return the new event logger
*/
static EventLogger createAsyncLogger(final String eventSource, final Executor executor) {
return new AsyncEventLogger(eventSource, StdoutEventWriter.of(JsonEventFormatter.builder().build()), executor);
}
/**
* Creates a new asynchronous event logger.
*
* @param eventSource the identifier for the source of the event this logger is used for
* @param writer the writer this logger will write to
* @param executor the executor to execute the threads in
*
* @return a new event logger
*/
static EventLogger createAsyncLogger(final String eventSource, final EventWriter writer, final Executor executor) {
return new AsyncEventLogger(eventSource, writer, executor);
}
/**
* Logs the event.
*
* @param event the event to log
*
* @return this logger
*/
EventLogger log(Map<String, Object> event);
/**
* Logs the event.
* <p>
* The supplier can lazily load the data. Note that in the cases of an
* {@linkplain #createAsyncLogger(String, Executor) asynchronous logger} the {@linkplain Supplier#get() data} will
* be retrieved in a different thread.
* </p>
*
* @param event the event to log
*
* @return this logger
*/
EventLogger log(Supplier<Map<String, Object>> event);
/**
* Returns the source of event this logger is logging.
*
* @return the event source
*/
String getEventSource();
}
|
120 F.3d 275
U.S.v.Hinton*
NO. 96-8440
United States Court of Appeals,Eleventh Circuit.
July 15, 1997
Appeal From: N.D.Ga. ,No.95002691CR1GET
1
Affirmed.
*
Fed.R.App.P. 34(a); 11th Cir.R. 34-3
|
Description:For three hundred years, Majeh's spirit has served as the King of Hell's envoy while Majeh's body lay preserved in a special hidden lake. However, when demons escape from the netherworld and hijack bodies in the world of the living, Majeh's spirit is restored to his body and he is charged with hunting down the escapees ... in less than a month. A master swordsman, Majeh is drawn to a town hosting a grand fighting competition. That same town is being plagued by strange and grisly murders. Could the two events somehow be connected? And, in a city full of fighters, could Majeh meet his match? |
1. Field of the Invention
The present invention relates generally to cryptography in computer networks and, more specifically, to a system and method to check whether a computer device runs the correct version of a software program based on obfuscated initiation values of a cryptography protocol.
2. Description of the Related Art
Content player software configured to run on client computing devices is typically fairly complex. Oftentimes, security flaws in the content player software are discovered after the software is released and downloaded by many client computing devices. Such security flaws may result in copyrighted content being viewed or copied by end-users or others without proper authorization. To remedy such security flaws, the client content player software is updated to a new version that is designed to address the security flaws, and a client computing device is not able to download copyrighted content until the client computing device verifies the new version of the content player software has been loaded properly onto the device.
Typically, each version of the content player software is represented by a different version number. The version number of the content player software currently residing on the client computing device is stored in a memory on the client computing device that is associated with the content player software. One drawback of this approach is that the end-user of a client computer can easily “hack” the content player software and change the version number without downloading a new version of the content player software corresponding to the modified version number and developed to address one or more security flaws in the old version of the content player software. As a result, the end-user of the client computing device may be able to avoid DRM and other copy protections implemented by the content provider and exposed through the one or more security flaw in the content player software.
As the foregoing illustrates, what is needed in the art is a more secure approach to verifying that an application currently installed on a client device is secure. |