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Heterogeneity of violence in schizophrenia and implications for long-term treatment. Most patients with schizophrenia are not violent. However, persistent violent behaviour in a minority of patients presents a therapeutic challenge. Published treatment guidelines and most pharmacological and epidemiological literature on violence in schizophrenia treat overt physical aggression as a homogeneous phenomenon. The aim of this review is to address the subtyping of violent behaviour in schizophrenia, and to relate the subtypes to treatment. Literature describing subtypes of violence in schizophrenia and the treatment of this problem was reviewed. 'Schizophrenia', 'violence', 'aggression', 'hostility' and 'personality disorders' were the principal search terms describing behaviours. Generic names of individual atypical antipsychotics and mood stabilisers were used in treatment searches. There are at least three aetiological subtypes of violence in schizophrenia (i) that related directly to positive psychotic symptoms, (ii) impulsive violence and (iii) violence stemming from comorbidity with personality disorders, particularly psychopathy. Current treatment of violence in schizophrenia relies on antipsychotics and mood stabilisers. The evidence of effectiveness is relatively strong for clozapine, but inconsistent for other treatments. No systematic recommendations relating the treatment to aetiological subtypes of violence were found. The inconsistent effectiveness of the current treatments of violent behaviour in schizophrenia is due, at least in part, to the aetiological heterogeneity of that behaviour. We should not expect that any given pharmacological treatment will be equally effective in reducing violent behaviour caused by psychosis, impaired impulse control or personality disorder. Violence in schizophrenia is aetiologically heterogeneous. This heterogeneity has therapeutic implications that impact clinical practice today and should be further explored in future studies. | High | [
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Thursday, 30 April 2015 People with insomnia and other sleep problems have increased sensitivity to pain, reports a new study. The effect on pain tolerance appears strongest in people who suffer from both insomnia and chronic pain, who may benefit from treatments targeting both conditions. Since when, in the 21st century, did it become an acceptable part of democratic dialogue to attempt to ridicule and reduce political opponents by systematically mocking their physical characteristics? Or by contemptuously defining and dismissing them as ill and disabled? Moreover, how has it become acceptable that ill and disabled people are held up as objects of political derision? Loneliness is bad for you. Some experts have even likened it to a kind of disease. What's unclear is how being being lonely leads to these adverse effects on our health. A new study looks at one possibility – that loneliness makes people feel hungrier than normal, thus increasing their food intake and putting them at risk of obesity with all its associated health problems. Wednesday, 29 April 2015 Monday, 27 April 2015 Brand new research published in the last few weeks reveals important information for people with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and Fibromyalgia (FM). The research helps explain why individuals dealing with these complex disorders have poor response to physical activity and poor energy production. The cutting-edge studies offer new insight and tools for supporting these devastating illnesses. A must-read letter which sums up the daily experience of ME very well indeed: The determination with which society refuses to acknowledge the severity of ME would be hard for me to believe if I didn’t witness it almost daily. A week after major surgery, I am multiple degrees less sick than Jeannette is almost every day, but–except for her fellow patients from whom she fortunately draws a lot of strength–nobody around her knows it. Worse, it seems that people don’t want to know it. Thursday, 23 April 2015 Being dangerously overweight is all down to bad diet rather than a lack of exercise, according to a trio of doctors who have reopened the debate about whether food, sedentary lifestyles or both are responsible for the obesity epidemic. In an article for a leading health journal the authors – who include British cardiologist Dr Aseem Malhotra, an outspoken critic of the food industry – accuse food and drink firms such as Coca-Cola of having wrongly emphasised how physical activity and sport can help prevent people becoming very overweight. The truth, they say, is that while physical activity is useful in reducing the risk of developing heart disease, dementia and other conditions, it “does not promote weight loss”. Researchers have uncovered the critical role in pain processing of a gene associated with a rare disease. Their breakthrough paves the way for a better understanding of chronic pain conditions, they say. Sunday, 19 April 2015 Researchers looking at how to tackle the country's obesity issue -- which costs the NHS £6billion pounds every year -- found that currently individuals are often treated the same regardless of how healthy they are, where they live or their behavioural characteristics. The research found those who have a BMI of 30 or over actually fit into one of six groups and strategies to successfully tackle weight loss should be tailored according to which group they fall into. In April it was the turn of the Wimborne Railway Society's biennial Wimbourne Model Railway Exhibition at Queen Elizabeth's School, from which the above is from Terry Harrington's layout Woodley Moor, a fictional ex Midland Region mainline station set in Yorkshire. We particularly like this scene with the cattle being driven (clearly, back out to the field after milking) as this creates the feeling that more is going on than if they were just standing in a field. The other takeaway from this show was seeing what can be done (see below) with some Celotex insulation board and Woodland Scenics Realistic Water™, as with cliffs, sea, river and a waterfall planned for our layout, this will undoubtedly prove to be invaluable knowledge. Thursday, 9 April 2015 According to study co-author Arif, while eating beans often carries health benefits, some types are not as strong nutritionally. "Baked beans are also rich in sodium, sugar and fat, and depending on the type, rich in uric acid. Some beans contain lectins that are linked to irritable bowel syndrome, multiple sclerosis, allergies and arthritis. EBV infection has been associated with all of these medical conditions." According to study co-author Arif, while eating beans often carries health benefits, some types are not as strong nutritionally. "Baked beans are also rich in sodium, sugar and fat, and depending on the type, rich in uric acid. Some beans contain lectins that are linked to irritable bowel syndrome, multiple sclerosis, allergies and arthritis. EBV infection has been associated with all of these medical conditions." Wednesday, 8 April 2015 “Dramatic” and “life-changing” benefits cuts will be imposed if the Tories are running the country after 7 May, Iain Duncan Smith has warned. They could include taxing DLA, PIP and AA, axeing contribution-based ESA and JSA, abolishing the work-related activity group of ESA, cutting carers allowance numbers by 40%, and making people pay the first 10% of their housing benefit. For many, these will be life-threatening cuts, rather than life-changing ones. But claimants are in a position to prevent them happening. And it won’t take a miracle. In fact, just an additional 5% turnout by working age claimants could have a dramatic and life-changing effect on IDS and his plans instead. But a higher turnout won’t happen by itself. Labour are too frightened of the tabloids to try to rally claimants. Many of the major charities and disability organisations have been scared into silence by the Lobbying Act. And the media has little interest in benefits cuts, other than to applaud them as a good thing. So it looks like it’s up to ordinary claimants to make sure as many other claimants as possible understand the threat they are facing. In this newsletter we tell you what’s at stake and how you can make a difference. Sunday, 5 April 2015 The fact that the alterations in the immune factors in the ME/CFS were almost as extreme as in multiple sclerosis – a disorder characterized by severe central nervous system dysfunction – suggests a major pathology is present in the central nervous systems of ME/CFS patients. The low cytokine levels suggests that some sort of immune exhaustion – caused by an infection or by immune upregulation – is present in ME/CFS. These findings parallel those of the recent Hornig/Lipkin study suggesting that immune up regulation early in the disorder may lead to immune burnout later on. Several of the immune factors in the ME/CFS patients spinal fluid suggest an allergic type of reaction may be occurring in their CNS. That is also found in some central nervous system infections – so an infection could be driving this process. The immune factor most identified with the ME/CFS patients has been associated with cognitive declines, aging and reduced neuron production. A Michigan research group following arthritis patients undergoing hip or knee replacement or remodeling has found you don’t need to have full-blown fibromyalgia to have major pain problems – you just need to have something like it. Like others in the field, they noticed that surgical outcomes often do not track what they see on their scans. Some patients with major structural problems are in less pain than patients with minor structural problems. Some patients with apparently successful surgeries aren’t have successful outcomes. Even after alleviating their structural problems some patients pain levels are still so high that their surgeries declared failures. Something other than knee or hip damage is impacting these patients. That something appears to be a ‘proto-fibromyalgia’ state; not full-blown fibromyalgia but a lesser form of it. Thursday, 2 April 2015 A recent study by the University of Florida has found that the neural pathways that transmit feelings of pain to the brain may do their job too well in ME/CFS patients, causing the exhaustion experienced by many after even the most minor of tasks. It also has found proof that muscles and other peripheral tissues contribute to the experience of fatigue. The study focussed on the role of muscle metabolites, demonstrating that the neural pathways are activated when a person exercises their muscles, causing the metabolites to be released. Researchers found that the pathways seemed to be more sensitive in ME/CFS patients than in healthy controls. Wednesday, 1 April 2015 Henderson, a psychiatrist, asserts herpesviruses are a major issue in misdiagnosed chronic fatigue syndrome adolescents and patients. Dr. William Pridgen, a surgeon, proposes antivirals and anti-inflammatories are knocking down herpesvirus infections in people with fibromyalgia. They’re bucking strong headwinds for sure, but their message is getting out there, and it’s getting into surprising places. Pages About "Chaos was experienced as a feeling of alienation from oneself, of being unable to determine one's own living conditions, and of being unable to handle stress situations by the same means as before. The path from chaos to cosmos was discovered by telling one's life story, which proved to be a creative process relating and integrating the present with the past, and providing an overview of one's life cycle." I believe "The moral test of a society is how that society treats those who are in the dawn of life . . . the children; those who are in the twilight of life . . . the elderly; and those who are in the shadows of life . . . the sick, the needy, and the handicapped." | Low | [
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Q: return in while loop I have a method in c# with a database. Now I try to return the value but because the string is created in the while loop it says that it doesn't exist. Is there a way that the string kampioen with its value created in the while read loop can be returned? public string getkampioen(string selecteditem) { using (MySqlConnection connection = new MySqlConnection(connectionString)) { connection.Open(); string query = ("select * FROM clubs where naam = '" + selecteditem + "'"); MySqlCommand cmd = new MySqlCommand(query, connection); MySqlDataReader Reader = cmd.ExecuteReader(); while (Reader.Read()) { string kampioen = (string)Reader["aantalkampioenschappen"].ToString(); } return kampioen; } } A: You can declare the string before the while loop. public string getkampioen(string selecteditem) { using (MySqlConnection connection = new MySqlConnection(connectionString)) { connection.Open(); string query = ("select * FROM clubs where naam = '" + selecteditem + "'"); MySqlCommand cmd = new MySqlCommand(query, connection); MySqlDataReader Reader = cmd.ExecuteReader(); string kampioen = ""; while (Reader.Read()) { kampioen = (string)Reader["aantalkampioenschappen"].ToString(); } return kampioen; } } | Mid | [
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The first is the price of natural gas in the U.S. – which is less than $4 per million British thermal units (mBtu). The second is the price of natural gas in Asia, where people will pay $10 per mBtu for natural gas they import from overseas. This is a disparity someone can make a lot of money on. The only reason it exists at all is because the natural gas market is still mainly a local market. It is not as easy to ship natural gas into a country as it is to ship oil. You have to supercool it so it liquefies. Then you can put it on a tanker and ship it to a terminal where your buyer can regasify it. This is the LNG trade. There are problems. U.S. energy companies, before the shale gas boom changed everything, thought the U.S. would need to import natural gas. So the U.S. has about 10 LNG import terminals and two more in the works. Now, with a natural gas glut in the U.S., these terminals are pretty much useless. Owners of these terminals want to refit the terminals to turn them into export terminals, where the gas is liquefied and shipped out. They are now petitioning the U.S. government for export licenses. As the Financial Times reported, "The U.S. could soon be competing with Russia and the Middle East to supply the world with natural gas, a shift in production that would reshape energy markets over the next decade." Even if the U.S. exported just 10% of its natural gas, it would become the largest exporter of LNG in the world. Few countries can match the U.S. in natural gas resources or low costs. So where will the natural gas go? This is an interesting question, because it yields some surprising answers. I attended the ASPO conference last month in Washington, D.C. (ASPO stands for the Association for the Study of Peak Oil and Gas.) One of the more fascinating presentations was by Jonathan Callahan, founder of Mazama Science. He looked at natural gas through the lens of the import/export markets. This is a good thing to do for any commodity because it can tip you off to what's happening in that market. When China went from being one of the biggest exporters of soybeans to the biggest importer, the effect on agricultural markets was huge. Anytime a big exporter becomes a big importer, you can bet it spells opportunity for that commodity. China, for instance, remains a big importer of oil and iron ore, which has been good for investors in those commodities. China will very soon become a big importer of coking coal – which is used to make steel. So will India and Brazil. This is good to know if you're an investor, as it will drive demand for coking coal. So Callahan looked at natural gas through the same kind of lens. He created these charts that capture the trends. For the U.K., it looks like this: You can see the U.K. was an importer of natural gas through the 1980s and 1990s. Then there was the North Sea boost, matched by a step up in consumption. Finally, as the North Sea supplies dwindle, the U.K. has gone deep in the red as an importer. This chart exhibits a pattern we see time and time again. Consumption is sticky and stubborn. It doesn't go down much. Using this same analysis, Callahan looks at all the big producers and consumers of natural gas. The big buyers here are Japan, South Korea, and Taiwan. All of the gas they import comes from LNG tankers. But what about, say, China? Here is another one of Callahan's charts. Note it is just starting to turn negative – which means China is just becoming a net buyer of natural gas. Per-capita consumption, Callahan points out, is only a fraction of China's neighbors'. He predicts – and I agree – it will soon be a huge importer of natural gas. Combine China with Japan, Taiwan, and South Korea and Callahan concludes, "Clearly, East Asian demand for LNG will not be letting up anytime soon." Callahan's data suggest this trend is present all around the world... from the Middle East to South America to Europe. The impact on the global market seems clear. "If shale gas doesn't turn out to be as prolific as hoped," Callahan wraps up, "we can expect to see increasingly expensive natural gas in the next decade. Forewarned is forearmed." (I encourage you to check out his website – mazamascience.com, where you can see his presentations and read his blog.) So put together Callahan's data on exports and imports with the glut in the U.S. and the lack of export terminals. I think it's pretty clear we'll see more export terminals in the U.S. It's too big of an opportunity to ignore. The U.S. could become the leading exporter of natural gas in the next decade. It's also pretty clear that worldwide, we'll see the LNG trade grow significantly to make up the shortfalls that are emerging in South America, Asia, Europe, and the Middle East. It's a great time to buy infrastructure firms that build these plants. It's also a great time to look at companies with lots of North American natural gas reserves. With natural gas in the dumps right now, these assets are cheap... but they won't stay that way for long. | Mid | [
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Islamic Action Society The Islamic Action Society ( Jamʿīyah al-ʿAmal al-ʾIslāmī), also referred to as Amal Party (), is one of the main Islamist political parties in Bahrain, and mainly appeals to Shīʻa followers of the Islamic philosopher Mohammad Hussaini Shirazi (1928-2001), who are known as "the Shirāzī faction". The party boycotted 2002's general election along with several other opposition groups, but did take part in 2006's parliamentary election, in which it won no seats. The party is the direct descendant of the militant organisation, the Islamic Front for the Liberation of Bahrain, whose members were pardoned after wide ranging political reforms instigated by King Hamad bin Isa Al Khalifa in 2001. With the reforms, they returned from exile or were released from prison and formed the Islamic Action Society. As with the Islamic Front for the Liberation of Bahrain, the party's spiritual leader is Iraqi cleric Hādī al-Mudarrisī, who was given asylum in Bahrain in the 1970s and acquired Bahraini citizenship while preaching religious awareness. He was though expelled to Iran after he set up the Front, but in 1981 he attempted to return to Bahrain as the head of a theocratic government in a failed coup d'état. The Front was accused by the government for a series of terror attacks on civilian targets in the 1990s including a bomb attack on the Diplomat Hotel in Manama in 1996 injuring four people. A spokesman claiming responsibility for the bombings told the Associated Press "We put a bomb in the Diplomat hotel 20 minutes ago ... after the feast ... tell the government that we will destroy everyplace." The party often calls for public demonstrations and political seminars focusing on the issues affecting the majority Shīʻa, who have been ruled by the minority Sunnis for many decades. In September 2005, its license was temporarily suspended after a crowded festival was held honouring those imprisoned by the government on suspicion of involvement in an alleged 1981 coup. The party resumed activities after the temporary suspension. The current president of the party is Shaykh Muħammad ʻAlī al-Mahfūð, a longtime opposition figure and a close aid to Āyatu l-Lāh al-Mudarrisī. Its vice-president is Salah al-Khawāja. While the party was allied with fellow Shīʻa Islamists al Wefaq, although the relationship was difficult: Shaykh al-Mahfūð said that attempts were being made by ʻAlī Salman and others to marginalise the party into its "Shirāzī base". The Islamic Action demanded al-Wefaq's support in several constituencies in the 2006 election, although the Islamic Action's spokesman Jawad ʻAbdu l-Waħab has said that no decision has yet been made because they want although it took part anyway. This led one commentator to accuse the party of having a stance "based on self-serving interests but under glossy principles to boost its prestige". Discussion about participation in elections prompted Vice President Salah Khawaja to resign from the party in March 2006 and announce his retirement from politics. Before February 2011, Islamic Action Society decided to support the Bahraini uprising. During February and March 2011, many representatives of Amal joined anti-Monarchy protesters in Lulu Square and vowed not to enter any dialogue until King Hamad relinquished his office. As a result, the government arrested all the prominent leaders of Amal and closed its headquarters, dissolving the party. References External links IAS website Religious body floats demands for elections Gulf News, 8 March 2006 Category:Bahraini uprising of 2011 Category:Organizations of the Arab Spring Category:Political parties in Bahrain Category:Politics of Bahrain Category:Shia Islamic political parties Category:Republicanism in Bahrain Category:Banned Islamist parties | Mid | [
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Q: Could life survive on a diet of dust? Could life survive on a diet of dust or some other substance that is both abundant and that we don't place any value on? A: The house dust mite already does that. Dust mites feed on organic detritus such as flakes of shed human skin and flourish in the stable environment of dwellings. A: Mourdos' answer mentions dust mites, which feed off organic matter in dust. Another possible answer is lithophilic bacteria, which literally survive by eating rocks. | High | [
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Welcome to Common Gunsense I hope this blog will provoke some thoughtful reflection about the issue of guns and gun violence. I am passionate about the issue and would love to change some misperceptions and the culture of gun violence in America by sharing with readers words, photos, videos and clips from articles to promote common sense about gun issues. Many of you will agree with me- some will not. I am only one person but one among many who think it's time to do something about this national problem. The views expressed by me in this blog do not represent any group with which I am associated but are rather my own personal opinions and thoughts.------------------------------------------------------------------------------------------ Thursday, February 16, 2012 Keeping score In the last few days it seems like an epidemic of gun permit holders and/or "law abiding" gun owners gone wrong. One of my commenters wanted to know how I could say that there are more incidents of shootings or near misses of law abiding gun permit holders? It's simple. It's the real life stories about permit holders using their loaded guns carelessly in public places. They are frequently in the news. Let's make a list of just a few in the past few days to highlight what I am talking about: An Indiana permit holder gets angry over the wax job on his car at a car wash and wields his gun- Really? Is this O.K.? What gets into people with guns that makes them think they can do things like this. From the article:"Witnesses told police a customer at Supersonic Car Wash, 1306 W. Chicago Ave., became irate after looking at the detailing to his 1995 Chevrolet Tahoe and then chased an employee through the waiting room with a gun in his hand. The pursuit allegedly continued outside, where witnesses said they heard a gunshot. The employee was not injured." It's hard to know what else to say about this one. This Nevada man was found naked on his back porch having discharged his gun in the neighborhood, luckily not hitting anyone with the bullets fired. " Todd Kitchner, 52, of Pahrump was arrested on suspicion of discharging a firearm at or into an occupied residence, assault with a deadly weapon, child endangerment, discharging a firearm on a public street, possession of a firearm while intoxicated and possession of drug paraphernalia." And from this more recent article: " As reported Friday by Las Vegas TV station KTNV, Kitchner said he regrets what happened and never intended to harm anyone.“I used to live in Alaska. We used to get away with this kind of crap,” he told the news station. “If I wanted to kill somebody, I would have.” Kitchner further said that he had been through a lot lately, including taunting from neighbors and an inability to sleep due to severe back pain." Yup. Those are all good reasons to shoot up your own house and shoot at innocent neighbors and passers by in cars. Do people really get away with that "kind of crap" in Alaska? You can take a look at the link to the Brady Campaign's new State Scorecard to check out how Alaska does compared to other states when it comes to laws to keep guns away from people who should not have them. Alaska is one of the states with the lowest ranking. And to think the guy can say he could have killed someone if he wanted to while not realizing that he could have killed someone by just shooting randomly! Wow. This guy has serious problems. An Ohio man shot himself with his loaded gun as he was getting out of his car. My readers know that I have written about quite a few similar incidents of this nature on my blog. Some gun permit holders are stupid and dangerous. It appears that there enough of them to make us stand up and take notice. The first question is why did the man think he needed his gun in the shopping center in the first place? Can't gun permit holders figure out that there is not a good reason for them to carry their loaded guns into every nook and cranny of our communities? The chances of shooting oneself or someone else are greater than needing that gun for self defense. Where is common sense? A Washington state permit holder shot and killed a young woman at a party over the week-end. This one was not only senseless and stupid but tragic. Guns and alcohol just do not go together. And bringing a loaded gun to a party? Why? What will you need your gun for at a party where you know alcohol will be served? Maybe you will need one to protect yourself from the other stupid and dangerous "law abiding" gun permit holders. Good grief. " Investigators believe DeJong fired a .40-caliber handgun while at a party early Sunday morning. The bullet went through a wall and hit a 20-year-old woman who was at the party and standing on the other side. "We do believe that it was due to reckless handling of the gun that caused it to go off," Bove said. "We do not believe it was premeditated."According to court documents, a man who call 911 to report the shooting told dispatchers "my best friend shot a girl in the house, he was drunk."" Bullets do travel through walls. Guns are dangerous. There are too many victims. “Guns don’t fall from the sky into the hands of criminals,” said Brady Acting President Dennis Henigan. “All too often, crime guns come from gun dealers in the states that stubbornly refuse to enact common sense, lifesaving gun laws. Every day, a river of illegal guns flows out of the states with weak gun laws, victimizing families in states that are doing their best to protect their residents. It is no accident that the states with the weakest gun laws are the exporters of death and injury.” Indeed. Also from the press release and the report: A fresh analysis of data for crime guns recovered by police and traced back to the dealer that sold the gun provides additional evidence showing that strong gun laws help to curb the supply of guns to the illegal market. The ATF data, available on its website, provide information on the source states of U.S. crime guns by state. The data show that states with weak gun laws have a crime gun export rate nine times higher than states with strong gun laws. The Brady Center analyzed the data to identify patterns in the movements of crime guns across the United States, including which states have the highest rates of crime guns moving across state borders, known as the crime gun export rate (per 100,000 population). Texas, Georgia, Ohio, Louisiana, South Carolina, Tennessee, Indiana, Mississippi, Wisconsin, Kentucky, and West Virginia are among the 31 states that together export crime guns at a rate nine times higher than states with strong gun laws. You can read much more about the scorecard on the website linked above. There are no surprises here. Today, in my own state of Minnesota, the Senate will vote on the "Shoot First" measure that will surely make it easier to shoot someone and get away with it. Minnesota got 14 points on the Brady Scorecard. That will change if this law goes into affect because not only will it increase the ability of people to shoot others under the guise of using deadly force when it may not be necessary, but the law will change the length of time between local background checks for permits to purchase handguns and assault weapons from one to five years. So if someone becomes a domestic abuser, drug abuser, adjudicated mentally ill, etc. in that five year period, there will be no way for local law enforcement to to deny that person their permit. The permit must be shown to Federally Licensed Firearms Dealers in order to purchase handguns and assault rifles. Any amount of these guns can be purchased in this one year period. So instead of working to make us safer, the NRA and its' minions in Minnesota intend to make us less safe. Read more about it at the Protect Minnesota website where you will see that law enforcement agencies and prosecutors are vehemently opposed to his bill. But never mind, the NRA knows better than the people who actually deal with the system. Where is common sense? UPDATE: The Senate vote on the "Shoot First" bill has been postponed. Perhaps our Minnesota Senators got some common sense and listened to law enforcement, prosecutors and the many people who contacted them in opposition to the bill. 24 comments: The one thing you are missing with the MN permit is that you still have to do a federal background check at the time of purchase. The MN permit was a stop gap measure to satisfy the Brady Bill that never went away after the NCIS was implemented. This is a timely article, japete, for Oregon. Here in Oregon, the state House just passed a bill to make private the names of CCL holders. Currently, those names are available after petition on a need-to-know basis. Keeping it open allows for public scrutiny of the sheriff's granting policy and allows people to check to see if potential abusers may endanger them (irate employees, adult babysitters, angry ex-boyfriends, etc), but keeps secret those who need it (such as domestic violence victims). The bill isn't likely to pass the Oregon Senate, and this is at least the third unsuccessful time the gun guys have tried to pass this. But the gun lobby isn't above continuing to waste our legislator's valuable time on it. The gun guys insist that bill is needed for privacy and that CCL holders never commit crimes. But they clearly DO commit crimes (here's a link to many deadly shootings by CCL holders since 2007: http://www.vpc.org/ccwkillers.htm), and their privacy isn't nearly as important as the safety of our community. To whom are you referring? The story says he is a permit holder but they were checking to see if the permit was valid. That would make it even worse. The guy was carrying when he might not have been a valid carrier. He also was a school district police officer until recently. Here is one story that states that it was revoked. It is sad that the media just runs with story and does not wait for the facts to be verified. japete writes: "One of my commenters wanted to know how I could say that there are more incidents of shootings or near misses of law abiding gun permit holders? It's simple. It's the real life stories about permit holders using their loaded guns carelessly in public places. They are frequently in the news. " Posting a set of stories is not the same as posting aggregate data that shows the actual trend. The actual facts, such as those I posted in a comment to a previous post of yours, show using Minnesota as an illustrative example that permit holders commit crimes - particularly involving firearms - at a rate far far less than the rate of the general population. Data from Texas, Indiana, and Florida show a quite similar trend. As long as permit holders are shooting people intentionally or not, we have a problem. The general population are also shooting too many people. There are no excuses for the incidents I write about. Permit holders are supposed to be more careful. That is what you all said would be the case. It's not working out so well. as to your statements above, what would you propose? Ban all guns? It seems that the only way to keep ALL shootings from happening, you would have to both ban and destroy all guns. (and stopping ALL shootings does seem to be your goal, as evidenced by your concern over the small number of shootings your referred to above, especially compared to even the lowest estimated number of crimes stopped by Defensive Gun Use, which is 108,000 / year.) The chief of police or sheriff must conduct a background check by means of electronic data transfer on a permit holder through the Minnesota Crime Information System and the National Instant Criminal Background Check System at least yearly to ensure continuing eligibility. Oops- one more CCW holder accidentally discharges gun at actual class to teach people how to properly use their guns. And in this case, it was the instructor himself. But never mind, let's not worry about those permit holders. They are perfectly safe- http://www.goupstate.com/article/20120219/ARTICLES/202191029/1027/OPINION?Title=Student-accidentally-shot-at-concealed-weapons-class I just hate it when I have to keep adding incidents of law abiding permit holders being stupid and dangerous but here goes anyway- http://www.wtxl.com/content/topstories/story/Woman-loses-gun-at-Governors-Square-Mall/QPb8sipmAEuV-ajtqoZylA.cspx People shouldn't take their guns along when they are shopping. Too many bad things can happen and I don't mean shootings by bad people. I mean mistakes by law abiding people. KEEP YOUR COMMENTS CIVIL PLEASE Comments are allowed but are moderated for civility and decency. My blog is intended to change public opinion about the gun debate and all readers will not agree with me. No comments that demean, debase, attack, call names, or are generally impolite, rude and offensive will be published. In general, comments that are "snarky", mean, overly aggressive or harassing will not be published. Keep the language clean and respectful. Anonymous commenters are not allowed on this blog. Thanks to my readers for participating. | Mid | [
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Q: Inequality holds? Can anyone prove that $$ \frac{\sum\limits_{i=1}^{k*} a_i i (x+\epsilon)^{(i-1)}}{\sum\limits_{i=1}^{k*} a_i (x+\epsilon)^{i}+k^*-1}>\frac{\sum\limits_{i=1}^{k*} a_i i x^{(i-1)}}{\sum\limits_{i=1}^{k*} a_i x^{i}+k^*-1} $$ where $a_i$ are some positive coefficients, $\epsilon$ is a positive number and $0<x<1$? A: I think it's the reversed inequality which is true: let $f(x):=\sum_{i=1}a_ix^i$, and define $g(x)=\frac{f'(x)}{f(x)+k^*-1}=\frac{d}{dx}(\ln f(x))$. Then $g'(x)=\frac{d^2}{dx^2}(\ln f(x))$, and since $f$ is increasing, and $\log$ is concave, $x\mapsto \ln f(x)$ is concave, so $g'\leq 0$ and $g$ is decreasing. | Mid | [
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Weight counseling for elderly patients in primary care: how often and how much time. Some 20 million Americans over the age of 60 will soon be obese. As a result, they will likely suffer lower life-expectancy, higher disability, and higher health care costs. How much time do physicians spend with elders, especially obese elders, in helping them plan weight loss? This study, which analyzed 352 videotaped visits with elderly patients and their provider, has found that only a third of the visibly obese patients were counseled, and that the average time spent discussing the subject--if discussed--was 103 seconds. This is probably less than a fifth of the time needed to adequately counsel patients about weight loss. In addition, the study has found that both provider and patient characteristics determine if and how long discussion lasts. | High | [
0.65648854961832,
32.25,
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|
package com.github.huajianjiang.expandablerecyclerview.widget; import android.view.View; /** * <p>父列表项 ViewHolder，监听父列表项的点击事件并根据当前展开或收缩状态触发父列表项展开或折叠事件 * 客户端父列表项 ViewHolder 应该继承它实现可展开的 {@code RecyclerView} * </p> * Created by jhj_Plus on 2015/12/23. */ public class ParentViewHolder<P extends Parent> extends BaseViewHolder { private static final String TAG = "ParentViewHolder"; private int parentPosition; private P parent; /** * 是否该可展开折叠 */ private boolean mExpandable = true; /** * 设置当前父列表项是否已展开 */ private boolean mExpanded = false; public ParentViewHolder(View itemView) { super(itemView); } public boolean isExpandable() { return mExpandable; } boolean setExpandable(boolean expandable) { if (expandable == mExpandable) return false; mExpandable = expandable; return true; } /** * 返回当前父列表项是否已展开 * * @return 父列表项是否已经展开 */ public boolean isExpanded() { return mExpanded; } /** * 设置父列表项是否已展开 * * @param expanded 父列表项是否已展开 */ boolean setExpanded(boolean expanded) { if (expanded == mExpanded) return false; mExpanded = expanded; return true; } /** * 返回该 parent 的位置，不一定是同步过的,例如在 parent move 之后该值并没有同步更新，因此需要重新查询 * * @return parent 的折叠位置 */ public int getParentPosition() { return parentPosition; } void setParentPosition(int parentPosition) { this.parentPosition = parentPosition; } public P getParent() { return parent; } void setParent(P parent) { this.parent = parent; } } | Mid | [
0.5495978552278821,
25.625,
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// Protocol Buffers - Google's data interchange format // Copyright 2008 Google Inc. All rights reserved. // https://developers.google.com/protocol-buffers/ // // Redistribution and use in source and binary forms, with or without // modification, are permitted provided that the following conditions are // met: // // * Redistributions of source code must retain the above copyright // notice, this list of conditions and the following disclaimer. // * Redistributions in binary form must reproduce the above // copyright notice, this list of conditions and the following disclaimer // in the documentation and/or other materials provided with the // distribution. // * Neither the name of Google Inc. nor the names of its // contributors may be used to endorse or promote products derived from // this software without specific prior written permission. // // THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS // "AS IS" AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT // LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR // A PARTICULAR PURPOSE ARE DISCLAIMED. IN NO EVENT SHALL THE COPYRIGHT // OWNER OR CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, // SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT // LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, // DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY // THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT // (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE // OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE. package com.google.protobuf; import protobuf_unittest.Vehicle; import protobuf_unittest.Wheel; import junit.framework.TestCase; import java.util.ArrayList; import java.util.List; /** * Test cases that exercise end-to-end use cases involving * {@link SingleFieldBuilder} and {@link RepeatedFieldBuilder}. * * @author [email protected] (Jon Perlow) */ public class NestedBuildersTest extends TestCase { public void testMessagesAndBuilders() { Vehicle.Builder vehicleBuilder = Vehicle.newBuilder(); vehicleBuilder.addWheelBuilder() .setRadius(4) .setWidth(1); vehicleBuilder.addWheelBuilder() .setRadius(4) .setWidth(2); vehicleBuilder.addWheelBuilder() .setRadius(4) .setWidth(3); vehicleBuilder.addWheelBuilder() .setRadius(4) .setWidth(4); vehicleBuilder.getEngineBuilder() .setLiters(10); Vehicle vehicle = vehicleBuilder.build(); assertEquals(4, vehicle.getWheelCount()); for (int i = 0; i < 4; i++) { Wheel wheel = vehicle.getWheel(i); assertEquals(4, wheel.getRadius()); assertEquals(i + 1, wheel.getWidth()); } assertEquals(10, vehicle.getEngine().getLiters()); for (int i = 0; i < 4; i++) { vehicleBuilder.getWheelBuilder(i) .setRadius(5) .setWidth(i + 10); } vehicleBuilder.getEngineBuilder().setLiters(20); vehicle = vehicleBuilder.build(); for (int i = 0; i < 4; i++) { Wheel wheel = vehicle.getWheel(i); assertEquals(5, wheel.getRadius()); assertEquals(i + 10, wheel.getWidth()); } assertEquals(20, vehicle.getEngine().getLiters()); assertTrue(vehicle.hasEngine()); } public void testMessagesAreCached() { Vehicle.Builder vehicleBuilder = Vehicle.newBuilder(); vehicleBuilder.addWheelBuilder() .setRadius(1) .setWidth(2); vehicleBuilder.addWheelBuilder() .setRadius(3) .setWidth(4); vehicleBuilder.addWheelBuilder() .setRadius(5) .setWidth(6); vehicleBuilder.addWheelBuilder() .setRadius(7) .setWidth(8); // Make sure messages are cached. List<Wheel> wheels = new ArrayList<Wheel>(vehicleBuilder.getWheelList()); for (int i = 0; i < wheels.size(); i++) { assertSame(wheels.get(i), vehicleBuilder.getWheel(i)); } // Now get builders and check they didn't change. for (int i = 0; i < wheels.size(); i++) { vehicleBuilder.getWheel(i); } for (int i = 0; i < wheels.size(); i++) { assertSame(wheels.get(i), vehicleBuilder.getWheel(i)); } // Change just one vehicleBuilder.getWheelBuilder(3) .setRadius(20).setWidth(20); // Now get wheels and check that only that one changed for (int i = 0; i < wheels.size(); i++) { if (i < 3) { assertSame(wheels.get(i), vehicleBuilder.getWheel(i)); } else { assertNotSame(wheels.get(i), vehicleBuilder.getWheel(i)); } } } public void testRemove_WithNestedBuilders() { Vehicle.Builder vehicleBuilder = Vehicle.newBuilder(); vehicleBuilder.addWheelBuilder() .setRadius(1) .setWidth(1); vehicleBuilder.addWheelBuilder() .setRadius(2) .setWidth(2); vehicleBuilder.removeWheel(0); assertEquals(1, vehicleBuilder.getWheelCount()); assertEquals(2, vehicleBuilder.getWheel(0).getRadius()); } public void testRemove_WithNestedMessages() { Vehicle.Builder vehicleBuilder = Vehicle.newBuilder(); vehicleBuilder.addWheel(Wheel.newBuilder() .setRadius(1) .setWidth(1)); vehicleBuilder.addWheel(Wheel.newBuilder() .setRadius(2) .setWidth(2)); vehicleBuilder.removeWheel(0); assertEquals(1, vehicleBuilder.getWheelCount()); assertEquals(2, vehicleBuilder.getWheel(0).getRadius()); } public void testMerge() { Vehicle vehicle1 = Vehicle.newBuilder() .addWheel(Wheel.newBuilder().setRadius(1).build()) .addWheel(Wheel.newBuilder().setRadius(2).build()) .build(); Vehicle vehicle2 = Vehicle.newBuilder() .mergeFrom(vehicle1) .build(); // List should be the same -- no allocation assertSame(vehicle1.getWheelList(), vehicle2.getWheelList()); Vehicle vehicle3 = vehicle1.toBuilder().build(); assertSame(vehicle1.getWheelList(), vehicle3.getWheelList()); } public void testGettingBuilderMarksFieldAsHaving() { Vehicle.Builder vehicleBuilder = Vehicle.newBuilder(); vehicleBuilder.getEngineBuilder(); Vehicle vehicle = vehicleBuilder.buildPartial(); assertTrue(vehicle.hasEngine()); } } | Mid | [
0.6146993318485521,
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|
Sometimes the most important scientific findings are not those that prove something, but those that disprove something. This was the case with a study published last week (and reported in the Telegraph) on the role of viruses in ME, the condition characterised by extreme fatigue and muscle pain. Scientists based at Columbia University in New York found no evidence that sufferers were infected with the viruses XMRV or pMLV, which had previously been isolated in tissue samples taken from ME suffers and were thought to have a role in the condition. Researchers found compelling evidence that detection of the viruses was as a result of contamination, thus corroborating two previous studies that had reached the same conclusion. The theory that XMRV or pMLV were factors in ME was dismissed ''once and for all’’, according to the study. This will no doubt come as a blow to those ME sufferers determined to prove that their ill health is a result of a biological agent. But despite this being such an important study, it wasn’t widely reported by British media. I suspect I know why. Last summer I wrote a column here about ME, after researchers had revealed the systematic abuse they had received from a group of ME protesters, who objected to the scientists’ suggestion that there might be a psychological component to the condition. The scientists, including highly respected clinicians, told how they had been subject to intimidation and even death threats. I suggested that perhaps the reason the protesters felt so strongly was because of the way society views mental illness, and the implication that it is not a real form of illness. I thought this was quite a reasonable observation. Nothing could have prepared me for what happened next. Within an hour of the article going online, I began to receive messages on Twitter. Within a few hours, I’d received several hundred. Within a few days, it was into the thousands. I was inundated with emails and letters, furious that I had backed the scientists who’d argued that a psychological component might play a role in ME. Those who targeted me displayed an astounding degree of paranoia and obsession, twisting anything I said, or any attempts to pacify them. I soon gave up bothering. For a group of people with such apparent low levels of energy, they seemed to have an incredible amount to waste on me. Some wrote to my agent and my publisher. The article was even referred to the Press Complaints Commission (which rejected all the complaints and vindicated the article). Others found contact details for the person who runs my website, for my partner and for several of my friends. They targeted journalists who voiced support for me. Some personal threats were made and I had to get lawyers involved. I had received emails from people with ME thanking me for my piece, but they explained they dare not speak out for fear of retribution. What on earth was going on? Then, the puzzlement changed to concern. It was brought to my attention that people had been discussing, via the internet, where I lived. My home is easily identifiable. Photographs of it had been posted online. The police became involved, and visited my flat to assess how secure it was. My telephone number and address were placed on a ''high-alert’’ rapid response list. It is clear that the people who targeted me in such a reprehensible way represent a very small minority of ME sufferers. As I analysed the messages on Twitter, it became apparent that there were, perhaps, 200 individuals repeatedly sending me those vile messages and emails. A proportion of them didn’t even live in the UK. Eventually, the frenzy began to die down. It coincided with appeals from some in the ME community not to harass me as they believed such extreme behaviour undermined their argument. Since then, medical journalists have told me that few of them would choose to tackle a story about ME because of the abuse it attracts. Media doctors I consulted agreed it was the one subject that they avoided at all costs. This chimes with the researchers’ original point: that the minority of militant sufferers are doing the majority a tremendous disservice by scaring off doctors and scientists from working in the area. The daft thing is that I actually have a deep sympathy for sufferers of ME. I’m very interested in the subject and have followed the medical literature on it for years. I think the difficulties such patients face in accessing services and state assistance is scandalous. I’d happily champion their cause, but after my experience I really don’t want to get involved. I have put my head above the parapet once more because I think it’s important that readers know what happens to those who try to discuss ME, and why the press are often reluctant to cover stories about it. The other thing is that the experience confirmed my original theory about the fears and prejudice surrounding mental illness. Those who denounced my column told me (often in capital letters) that they weren’t making up their symptoms, that they were physical, so how could it be psychological? And therein lies the rub: that mental illness is seen as being ''made up’’ or somehow inferior to physical illness. These ME sufferers pointed out that brain scans have shown possible neurological changes as evidence that their illness wasn’t psychological, completely failing to understand that such scans show significant changes in every psychiatric disease, too. This is the root of the problem – that we, as a society, still labour under the Cartesian legacy of the mind-body split, and that only physical illness is real. Meanwhile, because of a vocal, vexatious minority, the suffering of those with ME will continue to go largely unreported. We must admit to giving up this paper a long time ago owing to the uninformed articles by this psychiatrist promoting the usual Wessely garbage. Let's hope they do keep clear of the "psychology" of ME - nothing to do with psychology so nothing to do with them. He could of course educate himself and follow Lipkin and all the science findings. We have to in order to addresss all the pathologies found. This makes me so angry. I wish I was eloquent enough to leave a comment there. How convinient for him to say 'role of viruses' when only one has been proven to not be there. He makes it sound like this proves there are no viruses at all. This is such a manipulative way to speak! Sure, we all know that a virus might not be a cause. But that's just it: MIGHT NOT. It's so unscientific to claim otherwise. And I find it ironic that researchers are complaining of being harassed. I agree it's unforgivable to be sending threats to them, but isn't it us who get PTSD from mistreatment by doctors and researchers, not the other way around? I just hope that this time round nobody starts questioning the 'truth' behind his claims of harassment. It will do us no good whatsoever and such activity should not be condoned. Those doing it are beyond the pale whether done in 'jest' or otherwise. I agree to a certain extent (not violence etc) Firestormm but in the terrible history over decades in the UK from psychiatrics who will not "get it" can understand those driven to distraction by their hold over ME/CFS as "psychological", so knowledgeable criticism accepted. My concern is more: "Why few dare tackle the biology of ME?" how many researchers and doctors were bullied out of the field? How many had their career ended? Their funds stopped? Their reputation shattered? What makes me suspicious is the attacking of people just asking questions. This leads me to believe the 'establishment' or government(s) have something to hide. I can't speak for the UK government but I know the US government has giant biological weapons research labs all over the country. There is a great show called conspiracy theory with jesse ventura where they talk about plum island, and all of the secret germ testing that goes in that facility. In the US it's been proven that AMES strain anthrax was mailed to people shortly after 911. No one has ever discovered how this strain, made only in fort detrick MD, found it's way inside the mail system. Bayer also knowing shipping factor 8 blood clotting medicine to people around the world when they knew it was contaminated with HIV. Dr Len Horowitz and Dr Robert Strecker both say the government had a hand in creating HIV. You can watch the Strecker Memorandum online where he shows the documents where the US government asked for such a weapon to be created. Shortly after his brother committed suicide under dubious circumstances. You can also watch Horowitz's videos on youtube or read his book, Emerging Viruses. If attention is brought to some man made substance that brought about an entire new class of diseases, it might blow the whole lid off the secret germ testing that goes on in various governments. They would then have to admit this research goes on, and yeah we accidentally (or purposefully) released X microbe, etc. These facts may sound unbelievable but it's all true, and I urge you to research my claims for yourself. It always annoys me how criticism or questioning is conflated or confused with harassment, and how the stigma of mental illness strawman/redherring card is played whenever there is criticism for claims about psychological factors in ME/CFS. Claims about harassment tend to be exaggerated and lacking of hard evidence too, basically they are anecdotes. Claims about ironic hypergraphia, or prolific writers too exhausted for anything else, usually do not take into consideration the volume of content per person vs what is at stake for them or the medical abuse/dismissal they have endured. Hardly anyone seems to believe anecdotes from patients who claim to have experienced harassment, abuse, dismissal and neglect from health care professionals or other people, so why should we automatically believe anecdotes from journalists and researchers claiming to have been harassed by patients? We have been subject to dubious claims and deceived before, so unsurprisingly, trust is a major issue and can result in a degree of paranoia. However, I have to ask, what if some of the claims of harassment are true? What if some writers really are being inundated with abusive emails and occasional death threats? What if there really are a few unstable individuals out there involved in such activities? Such behaviour would indeed be unacceptable, disgusting, and damaging. And denying the existence of such behaviour would be offensive to victims, just as it is offensive to deny the harsh reality of ME/CFS. I have suggested numerous times that there may be (relatively minor) mental factors in some cases of ME/CFS, due to it being characterized by post-exertional symptomatology which would be worsened by the existence of such factors that exist in a general population. I have never been subject to abuse or harassment as a result, so I suspect that the anger is not towards the mere suggestion of such factors, but rather, the over-emphasis on such factors based on flawed evidence. Personally, I have not been able to find patients who endorse such harassment, so if existing they must be rare or working in secret and I am not part of the cabal. However, it is a slippery slope to just blame everything on some mysterious cabal, because news coverage tends to lump in all vocal critics as part of the fringe element. I just hope that this time round nobody starts questioning the 'truth' behind his claims of harassment. It will do us no good whatsoever and such activity should not be condoned. Those doing it are beyond the pale whether done in 'jest' or otherwise. Click to expand... I hope people do question the truth of these claims and let’s see the extent of the evidence. We all have access to a crime prevention officer and are all able to gain a high alert rapid response just by dialling 999. You would think reading this rubbish that there was an ME equivalent of a Taliban training camp. It is a pathetic article. Shades of Red Under The Bed and Guilt By Association! I do not condone violence nor threats of violence ... though I do think some events in ME history need official investigation - that isn't a threat, its a statement that there is a public interest in finding the truth. However if you can paint all critics with the same brush, then you are engaged in very negative spin. If someone is being harassed to have integrity they have to be specific about the complaints, or specific enough that it is clear what the nature of harassment is. I have not investigated the specifics involved here, but I gather there is insufficient information to really judge the situation. Asking someone to provide details to verify their claims is not harassment - threatening them to make them do so is. Furthermore in the case of both journalists and researchers they are justifiably questionable on matters relating to public interest or their research. So if one makes an unsubstantiated claim it is completely legitimate to question it, particularly if that claim appears outlandish. It is then up to them to either substantiate the claim or decline to do so. We are a community that has been systematically lied to for decades. We face hypotheses presented as facts, and "facts" which are contradicted by evidence. This means many of us, justifiably, have very little faith in unsubstantiated outlandish claims. We also appreciate careful science. The problem with a lot of the biopsychosocial research is that it typically does not gather or rationally use useful objective evidence, and many of us doubt it can even be called scientific. While there are some individuals who have extreme views on biomedical research, this is understandable. We have all been misinformed so many times its ridiculous. We also have different case histories, which sometimes bias our judgement, and this is also the case with most doctors. I am aware of one, perhaps two claims of violence use by ME or CFS patients. I am aware of a small number of claims of threats from more. This is a tiny minority of patients, though I cannot be sure how representative this is of the whole. What I do not doubt is that some of these figures receive extremely hostile emails or letters. That is entirely consistent with the patient community as I understand it. Such communications might be considered harassment, and it is clear that Max Pemberton views it that way. However, I still do not know how common this is. Most patients and advocates do not do this, nor do we condone it. Let me emphasize though that letters critical of a persons arguments or claims, especially if they have a public profile, is not by itself harassment. Citicisms of "persons" arguments or claims goes on all the time in the press, some very personal too. As a medical journalist (MP) should expect as strong views in response to his own claims. Now if he were an authority that is knew his subject matter - myalgic encephalomyelitis fully who knows we might even listen. What community ? There are contributors to this thread who are already being attacked by our 'fellow patients' on other forums, merely for holding views that are 'unacceptable'. The past five years have seen successive 'vocal, vexatious minorities', drive every dissenting reasoned voice away from any public discourse about M.E in what has become a progressive Talibanisation of the illness, where 'we' (the true believers, the belongers) is described by a witless anti psychiatric polemic. Hyperbolic claims of "been systematically lied to for decades", only reinforce the Masadaist internalisations of a myth of collective oppression that underwrites the increasingly cult like script that those who claim The [M.E/CFS] Community as their own, wish to see to played out. One can find exactly the language of "systematically lied to" on Alien Abductiontist websites, and it is exactly the kind of rhetoric that flows from such an internalised perspective which feeds the zealotry of those who feel free attack and harrass those who they identify as oppressors. No reasonable person wants to be part of community like that - if only for the most practical reason that all strategies for 'winning' that flow from it are doomed to fail, indeed they are lost from the outset because it is a fundamental error to accept the the enemy's description of the 'war'. Fight on the enemy's ground you lose, fight on the enemy's terms, you lose, allow th enemy to 'describe' you, you lose. Does, Pemberton's scribbling harm the interests of M.E/CFS patients ? Yes ! But the idiots who bombarded his email and twitter accounts only provided him with more ammunition, lesson = those idiots are fighting the wrong battle or the right battle in the wrong way. For some the motivation is probably emotional unburdening - unthinkingly getting their rocks off, for others, a degree of manipuation is probably involved, those who like to watch the crowd running in the wrong direction, or who want to play flag wavers or generals. But all we really need to know is - it's just dumb to fight like that and anyone who is serious about community building needs to start by making it plain that 'belonging' demands integrity and consideration - not fanaticism. I will not be holding my breath though, Pemberton and others will continue to excite the attention of the mob and they will continue to confirm for Pemberton and the bulk of his readers that opposition to psychiatric definition of M.E/CFS is evidence that M.E/CFS is by definition a psychiatric illness. "Systematically lied to" comes from specific, detailed numerous items, time after time, decade after decade, individual after individual ... and thats just my own history. When I compare notes I see it as systemic due to the widespread observation that this is happening to many of us. Did you know that a very large number of doctors told me I would be better in six months? They kept telling me that for several decades. How about decades of misdiagnoses? How about claims about treatment that were unfounded and dangerous? I could write a book on it just from my own case history. When I enquire about other case histories, I see the same pattern again and again. This is NOT a claim about conspiracies. Its totally different. This is a claim there is a severe misunderstanding and that many people, including professionals and authority figures, reply to any difficult situation with a dogmatic answers regardless of whether they know the answer or not, and frequenty its just a hope they got it right. Its the same issue that lets people believe in the hypothetical disease hysteria. "We don't know what is wrong, but maybe its hysteria, a hypothetical disease" is not what they say. Rather than acknowledging the unknown, saying "I don't know" these authority figures try to present the image that they know. Thats deception. Its a lie. Its one thing for a professional or government official to say "I don't know." Its another for them to say "clearly its X, Y or Z" when they do not have a clue. In the last couple of years I have caught several doctors speaking from ignorance, expounding things that are factually and provably false and I don't see doctors very often. This is not conspiracy. Its not suspicion. Its numerous instances of things I know about factually. Again, what they say is not posed as a question or hypothesis - its posed from a claimed position of truth. In other words, its a lie. Conflating systemic spin, falsehood and untruths with conspiracies just confuses the issue. It has nothing to do with oppression. Its an analysis of events. I do not like to try to analyze motivations behind the events as there is no way to be sure why its happening. Thats where conspiracy theories begin - might be rather than the facts. It is another thing entirely to analyze the facts and look at consequences, and another thing again to talk about how people perceive and describe those events. When a doctor says "I do not know' or " I am not qualified to deal with that" I respect those answers. When they say "its clearly this" when its contradicted by the facts, they lose my trust. As for cults, many articles and books have been written about Freud as a cult leader (I am reading one now) and the same pattern can be seen in modern psychobabble. I have seen, and agree, that there is some tendency toward group think in some patient groups. Its a problem. It is nothing like a cult however, at most its a nascent cult that can't quite organize, but I don't think it ever will, there are too many factors against it. What does happen though is that many who think alike get together on specific websites and expound their views. This is a consequence of the internet, and not specific to ME or CFS. It applies equally well to "sceptics" websites. If you were to argue, instead, that some individuals show excessive enthusiasm without critical analysis, I would agree. What community ? There are contributors to this thread who are already being attacked by our 'fellow patients' on other forums, merely for holding views that are 'unacceptable'. IVI Click to expand... Are there? I've not looked at other forums. I think one of the nice things about phoenix rising is that there is a good level of scientific discussion. I find the thought that people would go through posts and object to them on a different forum really strange. But then the world is strange. I do think its useful to add comments that describe the science that people like Max are clearly unaware of. Maybe they might read it and ask the people who are briefing them. Pemberton's "scribblings" I note have attracted over 132 responses at this point in time - of the kind one would expect to see, and in the good old press tradition just counter-claims put as strongly as his own views but with science and experience. | Mid | [
0.5944700460829491,
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|
Resolving Form-Structure-Function Relationships in Plants with MRI for Biomimetic Transfer. In many biomimetic approaches, a deep understanding of the form-structure-function relationships in living and functionally intact organisms, which act as biological role models, is essential. This knowledge is a prerequisite for the identification of parameters that are relevant for the desired technical transfer of working principles. Hence, non-invasive and non-destructive techniques for static (3D) and dynamic (4D) high-resolution plant imaging and analysis on multiple hierarchical levels become increasingly important. In this study we demonstrate that magnetic resonance imaging (MRI) can be used to resolve the plants inner tissue structuring and functioning on the example of four plant concept generators with sizes larger than 5 mm used in current biomimetic research projects: Dragon tree (Dracaena reflexa var. angustifolia), Venus flytrap (Dionaea muscipula), Sugar pine (Pinus lambertiana) and Chinese witch hazel (Hamamelis mollis). Two different MRI sequences were applied for high-resolution 3D imaging of the differing material composition (amount, distribution, and density of various tissues) and condition (hydrated, desiccated, and mechanically stressed) of the four model organisms. Main aim is to better understand their biomechanics, development, and kinematics. The results are used as inspiration for developing novel design and fabrication concepts for bio-inspired technical fiber-reinforced branchings and smart biomimetic actuators. | High | [
0.6862996158770801,
33.5,
15.3125
]
|
Q: How to remove an array element using a specific value Suppose I have an array structured like this: { q1: true, q2: false, q3: false, q4: true, q5:true } Is there a way to remove all the elements that has "false" for a value in AngularJS? I tried using splice() by getting the index number, with no luck. Now I'm looking for a way where I don't have to use a specific index number. Any help would be appreciated. Thank you. A: Simple JavaScript approach var r = {
q1: true,
q2: false,
q3: false,
q4: true,
q5: true
};
for (a in r) {
if (!r[a]) {
delete r[a]
}
}
console.log(r); | Mid | [
0.562841530054644,
25.75,
20
]
|
Mariana Berumen Mariana Berumen Reynoso (born October 30, 1991) is a Mexican model and beauty pageant titleholder who won the title of "Nuestra Belleza Mundo México" at the Nuestra Belleza México 2011 pageant. Born in Jalostotitlán Jalisco and moved to León, Guanajuato from an early age, Reynoso was chosen to represent her country in the 62nd Miss World pageant in 2012 during the 2011 edition of Nuestra Belleza México, held August 20, 2011 in Puerto Vallarta, Jalisco. The pageant was won by Aguascalientes's Karina González. Berumen was crowned Nuestra Belleza Mundo México by the outgoing titleholder Gabriela Palacio. References Category:1991 births Category:Living people Category:Top Model finalists Category:Nuestra Belleza México winners Category:Miss World 2012 delegates Category:Models from Guanajuato Category:People from León, Guanajuato | Mid | [
0.651948051948051,
31.375,
16.75
]
|
package org.enso.interpreter.instrument.execution import java.io.File import java.util.UUID /** * Provides locking capabilities for the runtime server. */ trait Locking { /** * Removes a lock for an execution context. * * @param contextId the context id */ def removeContextLock(contextId: UUID): Unit /** * Removes a lock for a file that contains enso code. * * @param file the file to lock */ def removeFileLock(file: File): Unit /** * Acquires a compilation write lock. */ def acquireWriteCompilationLock(): Unit /** * Releases a compilation write lock. */ def releaseWriteCompilationLock(): Unit /** * Acquires a compilation read lock. */ def acquireReadCompilationLock(): Unit /** * Releases a compilation read lock. */ def releaseReadCompilationLock(): Unit /** * Acquires a context lock. * * @param contextId a context to lock */ def acquireContextLock(contextId: UUID): Unit /** * Releases a context lock. * * @param contextId a context to unlock */ def releaseContextLock(contextId: UUID): Unit /** * Acquires a file lock. * * @param file a file to lock */ def acquireFileLock(file: File): Unit /** * Releases a file lock. * * @param file a file to unlock */ def releaseFileLock(file: File): Unit } | Mid | [
0.649651972157772,
35,
18.875
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/* * Copyright (c) 2010-2020 Evolveum and contributors * * This work is dual-licensed under the Apache License 2.0 * and European Union Public License. See LICENSE file for details. */ package com.evolveum.midpoint.rest.impl; import java.io.InputStream; import org.springframework.http.MediaType; import com.evolveum.midpoint.common.LocalizationService; import com.evolveum.midpoint.prism.PrismContext; import com.evolveum.midpoint.prism.PrismParser; import com.evolveum.midpoint.prism.PrismSerializer; public class MidpointYamlHttpMessageConverter extends MidpointAbstractHttpMessageConverter<Object> { public static final MediaType[] MEDIA_TYPES = { MediaType.valueOf("application/yaml"), MediaType.valueOf("text/yaml"), MediaType.valueOf("application/yml"), MediaType.valueOf("text/yml"), MediaType.valueOf("application/*+yaml"), MediaType.valueOf("text/*+yaml"), MediaType.valueOf("application/*.yaml"), MediaType.valueOf("text/*.yaml") }; protected MidpointYamlHttpMessageConverter( PrismContext prismContext, LocalizationService localizationService) { super(prismContext, localizationService, MEDIA_TYPES); } @Override protected PrismSerializer<String> getSerializer() { return prismContext.yamlSerializer(); } @Override protected PrismParser getParser(InputStream entityStream) { return prismContext.parserFor(entityStream).yaml(); } } | Low | [
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By: Blake Murphy Raptors 905 announce 2018-19 coaching staff We knew a few of the names already, but Raptors 905 unveiled their full coaching staff under new head coach Jama Mahlalela for the 2018-19 season on Wednesday. Here is a quick rundown of the names. HEAD COACH Jama Mahlalela will move from the front row of the Toronto Raptors bench to the lead chair with Raptors 905, something I covered more in depth here and here. If you’ve ever watched Open Gym, Giants of Africa, or even just media availability with Mahlalela, you’ll already have an idea of how positive and energetic the UBC product is. As a Swazi-Canadian and former USports player with ample experience in and around the Toronto and Canadian basketball community, he sets the tone for a staff that goes heavy on the Canadian content. RETURNING ASSISTANTS A.J. Diggs and Ryan Schmidt are back for their second respective seasons with the team. Diggs spent four years playing NCAA ball at UC-Berekely before having a brief run in the G League and then returning to Loyola Marymount for his MBA. After working as a coach and in the recreation field in California, Diggs helped found Elite Skills Academy, and he also served as the director of basketball operations for Athlete’s Performance. He joined the organization as an assistant under former head coach Jerry Stackhouse last season, coming over from the Austin Spurs (and Maine before that) where he’d assisted alongside current Raptors assistant Patrick Mutombo. Schmidt brings a little more of the Hawaii connection that pops up in the Raptors’ organization from time to time, as he played there in college before transferring to Western Oregon for his senior season. Like Diggs, Schmidt had a brief G League stint and also spent time in the ABA before transitioning to coaching. Last year, he landed with the 905 after a few seasons coaching at the high school and academy level in Oregon. Trevor Pridie (in white polo) during UFV huddle. NEW ASSISTANTS Mahlalela is bringing in four new names to the 905 bench in Charles Kissi, Charles Dube-Brais, Trevor Pridie, and Arsalan Jamil. We covered most of what you need to know about Kissi when we broke the news he’d be taking a leave from Brock University to join Mahlalela’s staff, and the Toronto native’s resume speaks for itself at the Canadian collegiate level. He also spent time as a mentor coach under Dwane Casey (more on mentor coaching shortly). Dube-Brais is a little tougher to find information on in English, as his most recent or notable experiences came in China, France, and Quebec and he went to school at Laval. He has an interesting profile, with 16 years of coaching experience from the high school level on upward. He was a guest coach with the San Antonio Spurs at Summer League in 2015, 2016, and 2017 and was a guest coach under Mahlalela and Nick Nurse with the Raptors this past summer, spending time as the head coach of a French Pro A U-21 team in between those earlier stints. Last year, he was the head coach of Chongson KungFu where he won ABL Coach of the Year. Abbotsford local – Trevor Pridie is a name I’m actually familiar with from Twitter, as he’s an insightful member of the online Canadian basketball community who has shared some of his knowledge with YouTube play breakdowns in the past. Most recently, he was an assistant coach at the University of Fraser Valley while also serving as a head coach and program director at BC basketball club. Before getting into coaching, he was a former Athlete of the Year at his Surrey high school and played at Kwantlen Polytechnic University (in the BCCAA). | High | [
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Become the owner of this obituary to manage the guestbook, edit the notice, and more. David Harris Sr. David Harris, Sr. was born August 17, 1932 in Thomas County Georgia, in the area of Boston also known as "Ninety Five". He was the second child of eight children born to the late Emma (Monroe) Harris and the late Ernest Harris, Sr. Most people in the community who knew him well called him "Dave" or "Uncle Dave". He was well known for his steel trapped, sharp mind and a very mild mannered personality. He was also known for his unique wittiness, colloquialism, and teachable moments during his conversations and interactions with others. Dave accepted Christ at an early age, and was baptized at Bethlehem Christian Methodist Episcopal Church, which was renamed Bethlehem-Midway Christian Methodist Episcopal Church. He was a very dedicated member for over 70 years serving as treasurer, class leader, laymen, President of the senior choir, Chairman of the Steward Board, Class leader, Sunday school teacher, and Sunday School Superintendent. On the district level, he served as a lay leader. On the conference level, he served as lay leader, delegate to the CME annual and general conference. He always demonstrated a compassion for the sick and shut-in, and visited them often. He was an active member of Tried Stone Lodge No. 1, Fraternal Order of Masons, where he served as Worshipful Master for several years. Furthermore, the Order of the Eastern Star, where he served as Patron for several years. Dave graduated from Douglas High School in 1949. Afterwards, he entered Meharry Medical College to pursue his dream of becoming a medical doctor. However, due a family crisis, he left college and enlisted the United States Army. He served diligently in the Korean War. He was honorable discharged from the Army. He went on to attend the prestigious FAMU Barber College. After graduating and working in the field of barbering, he met cosmetologist Atalene Farrah Holton. While working as a barber, he attended carpentry school in Thomasville. He served as a bus driver for the Grady County School System. As a contractor, "Dave" built and repaired many houses and churches throughout the South Georgia, North Florida, New Jersey, and New York areas. In later years, he was known for his successful hobby of metal recycling. On December 25, 1957, Dave married Atalene Farrah Holton. She preceded him in death on August 31, 1980. To that union were born six children. They resided in the community of Beachton, Georgia. He later married Elizabeth Willis of Cairo (divorced). Dave, was one is not gone... who touched the lives of others in such a warm and caring way. One is not lost... he was a person that knew no strangers, who got along with the lives of people all around with freely given friendship. One is not forgotten...who found the way to others hearts and mapped a route to love. On the early afternoon of October 1, 2018, the Angels of Silence came into Archbold Memorial Hospital and sealed the lips of our loving brother, father, uncle and friend. Funeral services for David Harris Sr will be Saturday, October 6, 2018 at 11 a.m. at Clifford Temple CME church. The Rev. Charles Jackson will be doing the words of comfort. Public viewing will be today from 12pm until 6pm and the wake service from 6pm until 8 pm in chapel of Hopkins Mortuary. | Mid | [
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look for the answer your.. tracks Rausch - My Planet Regarded as fine enough to supply the royal court, the cafe was the perfect spot for Tim and I to escape the cold and snow for a bit and have a little birthday dessert! Visitors tend to be lured into the ground floor shop and miss the second floor cafe and chocolate restaurant. We hopped in the elevator and headed straight upstairs to the cafe to indulge our sweet tooth. The menu boasts no less than 10 kinds of hot chocolate, some like hot chocolate with chili or orange essence. Tim chose a whole milk hot chocolate with espresso, amaretto, and cream. While Tim read over the almost poetic menu, deliciously describing the hot chocolate and cakes, the 16 types of cakes at the counter caught my eye. I picked out a little pink striped chocolate cake topped with a cherry. Our cakes were practically art: cherry with yogurt and an almond mouse wrapped in cherry chocolate for Rausch - My Planet and tiramisu wrapped in dark chocolate and topped with grated dark chocolate for Tim. Chocolate heaven on a little plate! Tummies full of chocolately goodness, we checked out the ground floor chocolate shop. In production sinceindividual plantations in exotic locations like Trinidad, Ecuador, Peru, Costa Rica, Venezuela, Madagascar, and Papua New Guinea are engaged in ecologically sound cocoa production Baby Dont Get Hooked On Me - Various - Believe In Music maintain the standard of quality outlined in the Rausch cacao manual. We bought a sampler box from the plantations around the world Madagascar was my favorite! We found the chocolates to be reasonably priced and Merzouga - Mekong Morning Glory make a great gift! Loved this post? We love when you share our content! Jennifer Dombrowski is an independent travel publisher and an American expat who has lived in Bordeaux, France since She previously lived in Northern Italy in a small village near Venice for seven years where she fell in love with wine and wine tourism. She is an award-winning travel writer. Blew it last week! You must go on your next trip, Brett! The chocolate was really delicious and we were surprised at how inexpensive it was for such high quality chocolate. Very true Jennifer. I was there last week and in my 6 days in Berlin I visited the store three times. Just could not resist their chocolate. Brought back enough with me to last a while lol. That chocolate A is too cool! Rausch - My Planet pics, Jennifer. My chocaholic husband is going to love it!! He will love it, Jenny! So delicious and so reasonably priced too. Mmm…now I am craving some of the Madagascar chocolate. Almost…but as soon as Rausch - My Planet plunged my fork into the chocolate, it was a delicious chocolate party happening in my mouth. Looks and sounds and I imagine tastes incredible. That Brandenburg Gate is Te Quiero Dijiste - Nat King Cole - Deluxe In Nat King Cole. I wonder if first class tastes better. The detail of the chocolate creations is just amazing. And we loved the plane too. What a find — and something for me to bookmark for a trip to Berlin which will happen one day soon. It was a great find thanks to talking with the locals. Definitely visit when you go to Berlin! OMG this looks amazing! I loved the chocolate place we went to in Brussels last summer, so this is definitely on my list for Rausch - My Planet now. Just wonder if your chocolates are suitable for lacto-ovo vegetarians meaning can consume eggs and milk products? Loved the chocolate so much. Was introduced by our friend who had been in Berlin for 14 years. Definitely the best chocolate you could find with such affordable price. Will visit Berlin again for sure. Your email address will not be published. Notify me of follow-up comments by email. Notify me of new posts by email. This site uses Akismet to reduce spam. Learn how your comment data is processed. Which would you choose? Chocolate Brandenburg Gate. Faberge egg. Chocolate volcano. Chocolate A Rausch - My Planet Tweet Buffer Pin Flipboard. My Planet is a virtual simulation game where you take control of a planet and try to grow a healthy and thriving population! It is like a virtual pet on a planetary level. Play God by manipulating the sunlight and the rain in order to grow as large a population as possible. My Planet runs in /5(K). Rausch: My children coming into this world and watching them grow. And then the grandchildren following them. My husband and I speak of the memories constantly all the time. Their current happenings and the kids’ events. GS: I’m sure you feel time . Hear what kids and educators think about field experiences at the planetarium! The Gheens Science Hall and Rauch Planetarium field experiences are designed to address the Next Generation Science Standards as well as state-level core curriculum science standards. Students are immersed in easy-to-comprehend visual information that is enhanced with live demonstrations and discussions led by. May your Gentle soul and all the souls of the faithful departed through the mercy God rest in Perfect peace. Will for ever Miss you my smiling soldier. You have left a legacy that will never be erased on this planet earth. My condolence to your family, your son and all your loved ones. I pray to God for strength for your family as they mourn you. | Mid | [
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The recent suicides of former UCLA basketball players Tyler Honeycutt and Billy Knight have prompted Bruins radio broadcaster Josh Lewin to launch a website to help people suffering from anxiety and depression. The site okaytogether.com, set to launch Thursday morning, is intended to provide a forum for people to realize they’re not alone in their struggles. The site will include advice from experts, pathways to organizations that can help and links to about 90 stories from athletes and entertainers detailing their issues and ways in which they’ve combated their problems. Those who go onto the site can also share their own stories. “The thought [is] that my God, if Kevin Love doesn’t see this as a stigma and is so open about it,” Lewin said Wednesday, referring to the NBA All-Star forward and former Bruins standout who has openly acknowledged experiencing mental health issues, “maybe it’s not so embarrassing to admit that this is something that I deal with too.” Lewin hopes to dovetail his project with UCLA’s Grand Challenges initiative, which is conducting a comprehensive depression study of 100,000 people to help better understand the disease and formulate more effective treatment methods. The broadcaster said he is scheduled to meet with school officials later this month to see how their endeavors might benefit each other. Lewin said he has felt the urge to help those suffering from mental health issues since the suicides several years ago of former San Diego Chargers players Junior Seau and Paul Oliver. “Those hit me very, very hard,” said Lewin, a former broadcaster for the Chargers. The deaths of Honeycutt and Knight, who authorities said killed themselves last month, nudged Lewin into action. He spent several weeks building his site in hopes that it could help others from feeling alone in their struggles. “The first step, to me, is coming to peace with the fact that you’re playing the game,” Lewin said. “You don’t really choose it, it chooses you and what I’ve told people is, if you’ve ever sat down to play a video game and you realize that your console control wasn’t hooked up, you’re mashing the A button and the B button and your character just isn’t moving, it’s frozen, and the monsters are coming at you, that’s a horrible feeling and my guess, the more that I kind of peel the layers back, is that that’s where a lot of people are. They just kind of feel like they don’t even have that ability to figure out the first step or what the hell this is that they’re dealing with. “The website isn’t how to beat the game, it’s just simply about how to at least get your console working so that you can begin the process of avoiding the monsters. It’s Step 1, just realize that you’re part of a community that’s welcoming.” | High | [
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Q: Swift 2 MKMapViewDelegate rendererForOverlay compiler warning I am trying to draw a polyline on a map in Swift 2. It all works well, but I get a compiler warning for this code: func mapView(mapView: MKMapView!, rendererForOverlay overlay: MKOverlay!) -> MKOverlayRenderer! { if overlay is MKPolyline { let polylineRenderer = MKPolylineRenderer(overlay: overlay) polylineRenderer.strokeColor = UIColor.redColor() polylineRenderer.lineWidth = 5 return polylineRenderer } return nil } This will give me a warning says that 'Result and parameters in mapView (rendererForOverlay) have different optionality than expected by protocol MKMapViewDelegate' Now, this will compile fine, but it bugs me that the compiler warning is showing. If I change the first line to func mapView(mapView: MKMapView, rendererForOverlay overlay: MKOverlay) -> MKOverlayRenderer { by removing the !, the warning will go away but I get an error that the return cannot be nil and the code will not compile anymore. This is also a follow up to this thread where the same problem was stated but no satisfying answer is available: Swift 2 MKMapViewDelegate rendererForOverlay optionality Can anyone shed any light on the correct way to use this function now in Swift 2? Thanks. A: Going by what autocomplete suggests the prototype looks like this: func mapView(mapView: MKMapView, rendererForOverlay overlay: MKOverlay) -> MKOverlayRenderer And apparently there's nothing you can do about it, except for returning return MKPolylineRenderer() where normally you would return nil. To me it looks like an implementation bug, because here's what the documentation says about the returned object: The renderer to use when presenting the specified overlay on the map. If you return nil, no content is drawn for the specified overlay object. I suggest you create a case for it in Apple's bug report A: Don't return nil. This is only called for overlays you create, so instead of checking if overlay is MKPolyline, check which of your overlays it is. If you have only one, return the specified polyline renderer without checking which one it is. | Low | [
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Methadone and caries. Case reports. Several cases of advanced tooth destruction from widespread severe carious lesions are presented where methadone syrup has been used intra-orally in a drug rehabilitation programme. Aetiological factors are discussed and suggestions made concerning treatment plans and social implications for these patients. | Mid | [
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Now that it's been almost a month since my January PLAY! unboxing, I wanted to update you on how all the products turned out. Youth to the People Kale + Spinach + Hyaluronic Acid Age Prevention Cream This was hands-down my favorite product in the January box. I went through this sample so fast that I bought the full size ($48) so I could continue to use it. Youth to the People's moisturizer has replaced my beloved Lush Enyzmion moisturizer. CLINIQUE Almost Lipstick in Black Honey Clinque's lipstick ($17) was another favorite this month. Black Honey is definitely not as dark as it looks in the tube, but I love this color. I'll add in a selfie below so you can see how the color looks on me. Ouai Treatment Masque I haven't actually used this product once since I got it, but I have used it before so I already know that I love it. The scent of this treatment masque ($32) is to die for and it makes your hair incredibly soft. I love to put this in my hair for about an hour before showering and it really hydrates my dry ends. tarte FRXXXTION Stick Exfoliating Cleanser I like this exfoliating stick ($22), but I'm not in love with it. I think it's a great product for a quick exfoliation, but I couldn't see it replacing my other exfoliators or face masks. Tory Burch Love Relentlessly I'm very picky when it comes to perfumes and Tory Burch's new fragrance ($86, 1.7 oz) didn't make the cut for me. I do like the floral notes, but I just don't think that this perfume mixes very well with my body chemistry. I'll stick to Marc Jacobs' Daisy Dream ($80, 1.7 oz) AmorePacific Color Control Cushion Compact Broad Spectrum SPF 50+ I'm also super picky about foundations, and honestly, this one ($60) sucked. I felt so greasy all day. My oily skin does not work with these cushion foundations, so I won't be using this one ever again. Another thing was that the shade selection was small and neither of these shades matched my skin, and I don't think any of the other three shades would have either. Are you subscribed to PLAY! by Sephora? If so, what products did you love and hate in your January and February boxes? Let me know in the comments!Bisous,Halle René It's time to dive into another PLAY! by Sephora unboxing! February's theme was "The Soft Side," very fitting for the month of love, I think. This month was all about showing natural beauty, so let's jump into the products that can help you look radiant this month. CLINIQUE Pep-Start HydroBlur Moisturizer First up this month was the CLINIQUE Pep-Start HydroBlur Moisturizer ($29.50). I love the CLINIQUE Pep-Start Eye Cream ($26.50), so I'm excited to try another product from the Pep-Start line. This moisturizer/primer claims to instantly blur imperfections while providing all-day hydration. It can also be applied over your makeup for quick fixes throughout the day. I'll probably be trying this as a primer since I'm too obsessed with my Youth to the People moisturizer right now to let that one go. Too Face Lip Injection Glossy in Milkshake This sheer tinted gloss claims to visibly plump lips instantly while also acting as a sort of lip balm and softening your lips all the time. I've heard that Too Faced's Lip Injection Glossy ($22) can tingle on the lips but isn't as strong as the Lip Injection Extreme. It recommends trying it every day for 30 days to see an improvement of the softness of your lips, so I guess that's what I will do starting today. I will report back. tarte Rainforest of the Sea Quench Lip Rescue in Nude The next thing in the box was another lip product. The tarte Rainforest of the Sea Quench Lip Rescue ($19) is a sheer lip balm with that hydrates and nurtures lips with a soft natural tint. Some of its ingredients include algae and marine flower extract, coconut oil, and vitamin E. It's vegan-friendly which is pretty cool as well. We'll see if this lip balm can give my beloved Glossier Balm dotcom ($12) a run for its money. SEPHORA COLLECTION LashCraft Length & Volume Mascara I love that Sephora decided to include a product from its own collection in this month's box. I'm always wanting to try their products but I'm never sure which ones are worth my precious dollars. SEPHORA COLLECTION's nylon-infused mascara ($12) seems to be right up my alley, though, with both lengthening and volumizing effects. Maybe I've just found my new go-to mascara. Prada CANDY I'll start by saying that I probably won't like this perfume. It's warm and spicy fragrance comes from notes of caramel, vanilla, benzion, and white musk. I haven't smelled it yet, but I'm sure Prada CANDY ($90, 1.7 oz) really does smell like candy. Origins GinZing Refreshing Eye Cream I've actually tried this product before and I can tell you that I like it. Origins GinZing Refreshing Eye Cream ($30) is infused with coffee beans, ginseng root, and magnolia extract to calm redness, fight aging, and energize your eyes. All things that I definitely need being a very tired college student. What are you guys excited to try in this month's box? Let me know in the comments!Bisous,Halle René | Low | [
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Q: Rails: selecting columns from multiple tables I am new to Rails. I have three tables a, b, c b has 2 columns: b1 and b2 c has 2 columns: c1 and c2 a has 3 columns: a1, b1 (foreign key) and c1 (foreign key) I want to get the distinct (b2, c2) pairs by giving a value for a1 I tried something like a.find(:all, :joins => [:b, :c], :select => "b2, c2", :conditions => {:a => {:a1 => Time.now.midnight. ... Time.now}}, :group => "b2, c2") The SQL that this produces works fine and I am able to see the results. But I think since I am doing a a.find, I am not able to retrieve b2, c2 from the result set. How can I modify this so that I can get b2 and c2? A: If you modify your :select clause to read: foo = a.find(:all, :joins => [:b, :c], :select => "distinct b.b2 as b2_value, c.c2 as c2_value", :conditions => {:a => {:a1 => Time.now.midnight. ... Time.now}}, :group => "b.b2, c.c2") I believe you will retrieve an array of records. Then try the following: b2_value = foo.first["b2_value"] That should retrieve the value you are looking for. Also, note that in the query I specified the table name with the columns wherever I used them -- I think it's better practice and will also avoid bad queries when you have duplicate column names (for example, created_at or id). | Mid | [
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z - 73 = 4*l, -z - w*l + 270 = 2*z. Is z composite? True Suppose 77 = 5*a - 103. Suppose 5*t - 411 = 2*w, t - 129 = -5*w - a. Is t composite? False Let l = 2 + 1. Is (-146)/(-4) - l/(-6) a prime number? True Suppose 0 = -4*q + 4*d + 40, -4*q + 5*d - 100 = -9*q. Let b = 6 + q. Suppose -3*l - 3*o = -0*l - b, 0 = 3*l - 5*o - 45. Is l prime? False Let a = 15 + -14. Is (-2 + a)/((-6)/1830) a prime number? False Suppose -t + 4*w = -1754, -4*t = -w - w - 7016. Is t prime? False Let j be 771 + (-3 - -7)*1. Suppose -8*n = -j - 241. Is n a composite number? False Let i(t) = t + 151. Let v be i(0). Let o be v/(-2) + (-3)/6. Let l = -29 - o. Is l prime? True Let l be -154 - 2/(2/1). Let i = 152 - l. Is i a composite number? False Suppose 0 = 2*z - 4*z. Suppose -3*a + 100 + 113 = z. Is a a prime number? True Suppose 3*t - 8*b = -4*b + 1433, -b = 5. Is t composite? True Let i be (-2)/11 - (-1060)/22. Suppose -r = -3*w + 5*w - 99, r + i = w. Is w a composite number? True Let b(p) = p**2 + 5*p - 13. Let d(g) be the third derivative of 13*g**6/120 + g**5/60 + 3*g**2. Let z be d(-1). Is b(z) composite? False Suppose -2*x + 172 = 4*o + x, o - 54 = 2*x. Let i = 5 + o. Is i prime? False Let j(v) be the third derivative of -19*v**4/24 - 3*v**2. Let g be 1/4 - (-15)/(-12). Is j(g) a composite number? False Suppose -4*x = y + 9, -2*y + 2*x + x = -15. Suppose 3*a = 0, -5*j - y*a = -56 - 14. Is j prime? False Let x(y) = 4*y - 1. Let v(h) = h**2 + 6 + 4*h - 4*h. Let i be v(0). Is x(i) composite? False Let y(k) = -k**2 + 6*k. Let f be y(6). Let a = -33 - -52. Let u = a - f. Is u a composite number? False Is 2998/4 - (-3)/2 a prime number? True Let z = 270 - -209. Is z prime? True Let x = 1 + -1. Suppose x = 3*y + 6 - 84. Is y a prime number? False Is (-3)/6 + 375/10 a composite number? False Let b be (-3)/((-12)/(-4)) + 1. Suppose -2*l + 6*l - 140 = b. Is l a prime number? False Let k = -160 + 81. Let i = -2 - k. Let w = 111 - i. Is w composite? True Let g(w) = -3*w**3 - 8*w**2 - 5*w + 7. Suppose -4*l = 10 + 18. Is g(l) composite? True Suppose -2*h = 3*h + 2*x - 1861, -5*h - 3*x = -1859. Is h prime? True Suppose -46 + 11 = 5*y - 5*n, -y + 5*n = 23. Let d = y - -5. Is d/9 - 1803/(-27) a prime number? True Let d(r) = r**3 - 4*r**2 + 4*r. Let p be d(3). Let g be (-5)/2*(-8)/10. Suppose 5*k - g*o - 66 = o, -p*k = -2*o - 39. Is k a prime number? False Let t be (24/20)/(6/20). Suppose 0 = -t*i - 15 + 39. Suppose i*f = 3*f + 177. Is f prime? True Let w(m) = -m - 10. Let p be w(-8). Is 93/p*2/(-3) composite? False Let h(q) = 12*q - 8. Let z be h(6). Suppose -68 - z = -4*x. Is x a prime number? False Let h = 862 - 559. Suppose 2*q - 3*q = 176. Let l = h + q. Is l a composite number? False Suppose -b + 5*b = 16. Suppose -3*r = -1 + b. Is 2 - -92 - (r + 1) a composite number? True Suppose -37 = -a + 4*b, -2*b = 2*a - 35 - 59. Suppose -a = -3*t - 0*t. Is t prime? False Let s = 10 + -8. Suppose -5*b + 361 = -3*i - 46, s*b - 3*i - 161 = 0. Is b a composite number? True Suppose -3320 - 2276 = -4*d. Is d prime? True Let s(k) = 3*k**2 + 13*k + 11. Let u be s(-8). Is u + -5 - (1 - 4) composite? False Let s(p) be the first derivative of 4*p + 6*p**3 + 5*p - 8*p - 1. Is s(-1) a composite number? False Let q(j) = 2*j**3 + 5*j**2 + j - 3. Is q(4) composite? True Let v(f) = -f**3 - 6*f**2 + 2*f + 8. Let d be v(-6). Let p = d + 3. Let w(s) = -162*s - 1. Is w(p) a prime number? False Suppose 2*t - 7*t = 3*d - 4006, -5*t - d + 4012 = 0. Is t a prime number? False Let f(r) be the second derivative of -r**5/20 - r**4/4 + r**3/2 + 3*r**2/2 + 8*r. Let l = -9 - -4. Is f(l) composite? True Is (-86544)/(-27) - (-1)/(-3) composite? True Let s be (-20)/(-2) + (5 - 3). Suppose 2*h + 4*b - 12 = 0, -4*h - 4*b + 4 = -s. Suppose h*w = -4*r + 50, -3*r + 24 = 2*w - 31. Is w a composite number? True Suppose 4*s - 2*s = 1112. Let z be (-2)/3 + s/6. Suppose k + 22 - z = p, 2*k - 125 = -3*p. Is k prime? True Let z be 2/6 + (-2)/(-3). Suppose -3*o - z = u - 81, -3*u = o - 32. Is o a composite number? True Let r(u) = 258*u**2 + u. Let i be 21/(-9) + 4/3. Is r(i) composite? False Is (-22)/((2/5)/(65/(-25))) a prime number? False Let i be 3/9*0 - 70. Let c = i + 98. Suppose 0*q - 4*q + c = 0. Is q a prime number? True Let y = 1790 + -1159. Is y a composite number? False Let a = 4 - 4. Suppose 195 = -5*g - a*g. Let t = g + 188. Is t prime? True Let m = 149 - 94. Is m a prime number? False Let r(s) = -s**3 + 5*s**2 + s - 4. Let w be r(4). Let t = w - 9. Suppose -t*y = -2*y - 325. Is y composite? True Suppose 6*q = 4*q + 370. Is q a prime number? False Suppose -5*k - 186 = -x, -3*k - 778 = -2*x - 2*x. Suppose j = -3*j + x. Is j a prime number? False Let i(k) = -k**2 - 5*k - 6. Let o be i(-8). Let l = 16 + o. Let h = l - -33. Is h a prime number? True Let k(z) = z**2 + 3*z + 8. Let t be k(9). Is t/8 + 1/(-2) a prime number? False Let d = 0 + 3. Suppose r - 2*r = 3*b - 158, d*r - 5*b - 488 = 0. Is r prime? False Let s(a) = 4*a**3 - 3*a**2 + 2*a + 2. Is s(3) prime? True Let z(c) = c**3 - 8*c**2 - 7*c - 11. Let b be z(9). Suppose -1 = -r + b. Suppose r*t = 3*t + 445. Is t composite? False Is (-2 - 434/(-6))/((-1)/(-15)) a composite number? True Let y(z) = -132*z + z**2 - 17 + 0*z**2 + 137*z. Is y(-12) prime? True Let z(o) = 18*o - 29. Is z(20) a prime number? True Let c(u) = -u**3 - 5*u - 16. Is c(-7) a composite number? True Suppose 0 = 3*j - 2*j - 1253. Is j a prime number? False Let d be -5 + 5 - -2*27. Let k = d + -29. Is k a prime number? False Let x(s) = s**3 + 8*s**2 + 7*s + 5. Let z be x(-7). Is 0/1 - (-80 - z) a prime number? False Suppose -5*y + y + 5*i - 122 = 0, -3*y = 2*i + 80. Is 14 - y - 3/1 a composite number? True Suppose -4 = -n + 2. Let o = -6 + n. Suppose 4*k - 196 = -o*k. Is k prime? False Let l = -60 + 91. Is l composite? False Let l = 292 + -81. Is l prime? True Suppose k + 17 = b - 507, -3*b + 4*k = -1575. Is b prime? True Is (10/(-6) + 2)/((-3)/(-29439)) a prime number? True Let f = -4 + 9. Suppose 0 = -f*a - 4*t + 1853, -3*t - 1116 = -3*a - 4*t. Is a prime? True Suppose -2*u - 2*u + 304 = 0. Is (1/(-2))/((-2)/u) prime? True Suppose -4*f + 638 = 2*r, 0*r - r - 4*f + 317 = 0. Is r a composite number? True Let q(o) = 835*o**3. Is q(1) composite? True Let o(z) = z**2 + z + 287. Suppose 3*f + 6 = 3, 0 = -4*d - 4*f - 4. Is o(d) composite? True Suppose 108 = 3*b + 21. Let j = 42 - b. Is j a composite number? False Suppose 15*u - 3 = 14*u. Suppose 0*n - 165 = -u*n. Is n composite? True Suppose 0*q + 70 = 2*q. Let f = q + 2. Is f a prime number? True Suppose 326 = 3*u - u. Is u composite? False Suppose 4*a - m = -3*m + 30, 3*a + m - 21 = 0. Is (a/12)/(2/484) a composite number? True Let x(s) = -273*s - 4. Is x(-1) prime? True Let j = -4 - -9. Let t(x) be the second derivative of -x**5/20 + 7*x**4/12 + 5*x**2/2 + 3*x. Is t(j) prime? False Let x(h) = -13*h - 4. Suppose 5*j - 2*v + 25 = 0, v - 1 = 4. Is x(j) composite? True Let n = 12 - 7. Suppose -w + 4*w + u - 34 = 0, -n*u = -4*w + 77. Is w prime? True Let x = -3 - -5. Suppose -15 = x*q - 517. Is q prime? True Let g(s) be the third derivative of -s**6/120 - s**5/20 + s**4/6 - 5*s**3/6 - s**2. Let f be g(-4). Is 1/f + (-532)/(-10) a composite number? False Let s = 17 - 14. Suppose -4*q - 3*p = -61, q + 3*p + 53 = s*q. Is q composite? False Suppose -2010 = -3*v + 4*l + 2359, -2*l = 8. Is v/9 - 8/36 a composite number? True Let d be ((-2)/(-4))/((-1)/(-6)). Suppose -57 = -b + d. Suppose 62 + 34 = 4*k - 5*x, 4*k + 4*x - b = 0. Is k prime? True Let d be (-4)/18 + 778/18. Let y = 125 - d. Let o = -5 + y. Is o prime? False Let f be 2 - -14 - (2 + -2). Is 20/f*2*6 a composite number? True Let m be (-18)/24*(-3 + -1). Suppose -m*w + 11 + 10 = 0. Suppose -3*p + w*f = 2*f - 67, -3*f - 6 = 0. Is p a composite number? False Let x be 6/(-9)*(-30)/(-2). Is x/(-25) - (-53)/5 a prime number? True Let d be (-10 + 3)*(-4)/14. Suppose 2*c + d*c - 676 = 0. Suppose 19 + c = 4*g. Is g a prime number? True Let v = 19 - 13. Suppose 3*l = -3*j + 42, l - 2*j + 79 = v*l. Is 2 + (l - -2 - 2) composite? False Suppose 0 = 2*t - 2 + 10. Let j be (-3)/(3*2)*t. Suppose j*m = -m + 66. Is m a composite number? True Let t = -1204 - -2091. Is t a prime number? True Let f(j) = -498*j**3 + 1. Le | Low | [
0.49441340782122906,
22.125,
22.625
]
|
--- abstract: 'Normalization layers are widely used in deep neural networks to stabilize training. In this paper, we consider the training of convolutional neural networks with gradient descent on a single training example. This optimization problem arises in recent approaches for solving inverse problems such as the deep image prior or the deep decoder. We show that for this setup, channel normalization, which centers and normalizes each channel individually, avoids vanishing gradients, whereas without normalization, gradients vanish which prevents efficient optimization. This effect prevails in deep single-channel linear convolutional networks, and we show that without channel normalization, gradient descent takes at least exponentially many steps to come close to an optimum. Contrary, with channel normalization, the gradients remain bounded, thus avoiding exploding gradients.' author: - Zhenwei Dai and Reinhard Heckel bibliography: - './reference.bib' date: May 2019 title: Channel Normalization in Convolutional Neural Network avoids Vanishing Gradients --- [****]{} -------------------------------------------------------------------------------------------------------- $^\ast$Dept. of Electrical and Computer Engineering and Dept. of Statistics$^\dagger$, Rice University $^\star$Dept. of Electrical and Computer Engineering, Technical University of Munich -------------------------------------------------------------------------------------------------------- Introduction ============ Deep learning and in particular convolutional neural networks have significantly improved the state-of-the-art in computer vision, image generation, and computational imaging, among many other fields. Deep neural networks are typically trained using first order methods such as gradient descent and the stochastic gradient method. However, the corresponding loss function is non-convex and therefore, depending on the initialization, convergence to an optimum is not guaranteed, and first order methods sometimes suffer from unstable training and/or vanishing or exploding gradients. Normalization layers are widely used to avoid vanishing or exploding gradients, stabilize training, and enable learning with higher rates and faster convergence. The perhaps most popular normalization technique is batch normalization [@ioffe2015batch]; but a number of (often closely related) variations and alternatives have been proposed such as layer normalization [@lei2016layer], weight normalization [@salimans2016weight], and instance normalization [@ulyanov2016instance]. A variety of recent works have proposed different explanations for the success of normalization layers. The original batch normalization paper [@ioffe2015batch] suggested that batch normalization aids optimization by reducing a quantity called internal covariate shift. In contrast, Santurkar et al. [@santurkar2018does] reason that batch normalization reparameterizes the underlying optimization problem and thereby make its landscape significantly smoother. Kohler et al. [@kohler_jonas2018] linked batch normalization to weight normalization [@salimans2016weight], and pointed out that batch normalization accelerates the training process by splitting the optimization task into optimizing the length and direction of the parameters separately, and Bjorck [@bjorck2018understanding] argues that (batch) normalization enables training with larger training rates. We add that whether normalization layers are useful or not depends strongly on the architecture and initialization. For example carefully initialized deep residual networks can be trained without any normalization layers [@zhang2019fixup]. In this paper, we study channel normalization, which is a special case of a number of the above mentioned normalization techniques, in the context of a convolutional generator network. Channel normalization standardizes each channel in a convolutional neural network, individually for each training example, and scales and shifts the resulting vector with a (trainable) scalar. Channel normalization is equivalent to instance normalization [@ulyanov2016instance] and to batch normalization for a single training example (then the batch size is one). We first train a convolutional network with gradient descent on a single training example, a problem that occurs in solving inverse problems without training data [@heckel2018deep; @ulyanov2018deep], and demonstrate that channel normalization avoids exploding and vanishing gradients and enables reaching a close-to-optimal point. Contrary, without channel normalization, gradient descent does not converge to an optimum in a reasonable number of iterations. We then show analytically, for a special case of linear convolutional networks, that without channel normalization, gradient descent requires at least exponentially many steps to converge under mild initialization conditions. The aforementioned works [@ioffe2015batch; @santurkar2018does; @kohler_jonas2018] have studied normalization techniques by focusing on shallow networks (i.e., networks with one hidden layer), since analytical gradient expressions for deep networks with non-linearities are almost intractable. Here, we sidestep this hurdle by exploring a simpler model, specifically a linear convolutional network with a single channel. Studying such a simple model is justified by observing that even for this simple model, normalization is critical for fast convergence. Channel normalization {#sec:channelnorm} ===================== at (-2.5,1.1) [ ]{}; +\[mark=none\] table\[x index=1,y index=2\][./conv\_gen\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=2\][./conv\_gen\_no\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./conv\_gen\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=4\][./conv\_gen\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=5\][./conv\_gen\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=6\][./conv\_gen\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=7\][./conv\_gen\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./conv\_gen\_no\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=4\][./conv\_gen\_no\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=5\][./conv\_gen\_no\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=6\][./conv\_gen\_no\_norm.dat]{}; +\[mark=none\] table\[x index=1,y index=7\][./conv\_gen\_no\_norm.dat]{}; We start by introducing channel normalization and then show empirically that it is critical for running gradient descent efficiently on a convolutional generators trained on a single example. The channel normalization operation normalizes each channel of a convolutional network individually. Let $\vz_{ij}$ be the input of the $j$-th channel and the $i$-th layer. Channel normalization performs the transformation $$\vz'_{ij} = \frac{ \vz_{ij} - {\mathrm{mean}}(\vz_{ij}) }{ \sqrt{ {\mathrm{var}}(\vz_{ij}) +\epsilon}}\gamma_{ij} + \beta_{ij},$$ where ${\mathrm{mean}}$ and ${\mathrm{var}}$ compute the empirical mean and variance, $\gamma_{i,j}$ and $\beta_{ij}$ are parameters learned independently for each channel, and $\epsilon$ is a fixed small constant added for numerical stability. We consider a variant of the deep decoder introduced in [@heckel2018deep]. The network works well for image compression and for regularizing a variety of inverse problems, when trained or fitted to a single image only. Specifically, we consider an extremely simple convolutional generator consisting of $d=5$ many 3x3 convolutional layers, followed by channel normalization and ReLU activation functions. Each layer has $k=32$ channels, and the last layer is a 1x1 convolutional layer mapping the $k$ channels to a single, 256x256 grayscale output image. The input to the network is a 32x256x256 volume that is chosen randomly and is fixed (i.e., we do not optimize over the input). Given an image $\vx^\ast$ we then fit the parameters of the network (i.e., the weights) by minimizing the loss $ {L}({\mC}) = {\ensuremath{{\left\|{G}({\mC}) - {\vx}^\ast \right\|}_{2}}}^2 $ with respect to the network parameters ${\mC}$ using plain gradient descent with fixed stepsize. Figure \[fig:phantormMRI\] shows the results for the phantom MRI image for a network with and without channel normalization. With channel normalization, the training loss converges rapidly and the gradients do not vanish. Contrary, without normalization, the network does not converge to a small error (even though the network has the capacity to represent the image), and the gradients vanish. This effect is not specific to the image (we have reproduced it using 100 randomly chosen images from imagenet), and it is also reproducible for a number of related convolutional generators, for example networks including upsampling operations. Isolating the effect of channel normalization {#sec:isolating} ============================================= We next show that to achieve the stabilizing effect of channel normalization, the trainable coefficients $\gamma_{ij}$ and $\beta_{ij}$ do not need to be learned and can be set to one and zero, respectively. We also demonstrate that even for linear networks, channel normalization is critical to avoid vanishing gradients. This justifies our theoretical study of linear networks in the next section. +\[mark=none\] table\[x index=1,y index=2\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=2\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=2\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=4\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=5\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=6\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=7\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=8\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=9\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=10\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=11\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=12\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=13\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=14\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=15\][./data/BN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=4\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=5\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=6\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=7\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=8\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=9\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=10\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=11\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=12\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=13\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=14\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=15\][./data/NL\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=4\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=5\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=6\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=7\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=8\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=9\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=10\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=11\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=12\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=13\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=14\][./data/LN\_grad\_mse.dat]{}; +\[mark=none\] table\[x index=1,y index=15\][./data/LN\_grad\_mse.dat]{}; **Multiple Channels CNN:** We first consider a one-dimensional convolutional network, again only consisting of convolutional layers followed by channel normalization and ReLU activation functions. We set the dimension of input/output vector to $n=256$, the number of channels to $k=4$, number of hidden layers to $d=12$, and convolutional kernel size to $3$. The entries of the input vector $\vx$ are sampled from a standard uniform distribution. As before, we minimize the least squares loss with respect to the weight parameters using gradient descent with fixed step size. We consider three different normalization operations: the original channel normalization, a variant where $\gamma_{ij}=1$ and $\beta_{ij}=0$ (called fixed norm), and no normalization. We consider the problem of fitting a simple step function. The results reported in Figure \[fig2\] show that both normalization versions enable efficient optimization with gradient descent (the training error is near-zero), whereas without channel normalization the training error does not improve after a few iterations and the gradients vanish. **Single Channel Linear CNN:** Next, we consider an even simpler network with only one channel and without activation functions. Without normalization, the network is linear. We set the dimension of input/output vector to $n=64$, number of hidden layers $d=10$, and convolution kernel size $k=9$. The results are very similar to the previous experiment in Figure \[fig2\] (see Figure \[fig3\] in the appendix), and demonstrates the critical role of channel normalization. We also evaluated the loss function landscape around the point at convergence (Figure \[fig:dist\_landscape\]). For both multi-channel CNNs and linear CNNs, without normalization, the loss function becomes very flat, in comparison to the more steep loss surface pertaining to the case with channel normalization. This indicates that the gradients around the point of convergence are close to $0$, and gradient descent makes little to no progress if the iterates fall into such flat regions. 3 \[surf,shader=faceted\] table [./data/Multi\_channel\_CNN\_Norm\_Landscape.dat]{}; 3 \[surf,shader=faceted\] table [./data/Multi\_channel\_CNN\_Linear\_Landscape.dat]{}; 3 \[surf,shader=faceted\] table [./data/Linear\_CNN\_Norm\_Landscape.dat]{}; 3 \[surf,shader=faceted\] table [./data/Linear\_CNN\_Linear\_Landscape.dat]{}; Theoretical analysis {#sec:theory} ====================== From the previous section, we know that channel normalization avoids vanishing gradients even for linear, one-layer convolutional neural networks, and that the scale and shift parameters can be set to one and zero. In this section, we provide theoretical justification for the difficulty of optimization in the absence of normalization, and justification for the stabilizing effect of channel normalization. Throughout this section, we consider a single channel linear convolutional neural network with $d$ layers, with output given as $f(\vx,\vw) = \prod_{i=1}^{d} \mW_i \vx$, where $\mW_i \in \reals^{n \times n}$ are circulant matrices implementing the convolution operation, and $\vw = (\vw_1,\vw_2,\ldots,\vw_d)$ is the set of weights or convolutional filters, given by the first columns of the respective circulant matrices $\mW_i,\ldots,\mW_{d}$ (which define all other entries of the matrices). We study gradient descent applied to the squared loss function $ {L}(\vw,\vx,\vy) = \frac{1}{2} {\ensuremath{{\left\|\vy - f(\vx,\vw) \right\|}_{2}}}^2 $. We start by showing that without channel normalization gradient descent needs at least exponentially many steps to converge under a standard initialization scheme. \[thm:expmanysteps\] Suppose that the signal $\vy$ doesn’t vanish, i.e., ${\ensuremath{{\left\|\vy\right\|}_{{}}}} / {\ensuremath{{\left\|\vx\right\|}_{{}}}} \geq d n^{d/2} \tau$, where $\tau$ is a constant. Moreover, suppose that $\vy$ is in the range of the generator $f$ and that the initial weights are Gaussian random variables with zero mean and covariance matrix $1/np$ ($p$ is the kernel size of $i$-th convolution layer). Then gradient descent with constant stepsize $\eta \leq \exp(cd)$ runs at least for $\exp(\Omega(d))$ steps until it reaches a point that is $c'$ close to optimal with probability larger than $1 - \exp(-\Omega(d))$. Here, $c$ and $c'$ are constants independent of $d$. The proof, deferred to the appendix, relies on diagonalizing the circulant matrices $\mW_i$ using the Fourier transform. Then, the optimization problem reduces to $n$ one-dimensional problems, and we can build on results by Shamir [@shamir2018exponential] on the hardness of optimizing one-dimensional deep neural networks. We also notice that when the kernel size of convolution layer $p$ is smaller than $n$, gradient descent is only applied to the first $p$ entries of $\vw_i$ and other entries are always fixed to $0$. In this case, the gradient descent on the first $p$ entries of $\vw_i$ is equivalent to the projected gradient descent on all entries of $\vw_i$ while projecting the last $(n-p)$ entries to $0$ during each iteration. Theorem \[thm:expmanysteps\] shows that the number of steps to come close to the optimum is at least exponential in the network depth $d$, even when the stepsize is large (exponential in $d$). This can be interpreted as a case of gradient vanishing. Also note that if we initialize the weight away from $0$ with another initialization scheme, e.g., $\vw_k$ is initialized following Gaussian distribution with covariance matrix $\mI$ , then the norms of the gradients increase exponentially fast with the network depth, and the network becomes difficult to optimize due to exploding gradients. Next, we evaluate the effect of channel normalization on the gradients. Since our experiments have shown that fixing scale and shift parameters or learning them yields comparable performance, we focus on the case where they are fixed to $\gamma_{ij}=1$ and $\beta_{ij}=0$. Suppose that the input $\vx$ has zero mean. Then the gradients pertaining to the loss function with normalized loss are (see Appendix \[sec:normlossgrad\]): $$\begin{aligned} \nabla_{\vw_k} L_N(\mW,\vx,\vy) = \transp{\mX}_k \frac{w_{d+1}}{{\ensuremath{{\left\| \mX_k \vw_k \right\|}_{{}}}}} \left( \mI - \mX_k \vw_k \transp{\vw}_k \transp{\mX}_k / {\ensuremath{{\left\|\mX_k \vw_k \right\|}_{{}}}}^2 \right) \vy, \quad \mX_k = \prod_{i\neq k} \mW_i \mX,\end{aligned}$$ where $\mX$ is the circulant matrix with first column $\vx$, and $w_{d+1}$ is a scale parameter that we optimize over and necessary so that the range of the network can exhaust $\reals^n$. By this expression, the gradients are obtained by projecting $\vy$ onto the orthogonal complement of the estimate at the $k$-th iteration, $\mX_k \vw_k$, followed by multiplication with $\transp{\mX}_k/{\ensuremath{{\left\|\mX_k \vw_k\right\|}_{{}}}}$. In contrast, the norm of the un-normalized gradients is given by $\nabla_{\vw_k} L(\mW,\vx,\vy) = \transp{\mX}_k (\vy - \mX_k \vw_k)$. In Figure \[fig:dist\_gradnorms\] Panel (a) and (b) we plot the distribution with and without normalization at initialization for a network with $n=100$ and $d=6$ layers. Note that the loss typically diverges at the first few iterations, which justifies considering the gradients at initialization. The results show that the normalization leads to the gradients to be significantly better behaved, i.e., the distribution does have a significantly smaller tail. In Figure \[fig:dist\_gradnorms\] Panel (c) and (d) we plot the distribution for a multi-channel CNN with ReLU activation functions, and likewise, the results shows that without channel normalization, the tail is significantly larger. Thus, without normalization for a given stepsize the network is much more susceptible to vanishing or exploding gradients. +\[ycomb,DarkBlue!65,mark=none\] table\[x index=0,y index=1\][./data/hist\_nonorm.data]{}; +\[ycomb,DarkBlue!65,mark=none\] table\[x index=0,y index=1\][./data/hist\_norm.data]{}; +\[ycomb,DarkBlue!65,mark=none\] table\[x index=0,y index=1\][./data/hist\_CNN\_linear\_b200.data]{}; +\[ycomb,DarkBlue!65,mark=none\] table\[x index=0,y index=1\][./data/hist\_CNN\_norm\_b200.data]{}; Code {#code .unnumbered} ==== Code to reproduce the experiments is available at [github.com/reinhardh/normalization\_dnns](https://github.com/reinhardh/normalization_dnns). Acknowledgements {#acknowledgements .unnumbered} ================ RH and ZD are partially supported by NSF award IIS-1816986. Appendix {#appendix .unnumbered} ======== Convergence for linear single layer convolutional networks ========================================================== +\[mark=none\] table\[x index=1,y index=2\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=4\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=5\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=6\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=7\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=8\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=9\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=10\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=11\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=12\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=13\][./data/BN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=2\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=4\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=5\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=6\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=7\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=8\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=9\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=10\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=11\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=12\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=13\][./data/NL\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=2\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=4\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=5\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=6\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=7\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=8\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=9\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=10\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=11\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=12\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=13\][./data/LN\_grad\_mse2.dat]{}; +\[mark=none\] table\[x index=1,y index=2\][./data/BN\_fitted2.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./data/BN\_fitted2.dat]{}; +\[mark=none\] table\[x index=1,y index=2\][./data/NL\_fitted2.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./data/NL\_fitted2.dat]{}; +\[mark=none\] table\[x index=1,y index=2\][./data/LN\_fitted2.dat]{}; +\[mark=none\] table\[x index=1,y index=3\][./data/LN\_fitted2.dat]{}; Proof of Theorem \[thm:expmanysteps\] ===================================== Our proof relies on diagonalizing the circulant matrices implementing the convolutions with the Fourier transform. Linear single channel CNNs in the Fourier domain ------------------------------------------------ Since the matrices $\mW_i$ are circulant, they can be diagonalized with the Fourier transformation. As a consequence, the loss function of a linear CNN becomes a sum of loss functions of one dimensional single channel deep linear neural networks. With $\mW_i = \mF{\mathrm{diag}}(\sqrt{n}\mF^{H}\vw_i) \mF^{H}$, where $\mF$ is the unitary $n \times n$ discrete Fourier transform matrix and $\vw_i$ is the first column of $\mW_i$, the network’s output without normalization can be expressed as $$\begin{aligned} f(\vx,\mW) = \prod_{i=1}^{d}\mW_i \vx = \prod_{i=1}^{d}\mF{\mathrm{diag}}(\sqrt{n}\mF^{H}\vw_i)\mF^H \vx = n^{d/2} \mF\left(\prod_{i=1}^{d} {\mathrm{diag}}(\mF^{H}\vw_i)\right)\mF^H \vx.\end{aligned}$$ With this expression, the loss function becomes $$\begin{aligned} L(\mW,\vx,\vy) = \frac{1}{2}{\ensuremath{{\left\|\vy-f(\vx,\mW)\right\|}_{{}}}}^2 &= \frac{1}{2} {\ensuremath{{\left\|\vy - n^{d/2} \mF \left(\prod_{i=1}^{d} {\mathrm{diag}}(\mF^{H}\vw_i)\right)\mF^H \vx\right\|}_{{}}}}^2 \\ &= \frac{1}{2} {\ensuremath{{\left\|\mF^H \vy - n^{d/2} \left(\prod_{i=1}^{d} {\mathrm{diag}}(\mF^{H}\vw_i)\right)\mF^H \vx\right\|}_{{}}}}^2 \nonumber \\ &= \frac{1}{2} \sum_{j=1}^{n} \abs{\vf_j^H \vy - n^{d/2} \left(\prod_{i=1}^{d} \vf_j^{H}\vw_i \right)\vf_j^H \vx}^2,\nonumber \end{aligned}$$ where $\vf_j$ is the $j$-th column of the Fourier matrix $\mF$. Proof of Theorem \[thm:expmanysteps\] ------------------------------------- In this section, we show that gradient descent takes exponentially many steps to converge under Xavier initialization, a standard initialization scheme. The proof follows a similar line of arguments as a very related result by Shamir [@shamir2018exponential] on the hardness of optimizing one-dimensional deep neural networks. Assume the kernel size of the $i$-th convolution layer is $p \geq 1$. Thus, $\vw_i \in \mathbb{S}_p$, where $\mathbb{S}_p = \{\vz=(z_1, z_2,\ldots,z_n)| z_1,\ldots,z_{p} \in \mathbb{R}, z_{p+1},\ldots,z_n =0 \}$. We further denote $\vw \in \mathbb{S}_{p \times d}$, where $\mathbb{S}_{p \times d} = \{\vu = (\vu_1, \vu_2, \ldots, \vu_d)| \vu_1, \vu_2, \ldots, \vu_d \in \mathbb{S}_p \}$. \[ass:xavier\] Assume $\vw_1, \vw_2, \ldots, \vw_d$ are drawn independently and the first $p$ entries of $\vw_i$ are drawn i.i.d from a distribution that satisfies $$\begin{aligned} &\PR{ {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \leq t } \leq c_1 t \quad \text{and} \\ &\EX{ {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} }\leq \frac{1}{\sqrt{n}} (1 - c_2),\end{aligned}$$ where the constants $c_1, c_2 >0$ are independent of $d$. The assumption holds for some widely used initialization distributions, like the distribution $\mc N(0, \frac{1}{np})$ in the statement of the theorem, which follows from $\EX{{\ensuremath{{\left\|\vw_i\right\|}_{{}}}}} \leq (1-c_2)/\sqrt{n}$ with $c_2 = 1 - \sqrt{\frac{2}{p}}\frac{\Gamma((p+1)/2)}{\Gamma(p/2)}>0$ (since $\EX{{\ensuremath{{\left\|\vw_i\right\|}_{{}}}}} = \sqrt{\frac{2}{np}}\frac{\Gamma((p+1)/2)}{\Gamma(p/2)}$). Next, we show that with the initialization satisfying Assumption \[ass:xavier\], gradient descent takes at least exponentially many gradient descent iterations to reach a close-to-optimal point with high probability. The key idea of the proof of Theorem \[thm:expmanysteps\] is to show that if we start from such a random initialization $\vw= (\vw_1,\vw_2,\ldots, \vw_d)$, then gradient descent must take exponentially many steps to escape a ball of radius $r$ around $\vw$, defined as $$\mc B(\vw,r) = \left\{\vv = (\vv_1,\vv_2,\ldots, \vv_d) \Big| \sum_{i=1}^{d}{\ensuremath{{\left\|\vv_i - \vw_i\right\|}_{{}}}}^2 \leq r^2 \right\}.$$ We then show that the loss function value evaluated at any point inside the ball is sub-optimal, i.e., for $\vv \in \mc B(\vw,r)$, $L(\vv) \geq c'$, where $c'$ is a constant. This will establish the proof. To show that there exist a radius $r>0$ such that gradient descent takes at least exponentially many steps to escape the ball $\mc B(\vw,r)$. We notice that for any $\vv \in \mathbb{S}_{p \times d}$, running gradient descent on the non-zero entries of $\vv_k$ is equivalent to performing projected gradient descent on $\vv_k$ while constraining $\vv_k \in \mathbb{S}_p$. Hence, after each iteration, $\vv_k$ is updated by $\Pi_{\mathbb{S}_p}(\vv_k - \eta \nabla_{\vv_k}L(\vv))$, where $\eta$ is the stepsize and $\Pi$ is the orthogonal projection operator. Moreover, since $\mathbb{S}_{p}$ is a closed and convex set, the distance between $\vv^{(t)}_k$ and $\vv^{(t+1)}_k$ after $t$-th iteration can be upper bounded by $$\begin{aligned} {\ensuremath{{\left\|\vv^{(t+1)}_k - \vv^{(t)}_k\right\|}_{{}}}} = {\ensuremath{{\left\|\Pi_{\mathbb{S}_p}(\vv^{(t)}_k - \eta \nabla_{\vv_k} L(\vv^{(t)})) - \vv^{(t)}_k\right\|}_{{}}}} &=& {\ensuremath{{\left\|\Pi_{\mathbb{S}_p}(\vv^{(t)}_k - \eta \nabla_{\vv_k} L(\vv^{(t)})) - \Pi_{\mathbb{S}_p}(\vv^{(t)}_k)\right\|}_{{}}}} \nonumber \\ &\leq& \eta {\ensuremath{{\left\|\nabla_{\vv_k}L(\vv^{(t)})\right\|}_{{}}}}. \nonumber\end{aligned}$$ Accordingly, $\vv^{(t)}$ is updated at most $\eta {\ensuremath{{\left\|\nabla L(\vv^{(t)})\right\|}_{{}}}}$ after $t$-th iteration. Therefore, the number of iterations required to escape a ball of radius $r$ is at least $r /(\eta \sup_{ \vv \in \mc B(\vw,r) } {\ensuremath{{\left\|\nabla L(\vv)\right\|}_{{}}}})$, since at each step, gradient descent can at most move by $\eta \sup_{ \vv \in \mc B(\vw,r)} {\ensuremath{{\left\|\nabla L(\vv)\right\|}_{{}}}}$. The following lemma provides an upper bound on ${\ensuremath{{\left\|\nabla L(\vv)\right\|}_{{}}}}$, which enables us to show that the number of iterations must be large. \[lem:grad\] Suppose that the initial point $\vw$ satisfies, for some $\alpha,\delta >0$, i) $\max_k \left(\prod_{i \neq k} {\ensuremath{{\left\|\vw_i\right\|}_{{}}}}\right) \leq \alpha$ and ii) $\min_i {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \geq \delta$. Then, there exists a radius $r$ such that for all $\vv \in \mc B(\vw,r)$, it holds that $\prod_{i=1}^{d} {\ensuremath{{\left\|\vv_i\right\|}_{{}}}} \leq \alpha \exp\left(\frac{\sqrt{d}r}{\delta}\right) \max_k {\ensuremath{{\left\|\vv_k\right\|}_{{}}}}$ and $\displaystyle {\ensuremath{{\left\|\nabla L(\vv)\right\|}_{{}}}} \leq {\ensuremath{{\left\|D(\vv)\right\|}_{{}}}} {\ensuremath{{\left\|\vx\right\|}_{{}}}}\alpha \sqrt{d} \exp\left(\frac{\sqrt{d}}{\delta}r\right)$, where $L(\vv) = \frac{1}{2}{\ensuremath{{\left\|D(\vv)\right\|}_{{}}}}^2$ and $D(\vv) = \mF^H\vy-n^{d/2}\prod_{i=1}^{d}{\mathrm{diag}}(\mF^H\vv_i)\mF^H\vx$. Lemma \[lem:grad\] guarantees that in a ball $\mc B(\vw,r)$ around the initialization, the gradients of the loss function are strictly upper bounded. So, provided the stepsize is not too large, the progress made in each step of gradient descent is also upper bounded. Then, we show with high probability, that there is a radius $r$ that is much larger than the updates in each step. Evoking Lemma \[lem:grad\], given a constant stepsize $\eta$, the number of steps required to escape the ball $\mc B(\vw,r)$ is at least $\frac{r}{\Omega(\eta n^{d/2} \alpha \sqrt{d} \exp(\frac{\sqrt{d}}{\delta}r))}$ if ${\ensuremath{{\left\|D(\vv)\right\|}_{{}}}} {\ensuremath{{\left\|\vx\right\|}_{{}}}}$ is upper bounded by a numerical constant. Next, we show that conditions i and ii from Lemma \[lem:grad\] hold with high probability for $\alpha = \frac{\exp(-2cd)}{n^{d/2}}$ and $\delta = \exp(-cd)$ given Assumption \[ass:xavier\]. We then show that there is a radius $r$ in which ${\ensuremath{{\left\|D(\vv)\right\|}_{{}}}}$ is upper bounded and gradient descent takes at least exponentially many steps to escape the ball $\mc B(\vw,r)$. We start by showing that conditions i and ii from Lemma \[lem:grad\] hold with high probability for $\alpha = \frac{\exp(-2cd)}{n^{d/2}}$ and $\delta = \exp(-cd)$. \[lem:condi-iii\] Suppose $\vw$ is initialized satisfying Assumption \[ass:xavier\]. With probability at least $1 - \Omega(d e^{-cd})$, the conditions $$\text{i) $\max_k \prod_{i \neq k}{\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \leq \frac{\exp(-2cd)}{n^{d/2}}$, ii) $\min_i {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \geq \exp(-cd)$, and iii) $\max_i {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \leq \exp(cd)$ }$$ hold simultaneously, where $c$ is a constant independent of $d$. With Markov’s inequality and Assumption \[ass:xavier\], we have, for $t>0$, that $$\begin{aligned} \PR{ \prod_{i \neq k}{\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \geq t } &\leq \frac{\prod_{i \neq k} \EX{ {\ensuremath{{\left\|\vw_i\right\|}_{{}}}}}}{t} \leq \frac{((1-c_2)/\sqrt{n})^{d-1}}{t}.\end{aligned}$$ Let $c$ be a constant so that $\exp(-4c) = 1-c_2$ and set $t = \frac{\exp(-2cd)}{n^{d/2}}$. Then we obtain $$\begin{aligned} \PR{ \prod_{i \neq k}{\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \geq \frac{\exp(-2cd)}{n^{d/2}} } \leq \frac{\sqrt{n}\exp(-4c(d-1))}{\exp(-2cd)} = \Omega(\exp(-2cd)). \end{aligned}$$ Thus, by the union bound, $\max_k \prod_{i\neq k} {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \leq \frac{\exp(-2cd)}{n^{d/2}}$ with probability at least $1- \Omega(d\exp(-2cd))$. We next consider $\min_i {\ensuremath{{\left\|\vw_i\right\|}_{{}}}}$. Again by Assumption \[ass:xavier\], it holds for all $i$ that $\PR{{\ensuremath{{\left\|\vw_i\right\|}_{{}}}}\leq \exp(-cd)} \leq \Omega(\exp(-cd))$. Then, by the union bound, $$\begin{aligned} \PR{\min_i {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \leq \exp(-cd)} \leq \sum_{i=1}^{d} \PR{ {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \leq \exp(-cd) } \leq \Omega(d\exp(-cd)).\end{aligned}$$ Finally, by the union bound, Markov’s inequality, and Assumption \[ass:xavier\], we have that $$\begin{aligned} \PR{ \max_i {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \geq \exp(cd) } \leq \sum_{i=1}^{d} \PR{{\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \geq \exp(cd)} \leq \Omega(d\exp(-cd)).\end{aligned}$$ Thus, by a union bound, with probability at least $$1-\Omega(\exp(-2cd)) - \Omega(d\exp(-cd)) - \Omega(d\exp(-cd)) = 1-\Omega(d\exp(-cd)),$$ the conditions i-iii are satisfied simultaneously, which concludes the proof. Next, we show that under conditions i-iii in Lemma \[lem:condi-iii\], provided that $d$ is large enough, ${\ensuremath{{\left\|D(\vv)\right\|}_{{}}}}$ is upper bounded by a constant independent of $d$ for radius $r = \Omega(\frac{\delta}{\sqrt{d}}) = \Omega(\frac{\exp(-cd)}{\sqrt{d}})$. Evoking Lemma \[lem:grad\], we have $$\begin{aligned} \prod_{i=1}^{d} {\ensuremath{{\left\|\vv_i\right\|}_{{}}}} &\leq \alpha\exp\left(\frac{\sqrt{d}r}{\delta}\right) \max_k {\ensuremath{{\left\|\vv_k\right\|}_{{}}}} \\ &\leq \frac{\exp(-2cd)}{n^{d/2}} \Omega(\exp(cd)) \max_k {\ensuremath{{\left\|\vv_k\right\|}_{{}}}} \\ &\leq \frac{\Omega(1)}{n^{d/2}},\end{aligned}$$ where the second inequality follows from our choice of $\alpha$ and $\exp(\frac{\sqrt{d}r}{\delta}) = \Omega(1)$ by our choice of $\delta$, and the third inequality follows from $\max_k {\ensuremath{{\left\|\vv_k\right\|}_{{}}}} \leq \max_k {\ensuremath{{\left\|\vw_k\right\|}_{{}}}} + r = \Omega(\exp(cd))$. Then, we can upper bound ${\ensuremath{{\left\|D(\vv)\right\|}_{{}}}}$ when $d$ is large, $$\begin{aligned} {\ensuremath{{\left\|D(\vv)\right\|}_{{}}}} &=& {\ensuremath{{\left\|\mF^H\vy-n^{d/2}\prod_{i=1}^{d}{\mathrm{diag}}(\mF^H\vv_i)\mF^H\vx\right\|}_{{}}}} \leq \sum_{j=1}^{n} \left(\abs{\vf^H_j \vy} + n^{d/2} \prod_{i=1}^{d} \abs{\vf^H_j\vv_i} \abs{\vf^H_j\vx} \right) \nonumber \\ &\leq& n \left({\ensuremath{{\left\|\vy\right\|}_{{}}}} + n^{d/2} \prod_{i=1}^{d} {\ensuremath{{\left\|\vv_i\right\|}_{{}}}} {\ensuremath{{\left\|\vx\right\|}_{{}}}} \right) \leq n \left({\ensuremath{{\left\|\vy\right\|}_{{}}}} + n^{d/2} {\ensuremath{{\left\|\vx\right\|}_{{}}}} \right). \nonumber \end{aligned}$$ Therefore, ${\ensuremath{{\left\|D(\vv)\right\|}_{{}}}}$ is upper bounded by a constant (given $\vy$ is constant, and $\vx$ satisfies the assumption in theorem \[thm:expmanysteps\] independent of $d$. Finally, we can prove that gradient descent takes at least exponentially many steps to escape $\mc B(\vw,r)$ with $r = \Omega(\frac{\exp(-cd)}{\sqrt{d}})$. By lemma \[lem:condi-iii\], with conditions i-iii satisfied, the number of steps in $\mc B(\vw,r)$ is at least $\frac{r}{{\ensuremath{{\left\|D(\vv)\right\|}_{{}}}} {\ensuremath{{\left\|\vx\right\|}_{{}}}} \Omega(\eta n^{d/2} \alpha \sqrt{d} \exp(\frac{\sqrt{d}}{\delta}r))}$. Since ${\ensuremath{{\left\|D(\vv)\right\|}_{{}}}}$ can be upper bounded by a constant, and using that ${\ensuremath{{\left\|\vx\right\|}_{{}}}}$ is upper bounded by a constant (from ${\ensuremath{{\left\|\vx\right\|}_{{}}}} < {\ensuremath{{\left\|\vy\right\|}_{{}}}}$, with ${\ensuremath{{\left\|\vy\right\|}_{{}}}}$ upper bounded by a constant) and $\eta \leq \exp(\frac{d}{2})$ (by the assumptions in theorem \[thm:expmanysteps\]), $\frac{r}{{\ensuremath{{\left\|D(\vv)\right\|}_{{}}}} {\ensuremath{{\left\|\vx\right\|}_{{}}}} \Omega(\eta n^{d/2} \alpha \sqrt{d} \exp(\frac{\sqrt{d}}{\delta}r))} \geq \frac{r}{\Omega(\exp(-\frac{3}{2}cd + \frac{\sqrt{d}}{\delta}r))} = \Omega(\exp(\frac{1}{2}cd))$, which increases exponentially in $d$. It remains to prove that for any $\vv \in \mc B(\vw,r)$ (with $r$ as chosen above), the loss function $L(\vv)$ is lower bounded away from the global minimum. We have proved that when $d$ is large, $\prod_{i=1}^{d} \abs{\vf^H_j \vv_i} \leq \prod_{i=1}^{d} {\ensuremath{{\left\|\vv_i\right\|}_{{}}}} \leq \Omega(1)$. From the assumption ${\ensuremath{{\left\|\vy\right\|}_{{}}}} - {\ensuremath{{\left\|\vx\right\|}_{{}}}} dn^{d/2} \geq \tau$, there exists $t \in [n]$ such that $\abs{\vf^H_t \vy} - n^{d/2} \abs{\vf^H_t \vx} \geq \tau$. So, we have $$\begin{aligned} \abs{\vf^H_t \vy - n^{d/2} \prod_{i=1}^{d} \left(\vf^H_t \vv_i\right) \vf^H_t \vx} &\geq \abs{\vf^H_t \vy} - \abs{n^{d/2} \prod_{i=1}^{d} \left(\vf^H_t \vv_i\right) \vf^H_t \vx} \nonumber \\ &\geq \abs{\vf^H_t \vy} - n^{d/2} \prod_{i=1}^{d} \abs{\vf^H_t \vv_i} \abs{\vf^H_t \vx} \nonumber \\ &\geq \abs{\vf^H_t \vy} - n^{d/2} \abs{\vf^H_t \vx} > \tau. \nonumber \end{aligned}$$ Thus, for $\vv \in \mc B(\vw,r)$, the loss function obeys $L(\vv) = \sum_{j=1}^{n} \abs{\vf^H_j \vy - n^{d/2} \prod_{i=1}^{d} \left(\vf^H_j \vv_i\right) \vf^H_j \vx} > \tau$ and is thus lower bounded away from zero-training error. Proof of Lemma \[lem:grad\] --------------------------- Let $\vv \in \mc B(\vw,r)$ as defined previously. We have $$\begin{aligned} {\ensuremath{{\left\|\nabla L(\vv)\right\|}_{{}}}}^2 &= \sum_{k=1}^{d} {\ensuremath{{\left\|\nabla_{\vv_k} L(\vv)\right\|}_{{}}}}^2 = \sum_{k=1}^{d} n^d {\ensuremath{{\left\|D(\vv)\right\|}_{{}}}}^2 \left(\prod_{i \neq k}{\ensuremath{{\left\|\vv_i\right\|}_{{}}}}\right)^2 {\ensuremath{{\left\|\vx\right\|}_{{}}}}^2 \nonumber \\ &\leq \sum_{k=1}^{d} n^d {\ensuremath{{\left\|D(\vv)\right\|}_{{}}}}^2 \left( \max_k \prod_{i \neq k}{\ensuremath{{\left\|\vv_i\right\|}_{{}}}}\right)^2 {\ensuremath{{\left\|\vx\right\|}_{{}}}}^2. \label{eq:adf}\end{aligned}$$ Here, we used that $${\ensuremath{{\left\| \nabla_{\vv_k} L(\vv) \right\|}_{{}}}} = {\ensuremath{{\left\| n^{d/2} {\ensuremath{{\left\|D(\vv)\right\|}_{{}}}} \diag(\herm{\mF} \vx_i ) \prod_{i\neq k} \diag(\herm{\mF} \vv_i ) \right\|}_{{}}}} \leq n^{d/2} {\ensuremath{{\left\|D(\vv)\right\|}_{{}}}} {\ensuremath{{\left\|\vx\right\|}_{{}}}} \prod_{i\neq k} {\ensuremath{{\left\|\vv_i\right\|}_{{}}}}.$$ The lemma now follows from $\max_k \left(\prod_{i \neq k}{\ensuremath{{\left\|\vv_i\right\|}_{{}}}}\right) \leq \left(\alpha \sqrt{d} \right) \exp\left(\frac{\sqrt{d}}{\delta}r\right)$. Define $\vr_i = \vv_i- \vw_i$, for notational convenience, and note that $\sum_{i=1}^{d} {\ensuremath{{\left\|\vr_i\right\|}_{{}}}}^2 \leq r^2$ since $\vv \in \mc B(\vw,r)$. Then, we have $$\begin{aligned} \prod_{i \neq k} {\ensuremath{{\left\|\vv_i\right\|}_{{}}}} &= \prod_{i \neq k} {\ensuremath{{\left\|\vw_i + \vr_i\right\|}_{{}}}} \nonumber \\ &\leq \left(\prod_{i \neq k} {\ensuremath{{\left\|\vw_i\right\|}_{{}}}}\right)\left[\prod_{i \neq k}\left(1 + \frac{{\ensuremath{{\left\|\vr_i\right\|}_{{}}}}}{{\ensuremath{{\left\|\vw_i\right\|}_{{}}}}} \right)\right] \nonumber \\ &\leq \left(\prod_{i \neq k} {\ensuremath{{\left\|\vw_i\right\|}_{{}}}}\right)\left[\prod_{i \neq k}\left(1 + \frac{{\ensuremath{{\left\|\vr_i\right\|}_{{}}}}}{\delta} \right)\right] \nonumber \\ &= \left(\prod_{i \neq k} {\ensuremath{{\left\|\vw_i\right\|}_{{}}}}\right)\exp\left[\sum_{i \neq k} \log\left(1 + \frac{{\ensuremath{{\left\|\vr_i\right\|}_{{}}}}}{\delta} \right)\right] \leq \left(\prod_{i \neq k} {\ensuremath{{\left\|\vw_i\right\|}_{{}}}}\right)\exp\left[\sum_{i \neq k} \frac{{\ensuremath{{\left\|\vr_i\right\|}_{{}}}}}{\delta} \right], \label{eq4}\end{aligned}$$ where the second inequality follows from the assumption $\min_i {\ensuremath{{\left\|\vw_i\right\|}_{{}}}} \geq \delta$. We also have $$\begin{aligned} r^2 \geq \sum_{i=1}^{d} {\ensuremath{{\left\|\vr_i\right\|}_{{}}}}^2 \geq \frac{\left(\sum_{i=1}^{d}{\ensuremath{{\left\|\vr_i\right\|}_{1}}}\right)^2}{d}. \label{eq5}\end{aligned}$$ Inserting equation into equation , we get $$\begin{aligned} \prod_{i \neq k}{\ensuremath{{\left\|\vv_i\right\|}_{{}}}} \leq \left(\prod_{i \neq k} {\ensuremath{{\left\|\vw_i\right\|}_{{}}}}\right)\exp\left(\frac{\sqrt{d}r}{\delta} \right) \leq \alpha \exp\left(\frac{\sqrt{d}r}{\delta} \right), \nonumber\end{aligned}$$ where the last inequality follows from the assumption $\max_k \left(\prod_{i \neq k} {\ensuremath{{\left\|\vw_i\right\|}_{{}}}}\right) \leq \alpha$. Therefore, $\prod_{i=1}^{d} {\ensuremath{{\left\|\vv_i\right\|}_{{}}}} \leq \alpha\exp\left(\frac{\sqrt{d}r}{\delta}\right) \cdot \max_k{\ensuremath{{\left\|\vv_k\right\|}_{{}}}}$. Application of this inequality in yields ${\ensuremath{{\left\|\nabla L(\vv)\right\|}_{{}}}} \leq \sqrt{d} \cdot \max_k {\ensuremath{{\left\|\nabla_k L(\vv)\right\|}_{{}}}} \leq n^{d/2} {\ensuremath{{\left\|D(\vv)\right\|}_{{}}}}{\ensuremath{{\left\|\vx\right\|}_{{}}}}\left(\alpha \sqrt{d} \right) \exp \left(\frac{\sqrt{d}}{\delta}r\right)$, which concludes the proof. Channel normalization on a single channel linear CNN {#sec:normlossgrad} ==================================================== We consider channel normalization with scale parameter fixed to $\gamma_{ij}=1$ and the shift parameter fixed to $\beta_{ij}=0$. Hence, merely varying the scale of the parameters does not change the output of the network with channel normalization $f_N(\mW,\vx)$. To simplify the derivation we assume the input vector $\vx$ is centered, i.e., its entries sum to zero. Let $\vz_i$ be the input of the $i$-th layer. Then, the output of the convolutional layer can be written as $\mW_i \vz_i$, where $\mW_i$ is the circulant matrix implementing the convolution operation. Channel normalization centers the mean and adjusts the empirical variance to one. Since $\mW_i$ is a convolution operation, given $\vz_i$ is centered, $\mW_i \vz_i$ is centered as well. Thus, the effect of channel normalization in this setup is to normalize the scale of the vector. It follows that the output of the network with channel normalization can be written as $$\begin{aligned} \label{eq:expfn} f_N(\mW,\vx) = w_{d+1} \frac{\prod_{i=1}^{d}\mW_i\vx}{{\ensuremath{{\left\|\prod_{i=1}^{d} \mW_i \vx\right\|}_{{}}}}},\end{aligned}$$ where $w_{d+1}$ is a scale parameter that we introduced so that $f_N(\mW,\vx)$ can exhaust $\reals^n$. To see that the output of the network can be written as in equation , note that the input of the first layer is $\vz_1 = \vx$, with $\vx$ centered. The normalization of the first layer yields the input of the second layer by division by ${\ensuremath{{\left\|\mW_1 \vz_1\right\|}_{{}}}}/\sqrt{n} = {\ensuremath{{\left\|\mW_1 \vx\right\|}_{{}}}}/\sqrt{n}$, which gives $$\vz_2 = \frac{\mW_1 \vx}{{\ensuremath{{\left\|\mW_1 \vx\right\|}_{{}}}}/\sqrt{n}}.$$ The normalization operation at the second layer divides by $${\ensuremath{{\left\|\mW_2 \vz_2\right\|}_{{}}}}/\sqrt{n} = {\ensuremath{{\left\|\frac{\sqrt{n}\mW_2 \mW_1 \vx}{{\ensuremath{{\left\|\mW_1 \vx\right\|}_{{}}}}}\right\|}_{{}}}}/\sqrt{n} = \frac{{\ensuremath{{\left\|\mW_2 \mW_1 \vx\right\|}_{{}}}}}{{\ensuremath{{\left\|\mW_1 \vx\right\|}_{{}}}}},$$ which yields $$\vz_3 = \frac{\mW_3 \vz_2}{{\ensuremath{{\left\|\mW_2 \mW_1 \vx\right\|}_{{}}}}/{\ensuremath{{\left\|\mW_1 \vx\right\|}_{{}}}}} = \frac{\mW_3 \mW_2 \mW_1 \vx}{{\ensuremath{{\left\|\mW_3 \mW_2 \mW_1 \vx\right\|}_{{}}}}/\sqrt{n}}.$$ Continuing this logic yields equation , where we absorbed $\sqrt{n}$ in the parameter $w_{d+1}$. Gradient analysis ----------------- Note that with $\mX \in \reals^{n\times n}$ the circulant matrix with first column equal to $\vx$, we have that $\mW_k \vx = \mX \vw_k$ and the channel normalized output of the network becomes $$f_N(\mW,\vx) = w_{d+1} \frac{ \mX_k \vw_k }{ {\ensuremath{{\left\| \mX_k \vw_k \right\|}_{{}}}} },$$ where we defined $\mX_k = \prod_{i\neq k} \mW_i \mX$ for notational convenience. We next compute the gradient $$\nabla_{\vw_k} L(\mW,\vx,\vy), \quad L(\mW,\vx,\vy) = {\ensuremath{{\left\| \vy - f_N(\mW,\vx) \right\|}_{{}}}}^2.$$ Towards this goal, first note that $$\nabla_\vz {\ensuremath{{\left\|\vy - \gamma \frac{\vz}{ {\ensuremath{{\left\|\vz\right\|}_{{}}}} } \right\|}_{{}}}}^2 = \frac{\gamma}{{\ensuremath{{\left\|\vz\right\|}_{{}}}}} \left( \mI - \vz \transp{\vz} / {\ensuremath{{\left\|\vz\right\|}_{{}}}}^2 \right) (\vy - \gamma \vz).$$ Thus, by the chain rule $$\begin{aligned} \nabla_{\vw_k} L(\mW,\vx,\vy) &= w_{d+1} \transp{\mX}_k \frac{1}{{\ensuremath{{\left\| \mX_k \vw_k \right\|}_{{}}}}} \left( \mI - \mX_k \vw_k \transp{\vw}_k \transp{\mX}_k / {\ensuremath{{\left\|\mX_k \vw_k \right\|}_{{}}}}^2 \right) (\vy - w_{d+1} \mX_k \vw_k)\\ &= \transp{\mX}_k \frac{w_{d+1}}{{\ensuremath{{\left\| \mX_k \vw_k \right\|}_{{}}}}} \left( \mI - \mX_k \vw_k \transp{\vw}_k \transp{\mX}_k / {\ensuremath{{\left\|\mX_k \vw_k \right\|}_{{}}}}^2 \right) \vy.\end{aligned}$$ From direct computation, $$\innerprod{ \nabla_{\vw_k} L(\mW,\vx,\vy) }{ \vw_k } = 0,$$ thus the gradient is orthogonal to $\vw_k$. Moreover, if $\vw_k$ is multiplied with a positive scalar $\gamma$, then the gradient scales with $1/\gamma$. | Mid | [
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Q: How Do I Do This In JavaScript? Search Text On Page And If No Text Show Tick And If Text Show X I have a webpage that has a lot of dynamic data showing usernames. This data isn't currently in a usable form but I want a simple way for our users to go onto a page which has a text box they can type in the username they want to use and it checks that page (JS + usernames on same page) and if no text showing then show a tick, they can use, and if username can be found then show an X. Effectively: 1. User enters text in an edit box 2. Javascript searches page 3. JS shows image if true and image if false A: You can use built-in function for this task: if (find('Thomas')) { // show image for found case } else { // Not found } Read mode about find method of window object. Try this demo: http://jsfiddle.net/VyFNt/ | Low | [
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Es ist der Transfer-Hammer der Saison! Dortmunds Ilkay Gündogan (25) wechselt im Sommer zu Manchester City. Nach BamS-Informationen hat der Nationalspieler einen Fünfjahresvertrag beim zukünftigen Klub von Pep Guardiola (45) unterschrieben. Pep und Gündogan – PASST DAS? Mehr zu Borussia Dortmund Gündogan weg! Und wer geht jetzt noch beim BVB? Dortmunds Mittelfeldstar Ilkay Gündogan wechselt im Sommer zu Manchester City – wer verlässt den BV jetzt noch? Tuchel: Es wäre Verrat, wenn wir uns bemitleiden Auch bei Tuchel sind die Wunden nach Liverpool nicht verheilt. Zumindest kann er etwas Positives aus der Niederlage mitnehmen. Klar ist: Pep wollte Gündogan unbedingt. Schon im Sommer versuchte der Spanier, den BVB-Star nach München zu holen. Doch die Gespräche brachten keine Einigung, weil die Bayern-Bosse von Gündogan nicht vollkommen überzeugt waren. Stattdessen kam Arturo Vidal (28). Wie wichtig es Pep war, Gündogan dann zu City zu lotsen, zeigte sich am 7. März: Der Noch-Bayern-Trainer reiste höchstpersönlich nach Amsterdam zu einem Treffen mit Manchesters Sportdirektor Txiki Begiristain. Zur gleichen Zeit im Hotel: Gündogans Onkel und Berater Ilhan. Auch Interessant Warum gerade der Dortmunder? Gündogan ist unheimlich sicher am Ball, kann die Kugel halten und verteilen. Er glänzt durch seine herausragende Übersicht und kurbelt das Spiel klug an. Eigenschaften, die Guardiola sehr schätzt. Pep Guardiola wechselt nach drei Jahren Bayern im Sommer zu Manchester City. Schon jetzt plant er den Kader Foto: Getty Images Und Eigenschaften, die Pep an einen der wichtigsten Spieler seiner Trainer-Karriere erinnern: Xavi (36). Der Mittelfeld-Stratege war in Barcelona bei fünf Meisterschaften sowie je drei Champions-League- und Pokalsiegen Guardiolas verlängerter Arm auf dem Platz. Zudem sind Passsicherheit und Spielintelligenz Qualitäten, die den Spieler Guardiola selbst auszeichneten. Kein Wunder, dass für Gündogan eine Ablöse in Höhe von 30 Mio Euro im Gespräch ist. Dortmund konnte nur noch diese Saison für den Nationalspieler kassieren, denn sein Vertrag läuft 2017 ab. Die Frage ist nur: Spielt Gündogan bei ManCity genauso unangefochten in der Startelf wie beim BVB? Er soll Yaya Touré ersetzten, der den Verein im Sommer verlässt. Damit geht auch Gündogans härtester Konkurrent auf seiner Position. Mit Fernandinho, Fernando und Fabian Delph ist das zentrale Mittelfeld der Citizens zwar quantitativ stark besetzt. Fernando und Delph sollten Gündogans aber keine Angst machen. Außerdem hat sich im Fall Thiago schon gezeigt: Wenn Pep einen Spieler will, dann spielt er auch. | Mid | [
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Teenagers' Babies Do Not Appear to Suffer from Poor Health Solely Because of Their Mothers' Young Age To the extent that infants born to adolescents need more health care services than babies born to older mothers, a study of South Carolina infants enrolled in fee-for-service Medicaid suggests that the disparity may be attributable to differences in maternal characteristics, rather than to teenage mothers’ inability to obtain proper care for their children.1 In each of the first two years of life, rates of use of five of six types of care were higher among babies born to teenagers than among those born to older women. The pattern was the same when infant and delivery characteristics were controlled for, but few significant differences remained in analyses that took maternal characteristics into account. The study used statewide data that linked Medicaid claims with birth certificate files for infants born in 2000–2002. Only healthy infants who were delivered at term, had a normal birth weight and were continuously enrolled in a fee-for-service plan from age two months through two years were included. These criteria yielded a sample of nearly 42,000 infants—about 4,000 whose mothers were teenagers (i.e., 11–17 years old) at delivery and 38,000 whose mothers were 18 or older. In separate analyses for each of the first two years of life, researchers assessed infants’ use of six types of health service: doctor visits for preventive care, doctor visits for illness, emergency department visits, hospital admissions, and both emergency department visits and hospital admissions for conditions that are treatable on an ambulatory basis (e.g., asthma, seizures and gastrointestinal infections). Differences by maternal age at delivery were examined in bivariate and multivariate models. Chi-square and t tests revealed significant—although generally small—differences in a wide range of maternal, infant and delivery characteristics according to the mother’s age at delivery. Most notably, teenage mothers had had less schooling than older women (9.8 vs. 11.8 years, on average), were less likely to be married (7% vs. 20%) and were more likely to have given birth only once (91% vs. 35%). They also were less likely to have received adequate prenatal care, as measured on a standard index (53% vs. 64%). On average, the number of doctor visits for illness did not differ by maternal age at delivery in either year; however, in each year, teenagers’ babies made greater use of every other health service examined than did infants born to older women. They made 5–6% more preventive medical visits than other infants and had 9–17% more hospital admissions, 20–24% more hospital admissions for conditions that can be managed through ambulatory care, and 33–36% more emergency department visits in general and for conditions that were treatable on an ambulatory basis. In analyses that controlled for infant and delivery characteristics, these findings were largely unchanged; the exception was that a marginally significant result suggested that infants born to teenagers made slightly more doctor visits due to illness than other babies during the first year. By contrast, when maternal characteristics were controlled for, maternal age was associated with differences in only two outcomes and only during the first year: Infants born to teenagers again had marginally more doctor visits because of illness than other infants, and they had 27% more hospital admissions for conditions treatable by ambulatory care. Results were similar when infant, delivery and maternal characteristics were controlled for simultaneously. In the full model, during the first year, babies born to teenagers made 8% more sick-infant doctor visits than children of older mothers (a marginally significant difference), had 9% more hospital admissions and had 29% more admissions for conditions that could be managed through ambulatory care. According to the analysts, despite data limitations that restrict the generalizability of the results and may lead to certain biases, the findings suggest that health problems among infants of adolescent mothers reflect mothers’ socioeconomic disadvantage, rather than an inherent inability of young mothers to care for their children. Thus, “policies that aim to provide additional social support to adolescent mothers or additional financial resources may be useful ways to improve the health outcomes of infants who are born to younger women.” | Mid | [
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/** * Question Link: https://leetcode.com/problems/verifying-an-alien-dictionary/ * Primary idea: Compare words one by one and make sure they are following the order * * Time Complexity: O(n), Space Complexity: O(n) * */ class VerifyingAlienDictionary { func isAlienSorted(_ words: [String], _ order: String) -> Bool { let charToOrder = Dictionary(uniqueKeysWithValues: order.enumerated().map { ($0.1, $0.0) }) for i in 0..<words.count - 1 { let currentWord = Array(words[i]), nextWord = Array(words[i + 1]) var j = 0 while j < min(currentWord.count, nextWord.count) { let currentChar = currentWord[j], nextChar = nextWord[j] guard currentChar != nextChar else { j += 1 continue } if charToOrder[currentChar]! > charToOrder[nextChar]! { return false } else { break } } // edge case: "apple" vs. "app"; "kuvp" vs. "q" if j == nextWord.count && currentWord.count > nextWord.count { return false } } return true } } | Mid | [
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The present invention relates to a mold tool for forming an electronic component having a semiconductor chip sealed on a substrate by resin, a method for forming the electronic component, and a lead frame on which a semiconductor chip can be put and thereafter the chip on the frame is sealed by resin. Referring to FIGS. 6-8, a known semiconductor sealing method will be described hereinafter. FIG. 6 is a schematic cross-sectional view of a known resin-molded electronic component 21 and FIGS. 7 and 8 show example phenomena caused by molding in the known semiconductor sealing method. In FIG. 6, a substrate 23 for attaching a semiconductor 22 is flat. The chip 22 is sealed on the substrate 23 by resin, resulting in a difference between the distance (c) from the upper surface of the chip 22 to the upper surface of a sealing portion 27 and the distance (d) from the lower surface of the substrate 23 to the lower surface of the sealing portion 27. However, since the configuration elements such as the sectional area and the thickness of the molded product have a great effect on the flow of the molten resin, the above construction causes the resin to firstly flow in the lower mold having a cavity with a larger depth than the depth of the upper mold as shown in FIG. 7 and then flow to the upper mold after the lower cavity of the lower mold is filled with resin. As a result thereof, the resin flow forces gas in the cavities to be held in the upper mold having the cavity with the smaller depth, forming voids in the upper cavity, thus causing disadvantages such as poor insulation properties of the product. As shown in FIG. 8, if the substrate 23 is easily deformed, the substrate 23 is easily deformed by the resin flow. The forward ends 28a and 28b of the two resin flows entering the upper and lower cavities after passing through a gate 24 are difficult to coincide with each other. Therefore, after the lower cavity is filled with the resin, the pressure caused in the lower cavity by the resin is applied to the substrate 23 to deform, resulting in a poor quality of the electronic component molded by resin. | Low | [
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Introduction ============ The *myo*-inositol phosphates (InsPs) are a family of intracellular signalling molecules containing monophosphate (P) and diphosphate (PP) groups arranged around the hexahydroxycyclohexane ring of *myo*-inositol (Ins).[@cit1] InsPs regulate many cellular processes, the best known being the release of Ca^2+^ from intracellular stores by [d]{.smallcaps}-*myo*-inositol 1,4,5-trisphosphate (InsP~3~), which binds to receptors on the endoplasmic reticulum.[@cit2] InsP~3~ is converted *via* a series of enzymatic phosphorylations[@cit3] into InsP~6~ ([Fig. 1](#fig1){ref-type="fig"}), which can then be further phosphorylated to give highly charged PP-InsPs containing diphosphate (pyrophosphate) groups.[@cit4],[@cit5] ![A. Biosynthetic pathway connecting Ins(1,4,5)P~3~ to the PP-InsPs. IP6K, inositol hexakisphosphate 5-kinase; PPIP5K, diphosphoinositol pentakisphosphate kinase; DIPP, diphosphoinositol polyphosphate phosphohydrolase. "InsP~3~", "5-InsP~7~", "1-InsP~7~" and "InsP~8~" are alternative names for Ins(1,4,5)P~3~, 5-PP-InsP~5~, 1-PP-InsP~5~ and 1,5-\[PP\]~2~-InsP~4~, respectively. B. Structure of Ins(1,4,5)P~3~. C. Structure of the synthetic analogue 1-PP-Ins(4,5)P~2~ (**1**).](c8md00149a-f1){#fig1} InsP~3~ receptors (IP~3~Rs) are tetrameric intracellular Ca^2+^ channels, expressed in most animal cells.[@cit2] When InsP~3~ binds to the *N*-terminal InsP~3~-binding core (IBC) of all four IP~3~R subunits,[@cit6] conformational changes propagate to the central pore. The pore then opens, allowing Ca^2+^ to flow into the cytosol, where it regulates many intracellular processes. The vicinal 4,5-bisphosphate structure of InsP~3~ is crucial (if not absolutely essential[@cit7]) for activating IP~3~Rs because it cross-links the two domains of the clam-like IBC, pulling them together and initiating the conformational changes. The 1-phosphate group has a less direct, but enhancing, effect on activity.[@cit8] Although PP-InsP signalling is thought to be more evolutionarily ancient than InsP~3~-mediated mobilisation of Ca^2+^,[@cit9] much less is known about the functions and protein targets of PP-InsPs. Nevertheless, evidence is accumulating that PP-InsPs play important roles at the interface of cell signalling and metabolism in the regulation of bioenergetic and phosphate homeostasis.[@cit4],[@cit5] Possible receptors for PP-InsPs include the PH (pleckstrin homology) domains[@cit10],[@cit11] and SPX (SYG1/Pho81/XPR1) domains[@cit12],[@cit13] of proteins. PP-InsPs may also exert some of their effects by direct non-enzymatic diphosphorylation of target proteins.[@cit14] Phosphorylating a phosphate monoester in an InsP~*n*~ to give a PP-InsP~*n*--1~ not only increases the overall negative charge of the molecule, but also changes its shape, solvation and metal complexation properties. Unsurprisingly, therefore, a diphosphate group may alter ligand affinity for protein binding sites.[@cit4] For example, some PH domains that bind InsP~6~ bind 5-InsP~7~ with higher affinity,[@cit10],[@cit11] while 1-InsP~7~ and InsP~8~ are weaker.[@cit11] In contrast, both 1-InsP~7~ and 5-InsP~7~ stimulate synthesis of inorganic polyphosphate (polyP) by the vacuolar transporter chaperone (VTC) by binding to its SPX domain, while InsP~6~ is inactive and InsP~8~ is 20-fold more potent.[@cit13] PP-InsPs can be dephosphorylated back to InsPs by diphosphoinositol polyphosphate phosphohydrolases (DIPPs, [Fig. 1](#fig1){ref-type="fig"}), which specifically hydrolyse the diphosphate group, leaving a phosphate monoester and liberating inorganic phosphate.[@cit3],[@cit15] Given that introducing a diphosphate into an InsP may modify its interaction with proteins, we were interested in the possible effects of converting one of the phosphate groups in InsP~3~ into a diphosphate. The 1-phosphate group of InsP~3~ has been a popular target for synthetic elaboration of InsP~3~ since early structure--activity studies showed that it is much more tolerant of modification than the 4- or 5-phosphate groups.[@cit8] Interest in the role of the 1-phosphate group was further stimulated by the discovery in 1993 of the adenophostins, fungal metabolites that are highly potent InsP~3~ receptor ligands.[@cit16] The adenophostins contain a glucopyranoside 3,4-bisphosphate structure that mimics the *myo*-inositol 4,5-bisphosphate of InsP~3~ but intriguingly, their third phosphate group is located on a separate (ribofuranoside) ring, suggesting that repositioning this phosphate group may enhance affinity.[@cit17] The X-ray structure[@cit18] of the IBC of type 1 InsP~3~ receptor bound to InsP~3~ confirmed the area of the binding pocket around the 1-phosphate of bound InsP~3~ to be relatively open. Our molecular docking experiments using this structure suggested that a 1-diphosphate should bind well to this region. We therefore set out to synthesise the 1-diphosphate analogue of InsP~3~, *i.e.* 1[d]{.smallcaps}-diphospho-*myo*-inositol 4,5-bisphosphate \[1-PP-Ins(4,5)P~2~ (**1**), [Fig. 1](#fig1){ref-type="fig"}\] and examine its interaction with InsP~3~ receptors. We were also interested to examine the interaction of 1-PP-Ins(4,5)P~2~ with DIPPs. Although DIPPs can hydrolyse the PP groups of highly phosphorylated PP-InsPs ([Fig. 1](#fig1){ref-type="fig"}), inorganic polyphosphate, 5-phosphoribosyl 1-pyrophosphate and nucleotide dimers,[@cit3],[@cit15] their catalytic mechanisms are poorly understood. 1-PP-Ins(4,5)P~2~ contains the target 1-PP structure found in the known DIPP substrate 1-PP-InsP~5~, but presented in the context of a molecule with only two phosphate monoester groups. There are no reports in the literature on whether "lower" PP-InsPs such as 1-PP-Ins(4,5)P~2~ could be recognised by the active sites of DIPPs. Results and discussion ====================== Chemistry --------- The synthesis of 1-PP-Ins(4,5)P~2~ (**1**) begins from the known alcohol **2** ([@cit19] and [@cit20]) ([Scheme 1](#sch1){ref-type="fig"}). To construct the diphosphate unit at *O*-1, we employed a modification of a recently described strategy,[@cit21],[@cit22] in which a temporarily protected phosphate group is introduced and then selectively deprotected to reveal a phosphate monoester. This phosphate is then phosphitylated to give a mixed P([iii]{.smallcaps})--P([v]{.smallcaps}) anhydride, which is oxidised to a partially protected pyrophosphate unit. Removal of all protecting groups by catalytic hydrogenolysis then yields the target PP-InsP. We reasoned that it might be possible to employ methylsulfonylethyl (MSE)[@cit23],[@cit24] as a temporary phosphate protecting group in this sequence. The MSE group can be removed by β-elimination, similar to the better-known β-cyanoethyl (β-CE)[@cit22],[@cit25] group. However, the MSE group is unaffected by catalytic hydrogenation, affording greater synthetic versatility, and the required phosphitylating reagent, phosphoramidite **5**, is a stable crystalline solid. {#sch1} Thus, the 1-OH group in **2** was reacted with **5** in the presence of 5-phenyl-1*H*-tetrazole to give an intermediate MSE-protected phosphite triester. Oxidation using *m*CPBA then gave **3**, containing the MSE-protected phosphate triester at *O*-1. The diphosphate unit at *O*-1 was then constructed using a sequence of transformations carried out as described previously,[@cit21],[@cit22],[@cit25] with slight modifications. The progress of each step was carefully monitored by ^31^P NMR spectroscopy (see Experimental section and ESI[†](#fn1){ref-type="fn"}). The protected diphosphate **4** was found to be rather unstable and was immediately deprotected by catalytic hydrogenolysis at atmospheric pressure. A final purification step by gradient elution anion exchange chromatography on Q-Sepharose Fast Flow resin gave 1-PP-Ins(4,5)P~2~ (**1**) as the triethylammonium salt, which was accurately quantified by total phosphate assay. Interactions of 1-PP-Ins(4,5)P~2~ with type 1 InsP~3~ receptors --------------------------------------------------------------- Both InsP~3~ and 1-PP-Ins(4,5)P~2~ (**1**) stimulated a concentration-dependent release of Ca^2+^ from the intracellular stores of permeabilised DT40 cells expressing type 1 InsP~3~ receptors ([Fig. 2A](#fig2){ref-type="fig"}). The maximal Ca^2+^ release evoked by each ligand and the half-maximally effective concentration (EC~50~) were similar for **1** and InsP~3~ ([Fig. 2A](#fig2){ref-type="fig"}). Membranes from Sf9 cells expressing rat type 1 InsP~3~ receptors were used for equilibrium competition binding studies with ^3^H-InsP~3~, because these membranes express full-length type 1 InsP~3~ receptors at ∼20-fold higher levels than cerebellar membranes, the richest endogenous source. The experiments were carried out in cytosol-like medium (CLM, pH 7.3) containing 1.5 mM Mg-ATP to match the conditions used for Ca^2+^-release assays. {#fig2} In agreement with the Ca^2+^-release assays, 1-PP-Ins(4,5)P~2~ (**1**) bound with the same affinity as InsP~3~ to InsP~3~ receptors ([Fig. 2B](#fig2){ref-type="fig"}). Thus, the two compounds were essentially indistinguishable in both functional and binding assays ([Table 1](#tab1){ref-type="table"}). Rapid chemical hydrolysis of **1** could in principle explain the similar behaviour of InsP~3~ and **1**, but we saw no evidence that **1** is unstable. The ^31^P NMR spectrum of **1** in D~2~O (see ESI[†](#fn1){ref-type="fn"}) was unchanged after the sample solution had been kept for several days at room temperature, followed by one year at 4 °C. ###### Interactions of InsP~3~ and 1-PP-Ins(4,5)P~2~ (**1**) with type 1 InsP~3~ receptors (*n* = 3) Ca^2+^ release Binding[^*a*^](#tab1fna){ref-type="table-fn"} --------------------------- ---------------- ----------------------------------------------- -------- ------------- ----- InsP~3~ 7.21 ± 0.08 62 82 ± 4 6.89 ± 0.07 128 1-PP-Ins(4,5)P~2~ (**1**) 7.17 ± 0.11 68 80 ± 1 6.96 ± 0.05 110 ^*a*^Binding was done using Sf9 cell membranes overexpressing rat type 1 InsP~3~ receptors in CLM (pH 7.3) containing 1.5 mM Mg-ATP to match the conditions used in the Ca^2+^ release assay. Molecular docking experiments (see Experimental section and ESI[†](#fn1){ref-type="fn"} for details) using the X-ray crystal structure of the IBC of type 1 InsP~3~ receptor[@cit18] suggested that the diphosphate group in **1** should be well-tolerated by the InsP~3~-binding pocket and may be capable of forming additional hydrogen bonds with residues in the binding site ([Fig. 3](#fig3){ref-type="fig"}). Nevertheless, it is well known that attempts to optimise drug candidates by adding polar groups may fail because the expected enthalpic gains from new polar interactions are opposed by ligand desolvation penalties and unfavourable entropic effects, resulting in no gain in binding affinity.[@cit26] Such compensatory effects may underlie the similar affinities of **1** and InsP~3~ for type 1 InsP~3~ receptors. ![A. Interactions of InsP~3~ with the IBC of type 1 InsP~3~ receptors, based on the X-ray crystal structure of IP~3~R1 in complex with InsP~3~ ([@cit18]) (1N4K). B. Model of 1-PP-Ins(4,5)P~2~ (**1**) in the IBC produced by molecular docking (see Experimental section and ESI[†](#fn1){ref-type="fn"} for details). For clarity, water molecules are not shown.](c8md00149a-f3){#fig3} Interaction of 1-PP-Ins(4,5)P~2~ with DIPPs ------------------------------------------- The dephosphorylation of PP-InsPs is catalysed by diphosphoinositol polyphosphate phosphohydrolases (DIPPs), which selectively cleave the diphosphate (PP) to give a phosphate monoester and inorganic phosphate (Pi).[@cit3] Humans express four DIPP types: DIPP-1 is the product of the NUDT3 gene; DIPP-2 (of which there are two isoforms, DIPP-2α and DIPP-2β, produced by alternative splicing) is the product of NUDT4; DIPP-3α is the product of NUDT10 and DIPP-3β is the product of NUDT11.[@cit3] We examined the interaction of 1-PP-Ins(4,5)P~2~ (**1**) with all four DIPPs in comparison with two naturally-occurring substrates 1-PP-InsP~5~ and 5-PP-InsP~5~ ("1-InsP~7~" and "5-InsP~7~", respectively) and also with the alternative substrates diadenosine polyphosphates Ap~3~A and Ap~5~A. Non-hydrolysable InsP~7~ analogues 1-PCP-InsP~5~ ([@cit27]) and 5-PCP-InsP~5~ ([@cit28]) were independently synthesised and included as controls. With Mg^2+^ present in the buffer, 1-PP-InsP~5~ and 5-PP-InsP~5~ were rapidly metabolised by all four DIPPs ([Fig. 4A](#fig4){ref-type="fig"}). The rate of hydrolysis of 1-PP-InsP~5~ was significantly higher than that for 5-PP-InsP~5~ in each case. This finding is in agreement with a previous study.[@cit15] As expected, the PCP analogues were not metabolised, confirming that DIPPs can hydrolyse only the diphosphate unit and not the phosphate monoesters. Ap~3~A and Ap~5~A were unaffected by all four enzymes in Mg^2+^-containing buffer, an observation that had been reported for NUDT10 and NUDT11, but not for NUDT3 and NUDT4.[@cit29] Perhaps surprisingly, 1-PP-Ins(4,5)P~2~ (**1**) was also not metabolised under these conditions. The presence of a divalent cation is required for the activity of NUDT10 and NUDT11 and also for NUDT3.[@cit3] When Mg^2+^ in the buffer was replaced by Mn^2+^, **1** was now hydrolysed by the DIPPs, while 1-PP-InsP~5~ and 5-PP-InsP~5~ resisted hydrolysis. In addition, Ap~5~A now also behaved as a substrate for all four DIPPs ([Fig. 4B](#fig4){ref-type="fig"}). In the absence of enzyme none of the compounds, including **1**, showed any sign of hydrolysis during the time course of the experiment in the presence of either Mg^2+^ or Mn^2+^-containing buffers. This further supports our conclusion above that **1** was not hydrolysed to InsP~3~ during the InsP~3~ receptor assays. ![Specific activities of DIPPs with 1-PP-Ins(4,5)P~2~ (**1**), known substrates 1-PP-InsP~5~ and 5-PP-InsP~5~ and controls. Experiments were conducted in buffer containing Mg^2+^ (A) or Mn^2+^ (B). Data shown represent the formed concentration of Pi (micromolar) per enzyme concentration (micromolar) per minute. A630 was converted to Pi concentration (micromolar) using the equation A630 = 0.01897\[P~i~\] -- 0.5877 (Mg^2+^ containing buffer) or A630 = 0.01923\[P~i~\] + 0.1053 (Mn^2+^ containing buffer). C. Structures of compounds examined, including methylenebisphosphonate (PCP) analogues of InsP~7~, and diadenosine polyphosphates Ap~3~A and Ap~5~A.](c8md00149a-f4){#fig4} Next, we used differential scanning fluorimetry (DSF) to measure the ability of the compounds to stabilise NUDT3 (DIPP1). While the effects of Ap~3~A and Ap~5~A were not significantly different from control ([Fig. 5A](#fig5){ref-type="fig"}), 1-PP-Ins(4,5)P~2~ (**1**) raised the melting temperature (*T*~m~) of NUDT3 by approx. 5 °C at a concentration of 0.1 mM. As expected, the more highly phosphorylated 1-PP-InsP~5~ had much stronger effects, resulting in a *T*~m~-shift of 20--25 °C. Similar DSF experiments were then carried out for NUDT4, NUDT10 and NUDT11. Ap~3~A did not stabilise any of the DIPPs, which supports our results for the activity assay. The results are summarised in [Fig. 5B](#fig5){ref-type="fig"}. {ref-type="fig"} on the melting temperature (*T*~m~) of NUDT3, measured using differential scanning fluorimetry (DSF). B. Comparison of melting temperature shifts (delta *T*~m~) induced by all compounds for all four DIPPs examined.](c8md00149a-f5){#fig5} We obtained further DSF data over a range of ligand concentrations for 1-PP-InsP~5~ and 1-PP-Ins(4,5)P~2~ (**1**), constructing dose--response curves for the two compounds ([Fig. 6](#fig6){ref-type="fig"}). It is interesting to note that the effect of **1** on NUDT10 was significantly lower compared to the other DIPPs and especially compared to NUDT11 ([Fig. 6B](#fig6){ref-type="fig"}). NUDT10 and NUDT11 have identical protein sequences apart from residue 89, which is either proline (NUDT10) or arginine (NUDT11). {#fig6} Noting the strong stabilisation of all the proteins by the PCP analogues, we obtained further DSF data over a range of ligand concentrations for 1-PCP-InsP~5~ and 5-PCP-InsP~5~ (ESI[†](#fn1){ref-type="fn"} Fig. S4 and S5) and calculated *K*~D~ values from these curves (ESI[†](#fn1){ref-type="fn"} Tables S1 and S2). We found that, in some cases, the PCP analogues had binding affinities comparable to those of their natural PP-containing ligands. Conclusions =========== Replacing a phosphate group in an inositol phosphate ligand with a diphosphate (PP) group can modify the interaction of the ligand with target proteins.[@cit10]--[@cit13] Structure--activity studies have previously shown that the 1-phosphate group of InsP~3~ is amenable to synthetic modification, and molecular docking experiments suggested that a 1-diphosphate group should be well-tolerated by the binding site of the InsP~3~ receptor. We therefore synthesised 1-PP-Ins(4,5)P~2~ (**1**), the first PP-containing analogue of InsP~3~. Using assays of Ca^2+^-release through type 1 InsP~3~ receptors, we found that **1** was equipotent to InsP~3~ and in binding assays its affinity was indistinguishable from that of InsP~3~. Thus, the 1-diphosphate modification of InsP~3~ does not affect its affinity for or activity at type 1 InsP~3~ receptors. Nevertheless, **1** is the first Ca^2+^-releasing PP-InsP and also the most potent P-1 modified ligand of InsP~3~ receptors yet identified.[‡](#fn2){ref-type="fn"} [^2] The novel diphosphate compound **1** was not metabolised by DIPPs in the presence of Mg^2+^-containing buffer, while the naturally-occurring InsP~7~ isomers, 5-PP-InsP~5~ and 1-PP-InsP~5~ were rapidly hydrolysed. Conversely, in the presence of Mn^2+^, **1** was hydrolysed while the two InsP~7~ isomers were unaffected. Synthetic PCP-containing analogues of the InsP~7~s were not hydrolysed under any conditions examined, but when evaluated for their ability to stabilise DIPP proteins using differential scanning fluorimetry (DSF), they gave temperature shifts comparable to their natural PP-containing equivalents. This strongly suggests that 1-PCP-InsP~5~ and 5-PCP-InsP~5~ could be promising ligands for co-crystallisation studies with DIPPs. Could 1-PP-Ins(4,5)P~2~ be an endogenous molecule? The mammalian enzymes known to synthesise PP-InsPs are 5-diphosphoinositol pentakisphosphate kinases (PPIP5Ks) and inositol hexakisphosphate kinases (IP6Ks). Inositol phosphate multikinase (IPMK) has also been reported to synthesise PP-InsP~4~ from InsP~5~*in vitro*,[@cit30] but the products of InsP~3~ phosphorylation by IPMK are Ins(1,3,4,5)P~4~ and/or Ins(1,4,5,6)P~4~.[@cit31] Phosphorylation of lower InsPs by PPIP5Ks seems unlikely, considering the constraints of the catalytic site[@cit32] and the recently discovered capture site;[@cit22] even Ins(1,3,4,5,6)P~5~ is not phosphorylated.[@cit32] Recombinant Kcs1p, a yeast homologue of IP6K1, was reported to phosphorylate InsP~3~ slowly, although the identities of the products could not be determined.[@cit33] Later work confirmed that InsP~3~ was phosphorylated by Kcs1 and the product was identified as Ins(1,3,4,5)P~4~ (*i.e.* in this case, Kcs1 functioned as a 3-kinase).[@cit34] More recently, a study found that EhIP6KA, an IP6K homologue from *Entamoeba histolytica*, was capable of slowly phosphorylating InsP~3~, although the products were identified as Ins(1,4,5,6)P~4~ and Ins(1,2,4,5)P~4~.[@cit35] On this basis, naturally occurring 1-PP-Ins(4,5)P~2~ seems unlikely. However, in both studies where the identities of the enzyme products were assigned,[@cit34],[@cit35] resistance to hydrolysis by DIPP1 was used to exclude the possibility that the products contained diphosphate groups. The present work shows that this criterion may not always be valid; in our hands, 1-PP-Ins(4,5)P~2~ was not metabolised in the presence of Mg^2+^ by any of the DIPPs, yet it does contain a diphosphate group. Notwithstanding the evidence for PP-InsPs playing physiological roles,[@cit4],[@cit5] the present work indicates that a physiological function for 1-PP-Ins(4,5)P~2~, at least in relation to the regulation of InsP~3~ receptor-mediated Ca^2+^ release, may be unlikely. Converting the 1-phosphate of InsP~3~ into a diphosphate neither attenuates nor enhances the ability of the ligand to activate InsP~3~R. As the first example of a diphosphate analogue of a second messenger, however, the results add a new component to structure--activity relationships. Co-crystallisation studies with DIPPs using some of the non-hydrolysable substrate analogues discussed here are currently in progress. Experimental ============ General chemistry methods ------------------------- General methods were as previously reported.[@cit36] Alcohol **2** = 1[d]{.smallcaps}-2,3,6-tri-*O*-benzyl-*myo*-inositol 4,5-bis-*O*-(dibenzylphosphate) was synthesised according to the literature[@cit19] and crystallised from diethyl ether/light petroleum; m.p. 90--91 °C; Lit.[@cit19] 90--91 °C; \[*α*\]20D = --18.2, (*c* = 2, CHCl~3~), Lit.[@cit19] \[*α*\]25D = --15.6, (*c* = 1, CHCl~3~); Lit.[@cit20] \[*α*\]20D = --17.8, (*c* = 1.7, CHCl~3~). *N*,*N*-Diisopropylamino-bis-\[2-(methylsulfonyl)ethyloxy\]-phosphine (**5**) was synthesised according to the literature[@cit24] and recrystallized from dichloromethane/ether; m.p. 75.5--77.0 °C; ^1^H NMR (CDCl~3~, 400 MHz) *δ* 1.20 (12 H, d, ^3^*J*~HP~ 6.8 Hz, 4 × CHC*H*~3~), 3.01 (6 H, s, 2 × SCH~3~), 3.22--3.34 (4 H, m, 2 × OCH~2~C*H*~2~S), 3.59 (2 H, dh, ^3^*J*~HP~ 10.4 Hz, ^3^*J*~HH~ 6.8 Hz, 2 × C*H*CH~3~), 4.01--4.15 (4 H, m, 2 × OC*H*~2~CH~2~S); ^13^C NMR (CDCl~3~, 101 MHz) *δ* 24.62 (^3^*J*~CP~ 7.3 Hz, 4 × CH*C*H~3~), 42.85 (2 × S*C*H~3~), 43.31 (^2^*J*~CP~ 12.4 Hz, 2 × *C*HCH~3~), 56.17 (^3^*J*~CP~ 8.3 Hz, 2 × OCH~2~*C*H~2~S), 57.58 (^2^*J*~CP~ 20.0 Hz, 2 × O*C*H~2~CH~2~S); ^31^P NMR (CDCl~3~, 162 MHz, ^1^H-decoupled) *δ* 148.98; HRMS (*m*/*z*) \[M + H\]^+^ calcd. for C~12~H~28~O~6~NPS~2~; 378.11684; found 378.11687. 5-PP-InsP~5~, 1-PP-InsP~5~ and their PCP analogues were synthesised using similar methods to those previously described.[@cit21],[@cit22],[@cit27],[@cit28],[@cit36] ### [d]{.smallcaps}-2,3,6-tri-*O*-Benzyl-*myo*-inositol-4,5-bis(dibenzylphosphate)-1-bis\[2-(methylsulfonyl)ethyl\]phosphate (**3**) To a solution of alcohol **2** (194 mg, 0.200 mmol) in dry dichloromethane (3 mL) was added 5-phenyl-1*H*-tetrazole (64 mg, 0.44 mmol) and *N*,*N*-diisopropylamino-bis-\[2-(methylsulfonyl)ethyloxy\]-phosphine (**5**) (130 mg, 0.344 mmol). The suspension was stirred under N~2~ at room temperature for 2 h, after which time TLC (dichloromethane : ethyl acetate 1 : 1) showed total conversion of **2** (*R*~f~ 0.56) into a more polar product (*R*~f~ 0.24). The mixture was then cooled to --78 °C, before *m*CPBA (70%, 100 mg, 0.406 mmol) was added. The mixture was allowed to warm to room temperature and then diluted with EtOAc (30 mL). The clear, colourless solution was washed with 10% aq. Na~2~SO~3~ solution (2 × 30 mL) and 1.0 mold per m^3^ HCl (30 mL), then dried over MgSO~4~ and concentrated. The residue was purified by flash chromatography on silica, eluting with methanol in ethyl acetate (0 to 15%) to give **3** as a colourless oil (225 mg, 0.178 mmole, 89%); TLC (ethyl acetate : methanol 10 : 1): *R*~f~ = 0.50; \[*α*\]20D = --10.3, (*c* = 1.4, CHCl~3~); ^1^H NMR (CDCl~3~, 400 MHz) *δ* 2.76 (3 H, s, SCH~3~), 2.82 (3 H, s, SCH~3~), 2.79--2.87 (1 H, m, OCH~2~C*H*CHS), 2.92--3.00 (1 H, m, OCH~2~C*H*CHS), 3.03--3.13 (2 H, m, 2 × OCH~2~CHC*H*S), 3.62 (1 H, dd, *J* 9.8, 1.9 Hz, H-3), 4.10 (1 H, dd, *J* 9.5, 9.5 Hz, H-6), 4.07--4.40 (6 H, m, H-1, H-2 and 2 × OC*H*~2~CH~2~CHS), 4.58--4.73 (6 H, m, H-5 and 2.5 AB systems of OC*H*~2~Ph), 4.82--5.03 (9 H, m, H-4 and 4 × OC*H*~2~Ph), 5.09, 5.11 (1 H, ^2^*J*~AB~ 11.9 Hz, ^3^*J*~HP~ 7.0 Hz, 0.5 ABX system of POC*H*~2~Ph), 6.95--6.97 (2 H, m, Ph), 7.09--7.40 (33 H, m, Ph); ^13^C NMR (CDCl~3~, 100 MHz) *δ* 42.34 (2 × CH~3~), 54.03 (^3^*J*~CP~ 7.7 Hz, POCH~2~*C*H~2~S), 54.20 (^3^*J*~CP~ 7.7 Hz, POCH~2~*C*H~2~S), 61.16--61.24 (overlapping signals with ^2^*J*~CP~ couplings, PO*C*H~2~CH~2~S), 69.14--69.55 (overlapping signals with ^2^*J*~CP~ couplings, PO*C*H~2~Ph), 72.64 (O*C*H~2~Ph), 74.75 (O*C*H~2~Ph), 75.08 (O*C*H~2~Ph), 75.19 (C-2), 77.78--78.12 (overlapping signals with *J*~CP~ couplings, C-1, C-3, C-4 and C-6), 78.81 (C-5), 127.32--128.36 (*C*H of Ph), 135.51 (^3^*J*~CP~ 7.4 Hz, *ipso-C* of POCH~2~*Ph*), 135.98--136.06 (overlapping signals with ^3^*J*~CP~ couplings, 3 × *ipso-C* of POCH~2~*Ph*), 137.53 (*ipso-C* of OCH~2~*Ph*), 138.13 (*ipso-C* of OCH~2~*Ph*), 138.19 (*ipso-C* of OCH~2~*Ph*); ^31^P NMR (CDCl~3~, 162 MHz) *δ* --3.37 (1 P), --1.94 (1 P), --1.59 (1 P); HRMS (*m*/*z*) \[M + Na\]^+^ calcd. for C~61~H~69~O~19~P~3~S~2~; 1285.2980; found 1285.3011. ### [d]{.smallcaps}-1-Diphospho-*myo*-inositol 4,5-bisphosphate (**1**) Compound **3** (63 mg, 50 μmol) was dissolved in dry CDCl~3~ (1.5 mL) and the solution was transferred to an NMR tube. A ^31^P NMR spectrum (^1^H decoupled) showed three peaks as described above. DBU (30 μL, 200 μmol), followed by BSTFA (53 μL, 200 μmol) was added and the sample was shaken to mix the liquids. A ^31^P NMR spectrum taken after 1 h now showed three peaks: *δ* --1.84 (1 P), --2.20 (1 P) and --18.10 (1 P), this last signal corresponding to the bis-silylated phosphate triester at *O*-1. Methanol (100 μL) was added and the tube was shaken again. After 10 min, TFA (15 μL, 200 μmol) was added and the solution was concentrated by evaporation under reduced pressure, then thoroughly dried under vacuum. A ^31^P NMR spectrum (CDCl~3~) of the residue showed that the silyl groups were completely cleaved, with three peaks at *δ* --0.18 (1 P, P-1), --2.23 (1 P) and --2.45 (1 P). To this residue was added 5-phenyl-1*H*-tetrazole (20 mg, 137 μmol). Then, under argon, dry dichloromethane (2 mL) followed by bis(benzyloxy)diisopropylaminophosphine (30 μL, 89 μmol) were added. The mixture was stirred under argon for 45 min, after which time a ^31^P NMR spectrum of a sample (CDCl~3~ added) showed major peaks at *δ* 127.24 (^2^*J*~PP~ 4.2 Hz, P-1~β~), 7.59 (H-phosphonate by-product from hydrolysis of excess P([iii]{.smallcaps}) reagent), --2.22 and --2.41 (P-4 and P-5) and --10.26 (^2^*J*~PP~ 4.2 Hz, P-1~α~). The solution was cooled to --78 °C and *m*CPBA (70%, 25 mg, 100 μmol) was added. After 5 min, the solution was allowed to warm to room temperature, then concentrated under reduced pressure (no heat). A ^31^P NMR spectrum of the residue now showed peaks at *δ* 7.62 (H-phosphonate by-product), --2.28 and --2.52 (P-4 and P-5) --11.97 (d, ^2^*J*~PP~ 14.7 Hz, P-1~β~) and --13.69 (d, ^2^*J*~PP~ 14.7 Hz, P-1~α~). This residue was purified by flash chromatography on silica (methanol in ethyl acetate, 0 to 20%) giving **4** as a colourless oil (59 mg, 45 μmol, 90%); TLC (ethyl acetate : methanol 10 : 1): *R*~f~ = 0.30; ^31^P NMR (CDCl~3~, 162 MHz, ^1^H-decoupled) *δ* --1.75 (1 P, s), --2.35 (1 P, s), --11.08 (1 P, broad s, P-1~β~), --12.32 (1 P, broad s, P-1~α~); HRMS (*m*/*z*) \[M + Na\]^+^ calcd. for C~69~H~70~O~18~P~4~; 1333.3405; found 1333.3377. In earlier trials, this material had been found to be unstable after flash chromatography; a portion of it was therefore deprotected immediately as follows. Compound **4** (37 mg, 28 μmol) was dissolved in methanol (4 mL) and deionised water (1 mL). Powdered NaHCO~3~ (14 mg, 168 μmol) was added followed by Pd(OH)~2~/C (30 mg). The suspension was stirred vigorously under H~2~ (balloon) for 24 h, after which time more water (4 mL) was added. A fresh balloon of H~2~ was attached and stirring was continued for a further 72 h. The catalyst was then removed by filtration through a PTFE filter, giving a colourless solution, which was concentrated under reduced pressure to give a solid white residue. Analysis of this residue by ^31^P and ^1^H NMR in D~2~O showed that deprotection was complete. The residue was purified by anion-exchange chromatography on Q-Sepharose Fast Flow resin, eluting with a gradient of 0 to 1.5 M triethylammonium bicarbonate (TEAB). The target compound **1** eluted at 70 to 77% 1.5 M TEAB. Fractions containing the target were identified using the Briggs phosphate assay, combined and evaporated under reduced pressure. De-ionised water was repeatedly added and evaporated until the triethylammonium salt of **1** remained as a colourless glassy solid (14 mg, 16 μmol, 57%). This material was accurately quantified using total phosphate assay[@cit37] before biological evaluation. For ^31^P and ^1^H NMR analysis of **1**, a small amount of EDTA (sodium salt, approx. 0.1 mg) was added to a sample of **1** (2.0 μmole in 0.4 mL D~2~O) to give sharper signals. This NMR sample containing EDTA was kept as the solution in D~2~O for \>1 year at 4 °C with no sign of deterioration. ^1^H NMR (D~2~O, 500 MHz, EDTA added) *δ* 3.77 (1 H, dd, *J* 9.8, 2.9 Hz, H-3), 3.95 (1 H, t, *J* 9.6 Hz, H-6), 4.08 (1 H, apparent q, *J* 9.1 Hz, H-5), 4.15 (1 H, ddd, *J* 9.9, 8.3, 2.8 Hz, H-1), 4.32 (1 H, apparent q, *J* 9.4 Hz, H-4), 4.35 (1 H, apparent t, *J* 2.8 Hz, H-2); ^13^C NMR (D~2~O, 101 MHz) *δ* 70.15 and 70.31 (C-2 and C-3), 70.88 (C-6), 76.28 (^2^*J*~CP~ 5.6 Hz, C-1), 76.82 (with *J*~CP~ couplings, C-4) and 78.11 (with *J*~CP~ couplings, C-5); ^31^P NMR (D~2~O, 202 MHz, EDTA added, ^1^H-decoupled) *δ* 1.11 (1 P), 0.45 (1 P), --10.48 (1 P, d, *J* 20.9 Hz, P-1~β~), --11.96 (d, *J* 20.9 Hz, P-1~α~); ^31^P NMR (D~2~O, 162 MHz, EDTA added, ^1^H-coupled) *δ* 1.13 (1 P, d, ^3^*J*~HP~ 8.8 Hz), 0.47 (1 P, d, ^3^*J*~HP~ 8.9 Hz), --10.46 (1 P, d, ^2^*J*~PP~ 20.5 Hz, P-1~β~), --11.94 (1 P, dd, ^2^*J*~PP~ 20.5, ^3^*J*~HP~ 8.3 Hz, P-1~α~); HRMS (*m*/*z*) M^--^ calcd. for C~6~H~16~O~18~P~4~; 498.9209; found 498.9214. ### Molecular docking of 1-PP-Ins(4,5)P~2~ (**1**) into type 1 InsP~3~ receptor Molecular docking experiments were carried out using the X-ray crystal structure of the *N*-terminal IBC of type 1 InsP~3~ receptor in complex with Ins(1,4,5)P~3~ (1N4K).[@cit18] Docking methods were optimised by docking flexible models of Ins(1,4,5)P~3~ into the 1N4K structure using GOLD[@cit38] (version 5.6, CCDC). In the most successful protocol, the binding site was defined as a sphere of 6 Å radius centred on the centroid of bound Ins(1,4,5)P~3~ and two water molecules (waters 1139 and 1198) were included in the docking protocol. These water molecules were toggled on and off and allowed to spin in the docking runs.[@cit39] The ligand was docked 100 times using the GoldScore scoring function, and genetic algorithm settings for very flexible ligands were used. This method accurately reproduced the observed pose of bound Ins(1,4,5)P~3~ in 1N4K; the ten highest scoring poses all closely resembled the conformation of bound Ins(1,4,5)P~3~ (mean RMSD 0.58 Å). When 1-PP-Ins(4,5)P~2~ (**1**) was docked using the same protocol, the highest-scoring poses were very similar to the bound conformation of Ins(1,4,5)P~3~ but often showed additional interactions of the 1-beta-phosphate group with residues in the binding site. More details are given in the ESI.[†](#fn1){ref-type="fn"} ### Assays of InsP~3~ receptor activity Ca^2+^ release from the intracellular stores of permeabilised DT40 cells expressing rat type 1 InsP~3~ receptors was measured in cytosol-like medium (CLM) using a low-affinity fluorescent Ca^2+^ indicator trapped within the endoplasmic reticulum as previously reported.[@cit40] Equilibrium competition binding of \[^3^H\]-InsP~3~ (1.5 nM, 19.3 Ci mmol^--1^) to membranes prepared from insect Sf9 cells expressing rat type 1 InsP~3~ receptors was determined in CLM at 4 °C. Bound and free ligand were separated by centrifugation and non-specific binding was determined by addition of 10 μM InsP~3~. ### DIPP purification cDNAs for all DIPPs were kind gifts from the Structural Genomics Consortium, Stockholm. cDNAs were modified as necessary in order to represent the full-length constructs, cloned into pET28a (+) and expressed as *N*-terminally His-tagged proteins. All proteins were expressed in BL21 (DE3) T1R pRARE2 at 18 °C overnight and purified by the Protein Science Facility (PSF) at the Karolinska Institute, Stockholm. Briefly, the proteins were first purified over a HisTrap HP column (GE Healthcare), followed by thrombin cleavage of the *N*-terminal His-tag. After removal of the His-tag through a second run over a HisTrap HP column, the proteins were further purified by gel filtration using a HiLoad 16/60 Superdex 75 column (GE Healthcare). ### Enzyme activity assay (DIPPs) Activity of DIPPs with a panel of potential substrates (1-PP-InsP~5~, 5-PP-InsP~5~, 1-PP-Ins(4,5)P~2~ (**1**), Ap~3~A, and Ap~5~A (Sigma Aldrich)) and control compounds (1-PCP-InsP~5~ and 5-PCP-InsP~5~) was assessed in technical triplicates in reaction buffer (100 mM Tris acetate, pH 7.5, 40 mM NaCl, 1 mM DTT) containing either 1 mM Mg acetate or MnCl~2~. Following an incubation time of 20 min at room temperature with shaking, the formed inorganic phosphate was detected through addition of malachite green reagent.[@cit41] After an additional 15 min incubation with shaking, absorbance at 630 nm was read using a Hidex Sense plate reader. ### Differential scanning fluorimetry (DSF) DSF[@cit42] was performed with 5 μM purified protein in 25 mM HEPES pH 7.5, 100 mM NaCl, 0.5 mM TCEP and 5× Sypro Orange added per well of a 96-well PCR plate. Substrates and substrate analogues were dissolved in water and diluted 1 : 10 in the assay mixture. The heat denaturation curves with a temperature increase of 1 °C min^--1^ from 25 °C to 95 °C were recorded on a CFX96 real-time PCR machine (Bio-Rad) by measuring the fluorescence of Sypro Orange with excitation and emission wavelengths of 470 and 570 nm, respectively. The Boltzmann equation was used to analyse the denaturation curves in GraphPad Prism. The determined melting temperature (*T*~m~) is the inflection point of the sigmoidal denaturation curve. Conflicts of interest ===================== There are no conflicts to declare. Supplementary Material ====================== Supplementary information ###### Click here for additional data file. BVLP (grant 101010) and CWT (grant 101844) are Wellcome Trust Senior Investigators. We also acknowledge funding by the Swedish Pain Relief Foundation and the Swedish Cancer Society (TH). We thank Dr Stephen B. Shears for helpful discussions on the enzymes that are known to synthesise PP-InsPs. [^1]: †Electronic supplementary information (ESI) available: NMR spectra, additional DSF data and details of molecular docking experiments. See DOI: [10.1039/c8md00149a](10.1039/c8md00149a) [^2]: ‡A synthetic InsP~3~ derivative featuring 4-carboxy-malachite green conjugated to the 1-phosphate group was reported to have ∼170-fold higher affinity than InsP~3~ for an *N*-terminal fragment of type 1 InsP~3~ receptors.[@cit43] In our hands, this compound was ∼5-fold less potent than InsP~3~ at each InsP~3~ receptor subtype and had an affinity ∼7-fold less than InsP~3~ for type 1 InsP~3~ receptors.[@cit44] | High | [
0.672868217054263,
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DescriptionHomid : Olive complexion with dark wavy hair. He is of average height and build. His eyes, while dark brown, seem to catch the light with a glint of cold in them. Crinos : White fur with grey fur wrapped up his arms, to his elbows, and his legs, up to his knees. Lupus : Fur as white as fresh snow, with grey around his paws. Biography Under Construction Rumors - Frost Paws, as a pup, stood still so long his feet froze to the tundra, turning his fur grey by his feet - Frost Paws's grey fur won't allow the cold to touch him - Coats made of the fur stave off the sharpest wind or harshest cold - Frost Paws killed Ambrose 'Silverheart' Laskaris - Frost Paws is despised by many of his tribe for his non-Native American appearance - Add gossip as needed Timeline - 2009 : Year of Birth - 2010 : Ambrose 'Silverheart' Laskaris, during the battle of the Crescent Moon, saved Frost Paws from a Nexus Crawler - 2010 : Priscilla to Caribou River Park Reserve (Manitoba, Canada) for safety after the attack on the Sept of the Crescent Moon - 2013 : Year of First Change - 2014 : Rite of Passage (Gains Rank of Cliath) - 2015 : Left Manitoba, Canada to travel - 2015 : Traveled briefly with Aiden around the US a bit (tag along) - 2016 : Join the pack Lux Tenebris to help raise a caern - 2016 : Participates in the raising of the Puerto Rico Caern - 2016 : Joins the Sept of the Gathering Tides in Puerto Rico Quotes - "I've rarely spent time in the lands claimed by the Wendigo. Frost Paws is the first I have come to know well of that Tribe. If he is any indication of their valor and their loyalty then I should count that lack among the few regrets I have in this life." - Ambrose Silverheart - "Call for Battle, fight Bane and Fomori. Wendigo came, gave good fight. Hear kill Alpha, will watch close, not allow happen." - Amasis Sabry - "He is stout. I like him. He needs more confidence in the gifts Gaia has given him, though. But he is young, and that confidence should come in time. Hopefully not too late though. It is hard to tell with the young." - Anton "Guards-The-Door" Rourke - "Getting to see him as the Garou he is now, makes all that effort worth it when I wisked him from that terrible battle years ago." - Priscilla Lamnidae - "They say that the young have lost their way, that in these times of Apocalypse we have lost all hope. And then I look into this ones bright eyes and it it is there that I find that hope." - Nedda white eyes - - " Fierce in his determination, adaptable and strong- A true Gaian Warrior and a loyal packmate" - Raine SafeGuard - Feel free to insert at your leisure Primary Items for Ties - Between 2015 and 2016 : Did I travel around with you while learning about the Nation and the Theurge role? (Fera and Garou welcome) - Between 2015 and 2016 : Did you mentor me for: Lores, General Theurgy Business, Languages, being Human acting - Between 2015 and 2016 : Did you mentor me for ideological views? - Between 2015 and 2016 : Did we protest deforestation or support some other Nature Protection cause? | Mid | [
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At least some example embodiments of the inventive concepts relate to video encoding, and more particularly, to video encoding apparatuses and methods adjusting quantization parameters. Video encoding may refer to a process of generating encoded data having a smaller size than original data from the original data, that is, image data or video data including a series of image data. Decoded data generated by decoding encoded data or a bitstream may be identical to or different from original data according to video encoding methods. For example, data decoded from encoded data according to lossless compression may be identical to original data, while data decoded from encoded data according to lossy compression may be different from original data. It is one of the main objects of video encoding to reduce the difference between decoded data and original data while reducing the size of data encoded according to lossy compression, that is, the bitrate of a bitstream. Accordingly, it is necessary to provide video encoding for accurately measuring distortion in decoded data from original data and reducing the measured distortion. | Mid | [
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--- title: NVv4 シリーズ description: NVv4 シリーズ VM の仕様。 services: virtual-machines ms.subservice: sizes author: vikancha-MSFT ms.service: virtual-machines ms.topic: conceptual ms.date: 02/03/2020 ms.author: jushiman ms.openlocfilehash: 9b841b6422a4314b43a594cb0b22040f884228eb ms.sourcegitcommit: 8def3249f2c216d7b9d96b154eb096640221b6b9 ms.translationtype: HT ms.contentlocale: ja-JP ms.lasthandoff: 08/03/2020 ms.locfileid: "87543896" --- # <a name="nvv4-series"></a>NVv4 シリーズ NVv4 シリーズ仮想マシンは [AMD Radeon Instinct MI25](https://www.amd.com/en/products/professional-graphics/instinct-mi25) GPU および AMD EPYC 7V12 (Rome) CPU を搭載しています。 NVv4 シリーズの場合、Azure では、部分的な GPU を備えた仮想マシンを導入しています。 16 GiB フレーム バッファーを備えた完全な GPU に対して 2 GiB フレーム バッファーを備えた 8 分の 1 の GPU を下限として、GPU で強化されたグラフィックス アプリケーションと仮想デスクトップに対して適正なサイズの仮想マシンを選択します。 NVv4 仮想マシンでは現在、Windows ゲスト オペレーティング システムのみがサポートされています。 <br> ACU: 230-260 Premium Storage: サポートされています Premium Storage キャッシュ:サポートされています ライブ マイグレーション: サポートされていません メモリ保持更新: サポートされていません | サイズ | vCPU | メモリ:GiB | 一時ストレージ (SSD) GiB | GPU | GPU メモリ: GiB | 最大データ ディスク数 | 最大 NIC 数/想定ネットワーク帯域幅 (MBps) | | --- | --- | --- | --- | --- | --- | --- | --- | | Standard_NV4as_v4 |4 |14 |88 | 1/8 | 2 | 4 | 2/1,000 | | Standard_NV8as_v4 |8 |28 |176 | 1/4 | 4 | 8 | 4/2,000 | | Standard_NV16as_v4 |16 |56 |352 | 1/2 | 8 | 16 | 8/4,000 | | Standard_NV32as_v4 |32 |112 |704 | 1 | 16 | 32 | 8/8,000 | <sup>1</sup> NVv4 シリーズ VM では、AMD 同時実行マルチスレッド技術を考慮しています [!INCLUDE [virtual-machines-common-sizes-table-defs](../../includes/virtual-machines-common-sizes-table-defs.md)] ## <a name="supported-operating-systems-and-drivers"></a>サポートされているオペレーティング システムとドライバー Windows を実行している Azure NVv4 シリーズ VM の GPU 機能を利用するには、AMD GPU ドライバーがインストールされている必要があります。 AMD GPU ドライバーを手動でインストールする場合、サポートされるオペレーティング システム、ドライバー、インストールおよび検証手順については、[Windows 用 N シリーズ AMD GPU ドライバーのセットアップ](./windows/n-series-amd-driver-setup.md)に関する記事を参照してください。 ## <a name="other-sizes"></a>その他のサイズ - [汎用](sizes-general.md) - [メモリの最適化](sizes-memory.md) - [ストレージの最適化](sizes-storage.md) - [GPU の最適化](sizes-gpu.md) - [ハイ パフォーマンス コンピューティング](sizes-hpc.md) - [旧世代](sizes-previous-gen.md) ## <a name="next-steps"></a>次のステップ [Azure コンピューティング ユニット (ACU)](acu.md) を確認することで、Azure SKU 全体の処理性能を比較できます。 | Mid | [
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Even those who do not go to the fitness center could achieve a level stomach. All it takes is some technique in your eating practices and a few added activities. Things You’ll Need Whole grains Lean proteins Fresh fruits and vegetables Exercise mat Pilates and/or yoga exercise workout DVD Diet and Movement Eat fresh fruits, vegetables, lean proteins, entire grains and low-fat milk. Entire grains such as oatmeal as well as brown rice have fiber, which aids avoid bloating relevant to bowel irregularity. Whole vegetables as well as fruits are nutrient-rich, yet low in calorie– helping you keep your weight with sufficient nutrition. Lean proteins assist you really feel full longer, so you could stick to your diet. Drink a great deal of water. Water helps flush out your system as well as maintains your gastrointestinal system routine. Drinking water likewise fends off meaningless snacking that can undermine your flat-belly diet. Eat usually. Little dishes (around 3-400 calories each) four or 5 times a day assist maintain your metabolism revved and also your stomach flatter. You never experience the distension connected with overstuffing, and your power degrees remain even. Limit consumption of certain foods. Avoid gas-producing foods such as cabbage and broccoli that distend the abdomen. Keep away from saturated fats and also simple white-flour and sugar products that motivate the accumulation of stomach fat. Processed foods filled with salt also trigger bloating. Perform workouts each day to strengthen your abdomen. Attempt traditional crunches. Lie in a supine position with your knees bent. Cup your hands gently behind your head. Curl the shoulder blades off the floor. Keep your feet and also reduced back pressed right into your workout mat throughout the crinkle. Yoga exercise and also Pilates both activate the core and assist with stance, so practice with dvds in your home to promote a flat belly. | Mid | [
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Conservative comeback plan for Chaves Mitchelton-SCOTT will take a conservative approach to the comeback of Colombian climber Esteban Chaves after he returned to the bike this week for the first time since finishing the Giro d’Italia ten weeks ago. After claiming a spectacular victory atop Mt Etna on stage six of the Italian Grand Tour, Chaves unexpectantly dropped out of overall contention on stage 10. The 28-year-old fought on in attempt to assist teammate Simon Yates in his 13 days in the Maglia Rosa before he and the Mitchelton-SCOTT medical team turned their attention to discovering the cause of symptoms impacting his ability to ride at his top level. After extensive testing, the two-time Grand Tour podium placer was diagnosed with a number of viruses, including Mononucleosis (also known as Epstein-Barr or Glandular Fever), along with sinus and allergy reactions. After treatment and an extensive period of rest, Chaves has now been given the all-clear to begin training but, with the support and guidance of the Mitchelton-SCOTT medical and high performance team, will remain cautious in his return to fitness. The 2016 Il Lombardia champion will not line up as previously planned at the upcoming Vuelta a Espana and any possible return to racing in 2018 will be determined by careful consideration of his progress. Esteban Chaves: “It’s been a hard period. Since 2012 I haven’t been off the bike this long, especially because I can’t. It was not fast like you want. In this sport, we are used to answers and results coming fast and this process was slow and the time can make you crazy. “But, we worked really well with the team and I want to thank you them for their support and patience, from the head with Shayne and Gerry, to the masseurs and mechanics that have been close to me in this process. “We discovered some sickness, the doctors can always explain better, we had a surgery as well, and after that it was just waiting and having confidence to overcome what was a weird case. “I’m happy to be back on the bike. It still hurts for sure, but I can already feel some differences; it’s a different suffering than I had before. Now it’s the normal suffering we get when starting again after such a long time off training. “We are on the right path again and we have to keep patience and confidence like always.” Manuel Rodriguez, Mitchelton-SCOTT doctor: “After thorough testing, Esteban was diagnosed with Epstein-Barr virus as well as chronic sinusitis process. “Epstein-Barr is not a new virus nor an uncommon one, but in Esteban tests showed that it was gaining strength and attacking when his immune system was down or in times of fatigue, most obviously in races or high intensity training periods. Its strength likely allowed the introduction of other viruses into his body. “After a period of rest and treatment for the viruses, Esteban was cleared for minor sinus surgery before undertaking a final recovery period. “We are confident that the treatments have been successful and it is safe for Esteban to return to training but to prevent the reoccurrence of symptoms we will monitor his health without a deadline to return to racing.” Photo courtesy of Kristof Ramon. | Mid | [
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Posts Tagged ‘karl’ [Editor's note: With fixed rate home mortgages at new record lows, now is the time to consider refinancing (again). How this is possible in the current financial paradigm, I am not sure. But the tool demonstrated below from Karl will show you how much cash you'll save over the long term by refinancing at a lower rate.] Instructions 1. Sliders Move the sliders to set the values of your principal, interest rate, loan length, and mortgage start date. Up and down arrows at either side of the slider allow the range of values covered by the slider to be adjusted. The checkboxes on the left of the sliders determine whether principal, interest, term or payment is calculated. By default, the Payment slider checkbox is ticked, meaning that moving the other sliders’ values will calculate the payment. Clicking on another slider checkbox, e.g. Principal checkbox, allows the user to modify term, interest and payment to see the Principal value calculated as these other values change. 2. Graphs & tables Use the buttons underneath the graphs and tables to choose how you want the output to be displayed: Amortization Graph – this shows how the monthly payments made each year are broken down. Note how the curves show increased principal and decreased interest being paid as time goes by. Also note that extra payments “push” up the principal curve, i.e. the annual principal amount shown is increased by the value of the extra payment. Repayment Chart – the percentage breakdown of the total payments made over the entire mortgage (or indeed, the breakdown of the average monthly payment). Balance Graph – this shows the balance outstanding over the term of the mortgage. It is useful when extra payments are made to visually see how much sooner the mortgage is paid off, and how quickly the balance drops. Interest Graph – this shows the rate of interest used over the term of the mortgage. Annual Amortization Table – how much interest and principal you pay each year. Monthly Amortization Table – how much interest and principal you pay each year, broken down month by month. Monthly Payments Table – the payment amount and any extra payment made each month. Useful when interest rates change or if extra payments reduce monthly payment. Summary – shows a summary of the current values. Settings: Monthly/Bi-weekly payments – Limited support for bi-weekly mortgages is present through this option. When Bi-weekly payments are selected, an extra 1/12th payment is made every month. This equates to making 13 monthly payments every 12 months – a close approximation of how a typical bi-weekly mortgage will work (52 weeks / 2 weeks = 26 half-monthly payments == 13 monthly payments). Note that extra payments are always considered monthly payments, so no equivalent bi-weekly approximation is made. Extra payments – default is to reduce term when extra payments are made, but alternative is to keep term unchanged and reduce monthly payment instead. Interest sliders – You can use either 1/8th increments or decimal places. Dynamic/static – Dynamic calculation means that calculations are done as you move the slider; this is the default. Static means that the calculations are done when you’ve finished dragging the slider. 3. Input boxes The bottom of the calculator is split in two: Fixed Loan Data Prepayment data Extra payments Interest rates ARM The Fixed Loan Data section stays constant while the other four sections can be chosen using the buttons at the bottom of the calculator. Fixed Loan Data – use this as an alternative to the sliders for entering values. This section is called fixed because it does not take interest rate changes into account. The annual Tax and Insurance fields are simply divided by 12 and added to the monthly payment amount. The inflation figure allows estimates in real terms (i.e. in “today’s money”) to be calculated. The total interest paid over the entire mortgage is shown on the right hand side along with the total interest paid as a percentage of all payments made (see the Repayment Chart for a graphical view). Finally, the total interest paid in real terms (“real interest”) is displayed – this figure is an attempt at calculating how much the total interest paid is worth in real terms. The four optional sections: Prepayment Data – this section gives you the opportunity to estimate how you can shorten the term of your mortgage by making either a single one-off payment or continuous extra monthly or annual payments. You must enter a starting month for the prepayment to take effect. The format is simply the month number i.e. 1 for the first month, 2 for the second month and so on. On the right-hand side, the Savings field shows you how much money you will save, while the Real Savings field once again uses the inflation rate to give a rough estimate of what these savings are in real terms given that the interest savings are spread over a number of years. The dates shown reflect what happens to the mortgage term when the extra payments have been factored in. Extra payments – add up to six extra one-time payments, giving the start and end months numbers to indicate the period when the extra payment is to be made. Interest rates – add up to five extra interest rates, giving the start and end month numbers to indicate when the interest rate is active. Months outside these ranges will use the fixed loan data interest rate. To specify a period where no principal is paid, enter a start and end month in the interest-only payments section. ARM – Adjustable Rate Mortgage support is provied in this section. Enter a start month to activate and click on the interest rate graph to view how this section alters the interest rates over the term of the mortgage. Notes Enter the nominal interest rate not an APR. All calculations are performed on a monthly basis. The figures are estimates only – your lender’s figures will vary! | Low | [
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Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task. Understanding the mechanistic basis of working memory, the capacity to hold representation "on line," is important for delineating the processes involved in higher cognitive functions and the pathophysiology of thought disorders. We compared the contribution of glutamate and dopamine receptor subtypes to temporal aspects of working memory using a modified rodent spatial working memory task that incorporates important elements of clinical working memory tasks. A discrete paired-trial variable-delay T-maze task was used. Initial characterization studies indicated that performance on this task is stable at seconds-long retention intervals, is sensitive to retention interval and proactive interference, and is dependent on the integrity of the medial prefrontal cortex. Consistent with clinical findings, low dose amphetamine (0.25 mg/kg) produced a delay-dependent improvement in performance, while higher doses impaired performance at all retention intervals. D1 receptor blockade produced the predicted dose- and delay-dependent impairment. D2 receptor blockade had no effect. Activation of metabotropic glutamate 2/3 (mGluR2/3) receptors, which in the prefrontal cortex inhibits the slow asynchronous phase of glutamate release, also produced a delay-dependent impairment. Low doses of an AMPA/kainate antagonist had effects similar to the mGluR2/3 agonist. In contrast, NMDA receptor antagonist-induced impairment was memory load-insensitive, resulting in chance-level performance at all retention intervals. These findings suggest that activation of NMDA receptors is necessary for the formation of mnemonic encoding while modulatory components involving slow asynchronous release of glutamate and phasic release of dopamine contribute to the active maintenance of information during the delay period. | High | [
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A. FIELD OF THE INVENTION The present invention relates to a hot melt pressure sensitive adhesive composition and to articles of manufacture incorporating the adhesive composition. The pressure sensitive adhesive of the present invention has the properties of low viscosity and high tensile strength without requiring viscosity adjusters, making it particularly useful for disposable diaper construction and hinge gluing in books. Further, it was discovered that the pressure sensitive adhesive of the present invention also has good high and low temperature performance making it useful for PET bottle labeling or mounting HDPE bases to PET beverage bottles. B. Prior Art Hot melt adhesive compositions are known throughout the disposables industry. However, it is equally well-known that a hot melt adhesive composition which is suited for bonding in one application may be completely unsuitable for other applications. For example, disposable diaper construction presents a unique set of problems to the adhesives formulator. The adhesive must possess a high degree of adhesion since it is applied in a series of very narrow lines or dots. Moreover, the adhesive must also possess sufficient adhesive and cohesive strength to provide high tensile strength bonds when subjected to stress so that the laminates used in the construction cannot be easily separated. Additionally, the adhesives must remain flexible and secure with age and not break down in a wet environment. Aesthetically, the adhesive should be white or clear in color. U.S. Pat. No. 4,526,577 (Schmidt, Jr., et al.) discloses a multi-line construction disposable diaper employing a pressure sensitive hot melt adhesive whose composition requires at least four classes of components. The composition for the Schmidt adhesive comprises a block or multi-block copolymer; tackifying resins having high softening points (about 100.degree.-120.degree. C.); a plasticizing oil; optionally, a petroleum wax; and one or more stabilizers. Pressure sensitive hot melt adhesive compositions have generally not been suited for performance in the disposable polyethyleneteriphthalic acid (PET) bottle industry, because these adhesive compositions lacked sufficient tensile strength at high and low temperatures. High and low temperature performance is important for maintaining the adherence of labels and the adherence of base cups on beverage bottles where the bottles are subject to repeated cycles of contraction and expansion caused by repeated cycles of refrigeration and room temperature warming. U.S. Pat. No. 4,212,910 (Taylor et al.) discloses a hot melt adhesive composition suitable for PET bottle assemblies consisting essentially of four classes of components: (1) a block copolymer or a teleblock copolymer; (2) at least one tackifying resin; (3) at least one stabilizer; and (4) at least one wax or oil diluent. | High | [
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// Created on: 1997-05-05 // Created by: Joelle CHAUVET // Copyright (c) 1997-1999 Matra Datavision // Copyright (c) 1999-2014 OPEN CASCADE SAS // // This file is part of Open CASCADE Technology software library. // // This library is free software; you can redistribute it and/or modify it under // the terms of the GNU Lesser General Public License version 2.1 as published // by the Free Software Foundation, with special exception defined in the file // OCCT_LGPL_EXCEPTION.txt. Consult the file LICENSE_LGPL_21.txt included in OCCT // distribution for complete text of the license and disclaimer of any warranty. // // Alternatively, this file may be used under the terms of Open CASCADE // commercial license or contractual agreement. // Modified: Mon Nov 3 10:24:07 1997 // ne traite que les GeomAdaptor_Surface; // plus de reference a BRepAdaptor #include <GeomPlate_CurveConstraint.ixx> #include <GCPnts_AbscissaPoint.hxx> #include <Adaptor2d_HCurve2d.hxx> #include <Adaptor3d_HSurface.hxx> #include <GeomAdaptor.hxx> #include <Precision.hxx> #include <GeomAdaptor_HSurface.hxx> #include <GeomAdaptor_HCurve.hxx> #include <ProjLib_ProjectedCurve.hxx> #include <Approx_Curve2d.hxx> #include <GeomAbs_Shape.hxx> //--------------------------------------------------------- // Constructeur vide //--------------------------------------------------------- GeomPlate_CurveConstraint :: GeomPlate_CurveConstraint () : myLProp(2,1.e-4) { } //--------------------------------------------------------- // Constructeurs avec courbe sur surface //--------------------------------------------------------- GeomPlate_CurveConstraint :: GeomPlate_CurveConstraint (const Handle(Adaptor3d_HCurveOnSurface)& Boundary, const Standard_Integer Tang, const Standard_Integer NPt, const Standard_Real TolDist, const Standard_Real TolAng, const Standard_Real TolCurv ) : myFrontiere(Boundary), myLProp(2,TolDist), myTolDist(TolDist), myTolAng(TolAng), myTolCurv(TolCurv) { myOrder=Tang; if ((Tang<-1)||(Tang>2)) Standard_Failure::Raise("GeomPlate : The continuity is not G0 G1 or G2"); myNbPoints=NPt; myConstG0=Standard_True; myConstG1=Standard_True; myConstG2=Standard_True; if (myFrontiere.IsNull()) Standard_Failure::Raise("GeomPlate_CurveConstraint : Curve must be on a Surface"); Handle(Geom_Surface) Surf; Handle(GeomAdaptor_HSurface) GS1; GS1 = Handle(GeomAdaptor_HSurface)::DownCast(myFrontiere->ChangeCurve().GetSurface()); if (!GS1.IsNull()) { Surf=GS1->ChangeSurface().Surface(); } else { // Handle(BRepAdaptor_HSurface) BS1; // BS1=Handle(BRepAdaptor_HSurface)::DownCast(myFrontiere->ChangeCurve().GetSurface()); // Surf = BRep_Tool::Surface(BS1->ChangeSurface().Face()); Standard_Failure::Raise("GeomPlate_CurveConstraint : Surface must be GeomAdaptor_Surface"); } myLProp.SetSurface(Surf); my2dCurve.Nullify(); myHCurve2d.Nullify(); myTolU=0.; myTolV=0.; myG0Crit.Nullify(); myG1Crit.Nullify(); myG2Crit.Nullify(); } //--------------------------------------------------------- // Constructeurs avec courbe 3d (pour continuite G0 G-1) //--------------------------------------------------------- GeomPlate_CurveConstraint :: GeomPlate_CurveConstraint (const Handle(Adaptor3d_HCurve)& Boundary, const Standard_Integer Tang, const Standard_Integer NPt, const Standard_Real TolDist) : my3dCurve(Boundary), myLProp(2,TolDist), myTolDist(TolDist) { myOrder=Tang; if ((Tang!=-1)&&(Tang!=0)) Standard_Failure::Raise("GeomPlate : The continuity is not G0 or G-1"); myNbPoints=NPt; myConstG0=Standard_True; myConstG1=Standard_True; myConstG2=Standard_True; my2dCurve.Nullify(); myHCurve2d.Nullify(); myTolU=0.; myTolV=0.; myG0Crit.Nullify(); myG1Crit.Nullify(); myG2Crit.Nullify(); } //--------------------------------------------------------- // Fonction : FirstParameter //--------------------------------------------------------- Standard_Real GeomPlate_CurveConstraint :: FirstParameter() const { if (!myHCurve2d.IsNull()) return myHCurve2d->FirstParameter(); else if (my3dCurve.IsNull()) return myFrontiere->FirstParameter(); else return my3dCurve->FirstParameter(); } //--------------------------------------------------------- // Fonction : LastParameter //--------------------------------------------------------- Standard_Real GeomPlate_CurveConstraint :: LastParameter() const { if (!myHCurve2d.IsNull()) return myHCurve2d->LastParameter(); else if (my3dCurve.IsNull()) return myFrontiere->LastParameter(); else return my3dCurve->LastParameter(); } //--------------------------------------------------------- // Fonction : Length //--------------------------------------------------------- Standard_Real GeomPlate_CurveConstraint :: Length() const { GCPnts_AbscissaPoint AP; if (my3dCurve.IsNull()) {// GCPnts_AbscissaPoint A(myFrontiere->Curve(),AP.Length(myFrontiere->Curve())/2,myFrontiere->FirstParameter()); // Standard_Real toto=A.Parameter(); //cout<<toto<<endl; return AP.Length(myFrontiere->GetCurve()); } else { // GCPnts_AbscissaPoint A(my3dCurve->Curve(),AP.Length(my3dCurve->Curve())/2,my3dCurve->FirstParameter()); // Standard_Real toto=A.Parameter(); //cout<<toto<<endl; return AP.Length(my3dCurve->GetCurve()); } } //--------------------------------------------------------- // Fonction : D0 //--------------------------------------------------------- void GeomPlate_CurveConstraint :: D0(const Standard_Real U,gp_Pnt& P) const { gp_Pnt2d P2d; if (my3dCurve.IsNull()) { P2d = myFrontiere->ChangeCurve().GetCurve()->Value(U); myFrontiere->ChangeCurve().GetSurface()->D0(P2d.Coord(1),P2d.Coord(2),P); } else my3dCurve->D0(U,P); } //--------------------------------------------------------- // Fonction : D1 //--------------------------------------------------------- void GeomPlate_CurveConstraint :: D1(const Standard_Real U, gp_Pnt& P,gp_Vec& V1,gp_Vec& V2) const { gp_Pnt2d P2d; if (!my3dCurve.IsNull()) Standard_Failure::Raise("GeomPlate_CurveConstraint.cxx : Curve must be on a Surface"); P2d = myFrontiere->ChangeCurve().GetCurve()->Value(U); myFrontiere->ChangeCurve().GetSurface()->D1(P2d.Coord(1),P2d.Coord(2),P,V1,V2); } //--------------------------------------------------------- // Fonction : D2 //--------------------------------------------------------- void GeomPlate_CurveConstraint :: D2(const Standard_Real U, gp_Pnt& P,gp_Vec& V1,gp_Vec& V2, gp_Vec& V3,gp_Vec& V4,gp_Vec& V5) const { gp_Pnt2d P2d; if (!my3dCurve.IsNull()) Standard_Failure::Raise("GeomPlate_CurveConstraint.cxx : Curve must be on a Surface"); P2d = myFrontiere->ChangeCurve().GetCurve()->Value(U); myFrontiere->ChangeCurve().GetSurface()->D2(P2d.Coord(1),P2d.Coord(2),P,V1,V2,V3,V4,V5); } //--------------------------------------------------------- // Fonction : SetG0Criterion //--------------------------------------------------------- void GeomPlate_CurveConstraint :: SetG0Criterion(const Handle(Law_Function) &G0Crit) { myG0Crit=G0Crit; myConstG0=Standard_False; } //--------------------------------------------------------- // Fonction : SetG1Criterion //--------------------------------------------------------- void GeomPlate_CurveConstraint :: SetG1Criterion(const Handle(Law_Function) &G1Crit) { if (!my3dCurve.IsNull()) Standard_Failure::Raise("GeomPlate_CurveConstraint.cxx : Curve must be on a Surface"); myG1Crit=G1Crit; myConstG1=Standard_False; } //--------------------------------------------------------- // Fonction : SetG2Criterion //--------------------------------------------------------- void GeomPlate_CurveConstraint :: SetG2Criterion(const Handle(Law_Function) &G2Crit) { if (!my3dCurve.IsNull()) Standard_Failure::Raise("GeomPlate_CurveConstraint.cxx : Curve must be on a Surface"); myG2Crit=G2Crit; myConstG2=Standard_False; } //--------------------------------------------------------- // Fonction : G0Criterion //--------------------------------------------------------- Standard_Real GeomPlate_CurveConstraint :: G0Criterion(const Standard_Real U) const { if (myConstG0) return myTolDist; else return myG0Crit->Value(U); } //--------------------------------------------------------- // Fonction : G1Criterion //--------------------------------------------------------- Standard_Real GeomPlate_CurveConstraint :: G1Criterion(const Standard_Real U) const { if (!my3dCurve.IsNull()) Standard_Failure::Raise("GeomPlate_CurveConstraint.cxx : Curve must be on a Surface"); if (myConstG1) return myTolAng; else return myG1Crit->Value(U); } //--------------------------------------------------------- // Fonction : G2Criterion //--------------------------------------------------------- Standard_Real GeomPlate_CurveConstraint :: G2Criterion(const Standard_Real U) const { if (!my3dCurve.IsNull()) Standard_Failure::Raise("GeomPlate_CurveConstraint.cxx : Curve must be on a Surface"); if (myConstG2) return myTolCurv; else return myG2Crit->Value(U); } //--------------------------------------------------------- // Fonction : Curve2dOnSurf //--------------------------------------------------------- Handle(Geom2d_Curve) GeomPlate_CurveConstraint :: Curve2dOnSurf () const { if(my2dCurve.IsNull() && !myHCurve2d.IsNull()) { Handle(Geom2d_Curve) C2d; GeomAbs_Shape Continuity = GeomAbs_C1; Standard_Integer MaxDegree = 10; Standard_Integer MaxSeg=20+myHCurve2d->NbIntervals(GeomAbs_C3); Approx_Curve2d appr(myHCurve2d,myHCurve2d->FirstParameter(),myHCurve2d->LastParameter(), myTolU,myTolV,Continuity,MaxDegree,MaxSeg); C2d = appr.Curve(); return C2d; } else return my2dCurve; } //--------------------------------------------------------- // Fonction : SetCurve2dOnSurf //--------------------------------------------------------- void GeomPlate_CurveConstraint :: SetCurve2dOnSurf (const Handle(Geom2d_Curve) &Curve) { my2dCurve=Curve; } //--------------------------------------------------------- // Fonction : ProjectedCurve //--------------------------------------------------------- Handle(Adaptor2d_HCurve2d) GeomPlate_CurveConstraint :: ProjectedCurve () const { return myHCurve2d; } //--------------------------------------------------------- // Fonction : SetProjectedCurve //--------------------------------------------------------- void GeomPlate_CurveConstraint :: SetProjectedCurve (const Handle(Adaptor2d_HCurve2d) &Curve, const Standard_Real TolU,const Standard_Real TolV) { myHCurve2d=Curve; myTolU=TolU; myTolV=TolV; } //--------------------------------------------------------- // Fonction : Curve3d //--------------------------------------------------------- Handle(Adaptor3d_HCurve) GeomPlate_CurveConstraint :: Curve3d () const { if (my3dCurve.IsNull()) return myFrontiere; else return my3dCurve; } //------------------------------------------------------------ //Fonction : NbPoints //------------------------------------------------------------ Standard_Integer GeomPlate_CurveConstraint::NbPoints() const { return myNbPoints; } //------------------------------------------------------------ //Fonction : Order //------------------------------------------------------------ Standard_Integer GeomPlate_CurveConstraint::Order() const { return myOrder; } //------------------------------------------------------------ //Fonction : SetNbPoints //------------------------------------------------------------ void GeomPlate_CurveConstraint::SetNbPoints(const Standard_Integer NewNb) { myNbPoints = NewNb; } //------------------------------------------------------------ //Fonction : SetOrder //------------------------------------------------------------ void GeomPlate_CurveConstraint::SetOrder(const Standard_Integer Order) { myOrder = Order; } //------------------------------------------------------------ //Fonction : LPropSurf //------------------------------------------------------------ GeomLProp_SLProps &GeomPlate_CurveConstraint::LPropSurf(const Standard_Real U) { if (myFrontiere.IsNull()) Standard_Failure::Raise("GeomPlate_CurveConstraint.cxx : Curve must be on a Surface"); gp_Pnt2d P2d= myFrontiere->ChangeCurve().GetCurve()->Value(U); myLProp.SetParameters(P2d.X(),P2d.Y()); return myLProp; } | Low | [
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Stephen Shankland/CNET It seemed like it was only a matter of time before e-commerce giant eBay and its payment platform PayPal addressed the sale and use of Bitcoin on its sites. And, despite concern from government regulators, it appears the company believes in virtual currencies -- so much so, that it will soon start allowing their sale on its US and UK sites. Last week, PayPal President David Marcus tweeted "To clarify: we have no policies against using PayPal to sell Bitcoin mining rigs. We don't support any currency txn whether fiat or BTC... for a host of regulatory issues. But we treat BTC and any FX txn the same way. We're believers in BTC though." Then, a couple of days later, eBay UK sent an e-mail to one of its merchants that was published on Reddit, which said the company plans to open a "Virtual Currency" category for the sale of Bitcoin and other digital currencies on the UK site. Please know that per our recent policy update, Virtual Currency (i.e. Bitcoin and Litecoin), whether digitally or physically delivered, cannot be listed in Auction-style or Buy-It-Now listing formats. eBay is opening a Virtual Currency category to allow the sale of virtual currency in Classified Ads format on February 10, 2014. We request that you do not list these items until that date. Please be informed that repeated breach of the policy may further jeopardize your account status. To avoid any inconvenience in future, we'd appreciated it if you go through our help pages or contact us before listing any such items. While eBay US and UK will start allowing Bitcoin to be sold in its classified ads format, it won't yet let users sell the currency in the auction or buy-it-now formats. Additionally, all transactions will be required to happen outside of eBay. A eBay UK spokesman told CNET that virtual currency sales will only be allowed on eBay US and eBay UK for now; it's unclear if the policy will spread to other countries where eBay operates. "To promote a trustworthy marketplace and ensure compliance with applicable regulations, eBay is updating its Currency Policy ," eBay UK spokesman Steve Heywood told CNET in an e-mail. "The updated policy clarifies that listings for Bitcoin and other similar virtual currencies must be listed in the Virtual Currency Category in the Classified Ad format. This applies to both the US (effective immediately) and the UK (effective 10 February)." Marcus told CNET in an interview last month, "I really like Bitcoin. I own bitcoins." But, he also said he's not yet ready to let people link their Bitcoin wallets with their PayPal accounts. "Whenever the regulatory framework is clearer, and the volatility comes down, then we'll consider it," he said. Bitcoin has proven that it can do well as a traded currency. It's been around since 2009, but didn't really get going until 2011 when it was worth $2 per coin. By 2013, the currency had climbed to $20 per coin, and then jumped to $266 last April. Within the past couple of months, it had another price jump and is now hovering around $1,000. While eBay appears to be opening its doors to virtual currency, China's largest e-commerce site Alibaba shut the door on Bitcoin earlier this month. The company announced that the sale of Bitcoins on its Web site is now banned. While the majority of site's sales are made via Taobao's Alipay system, a handful of merchants were accepting Bitcoin payments or selling the digital currency. [Via CoinDesk] Updated January 21 at 11:05 a.m. PT to clarify that virtual currency can be sold on both the US and UK eBay sites and to add comment from eBay UK spokesman Steve Heywood. | Mid | [
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Pro-amnesty From Conservapedia Pro-amnesty is the support of illegal immigration so that these people gain citizenship and not be deported for breaking existing laws. Beside granting citizenship, pro-amnesty supporters fight for the inclusion of these people to attend universities, find employment, receive government benefits and vote. None of the rules that apply to legal immigration are applied or enforced, such as having to learn English. | Low | [
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package Collectd::Graph::TypeLoader; =head1 NAME Collectd::Graph::TypeLoader - Load a module according to the "type" =cut # Copyright (C) 2008,2009 Florian octo Forster <octo at verplant.org> # # This program is free software; you can redistribute it and/or modify it under # the terms of the GNU General Public License as published by the Free Software # Foundation; only version 2 of the License is applicable. # # This program is distributed in the hope that it will be useful, but WITHOUT # ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS # FOR A PARTICULAR PURPOSE. See the GNU General Public License for more # details. # # You should have received a copy of the GNU General Public License along with # this program; if not, write to the Free Software Foundation, Inc., # 51 Franklin Street, Fifth Floor, Boston, MA 02110-1301, USA. use strict; use warnings; use Carp (qw(cluck confess)); use Exporter (); use Config::General ('ParseConfig'); use Collectd::Graph::Config ('gc_get_config'); use Collectd::Graph::Type (); @Collectd::Graph::TypeLoader::ISA = ('Exporter'); @Collectd::Graph::TypeLoader::EXPORT_OK = ('tl_load_type'); our @ArrayMembers = (qw(data_sources rrd_opts custom_order)); our @ScalarMembers = (qw(rrd_title rrd_format rrd_vertical scale ignore_unknown stacking)); our @DSMappedMembers = (qw(ds_names rrd_colors)); our %MemberToConfigMap = ( data_sources => 'datasources', ds_names => 'dsname', rrd_title => 'rrdtitle', rrd_opts => 'rrdoptions', rrd_format => 'rrdformat', rrd_vertical => 'rrdverticallabel', rrd_colors => 'color', scale => 'scale', # GenericIO only custom_order => 'order', # GenericStacked only stacking => 'stacking', # GenericStacked only ignore_unknown => 'ignoreunknown' # GenericStacked only ); return (1); sub _create_object { my $module = shift; my $obj; # Suppress warnings and error messages caused by the eval. local $SIG{__WARN__} = sub { return (1); print STDERR "WARNING: " . join (', ', @_) . "\n"; }; local $SIG{__DIE__} = sub { return (1); print STDERR "FATAL: " . join (', ', @_) . "\n"; }; eval <<PERL; require $module; \$obj = ${module}->new (); PERL if (!$obj) { return; } return ($obj); } # _create_object sub _load_module_from_config { my $conf = shift; my $module = $conf->{'module'}; my $obj; if ($module && !($module =~ m/::/)) { $module = "Collectd::Graph::Type::$module"; } if ($module) { $obj = _create_object ($module); if (!$obj) { #cluck ("Creating an $module object failed"); warn ("Creating an $module object failed"); return; } } else { $obj = Collectd::Graph::Type->new (); if (!$obj) { cluck ("Creating an Collectd::Graph::Type object failed"); return; } } for (@ScalarMembers) # {{{ { my $member = $_; my $key = $MemberToConfigMap{$member}; my $val; if (!defined $conf->{$key}) { next; } $val = $conf->{$key}; if (ref ($val) ne '') { cluck ("Invalid value type for $key: " . ref ($val)); next; } $obj->{$member} = $val; } # }}} for (@ArrayMembers) # {{{ { my $member = $_; my $key = $MemberToConfigMap{$member}; my $val; if (!defined $conf->{$key}) { next; } $val = $conf->{$key}; if (ref ($val) eq 'ARRAY') { $obj->{$member} = $val; } elsif (ref ($val) eq '') { $obj->{$member} = [split (' ', $val)]; } else { cluck ("Invalid value type for $key: " . ref ($val)); } } # }}} for (@DSMappedMembers) # {{{ { my $member = $_; my $key = $MemberToConfigMap{$member}; my @val_list; if (!defined $conf->{$key}) { next; } if (ref ($conf->{$key}) eq 'ARRAY') { @val_list = @{$conf->{$key}}; } elsif (ref ($conf->{$key}) eq '') { @val_list = ($conf->{$key}); } else { cluck ("Invalid value type for $key: " . ref ($conf->{$key})); next; } for (@val_list) { my $line = $_; my $ds; my $val; if (!defined ($line) || (ref ($line) ne '')) { next; } ($ds, $val) = split (' ', $line, 2); if (!$ds || !$val) { next; } $obj->{$member} ||= {}; $obj->{$member}{$ds} = $val; } # for (@val_list) } # }}} for (@DSMappedMembers) return ($obj); } # _load_module_from_config sub _load_module_generic { my $type = shift; my $module = ucfirst (lc ($type)); my $obj; $module =~ s/[^A-Za-z_]//g; $module =~ s/_([A-Za-z])/\U$1\E/g; $obj = _create_object ($module); if (!$obj) { $obj = Collectd::Graph::Type->new (); if (!$obj) { cluck ("Creating an Collectd::Graph::Type object failed"); return; } } return ($obj); } # _load_module_generic =head1 EXPORTED FUNCTIONS =over 4 =item B<tl_load_type> (I<$type>) Does whatever is necessary to get an object with which to graph RRD files of type I<$type>. =cut sub tl_load_type { my $type = shift; my $conf = gc_get_config (); if (defined ($conf) && defined ($conf->{'type'}{$type})) { return (_load_module_from_config ($conf->{'type'}{$type})); } else { return (_load_module_generic ($type)); } } # tl_load_type =back =head1 SEE ALSO L<Collectd::Graph::Type::GenericStacked> =head1 AUTHOR AND LICENSE Copyright (c) 2008 by Florian Forster E<lt>octoE<nbsp>atE<nbsp>verplant.orgE<gt>. Licensed under the terms of the GNU General Public License, VersionE<nbsp>2 (GPLv2). =cut # vim: set shiftwidth=2 softtabstop=2 tabstop=8 et fdm=marker : | Low | [
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Canada's cities say a Liberal proposal to scrap a $1-billion infrastructure fund will rob them of one of their few remaining sources of federal cash. Weighing in on the election campaign, the Federation of Canadian Municipalities says the Liberal plan would give cities money with one hand while taking with the other. "It's a bit of a shell game," Calgary Mayor Naheed Nenshi said in an interview with The Globe and Mail. "I was surprised to see it in their platform. Their platform certainly says some good things about affordable housing, but it says basically nothing about infrastructure or transit or any of the other issues that are important to cities, which I found a bit surprising." The Liberal plan, released Sunday, promises a $275-million-a-year "Affordable Housing Framework," aiming to reduce homelessness, and build and maintain social housing. To pay for this, a Liberal government would end the $1-billion Public Private Partnership Infrastructure Fund on the grounds that it has "accomplished virtually nothing." While that may be true - it has only funded a handful of projects since it was launched in 2008 - many municipalities have submitted or are planning to submit projects in the hope that the Crown corporation will share construction costs with cities and the private sector. Calgary has asked the P3 fund to help pay for four urban recreation centres, which the mayor said are sorely needed in Calgary. While the recent two-year flurry of stimulus spending by federal and provincial governments was welcome, Mr. Nenshi said it barely made a dent in the infrastructure deficit that cities continue to face. Yet now that the stimulus spending is over, the P3 fund is essentially the only place left for cities to turn to when they are looking for infrastructure help. The Liberals said Monday they want to scrap the fund because it wasn't effective. "We are not putting one dime less into Canada's cities than the Conservatives, whose track record points to a scattershot and often partisan approach to infrastructure funding," Liberal Leader Michael Ignatieff's director of communications said. "We're just taking an approach that works better than the failed (P3 fund), which has only put 8 per cent of funds out the door." Instead, Leslie Church said, the Liberals are "diverting that funding toward affordable housing," arguing it has been a priority for cities for years now. "As Building Canada winds down in 2014, we'll be working with provinces and municipalities on a new, long-term infrastructure plan that focuses on public transit and commuter rail, as well as highways, major roads, and municipal projects," she said. The federal P3 fund may be low profile, but the projects cities have in mind are certainly not. In addition to the Calgary recreation centres, the fund is also being eyed as part of Toronto's subway-expansion plans. The Toronto Transit Commission recently indicated that it would be asking the fund for $333-million toward a 25-kilometre underground line. Saskatoon is expected to ask the fund for public-transit cash, while the city of Regina and the province of Saskatchewan submitted a bid to have the fund as a partner in a new CFL stadium. Mr. Nenshi said he hopes all parties will make urban issues like public transit a key part of the federal campaign. Liberal infrastructure critic John McCallum said his party - should it form government - is committed to sitting down with municipalities to sort out what future infrastructure programs are needed. "The P3 fund has been there for close to three years and only 8 per cent has been used," he said. "On the other hand, whenever I talk to mayors, they always emphasize the high priority they attach to affordable housing." Mr. McCallum said discussions with municipalities would determine what the government's full infrastructure plan would look like. "We completely agree with a major federal role for infrastructure," he said. Liberal Party support is generally concentrated in urban ridings, whereas Canada's rural ridings are more likely to support the Conservatives or NDP. In the Liberal platform, the party is attempting to please both rural and city dwellers with an $80-million "buy local" fund to increase the availability of local produce and other measures aimed at rural Canada, such as expanded broadband Internet access. The Conservative Party's campaign is largely focused on expanding on its rural base by winning more suburban ridings. NDP Leader Jack Layton has yet to release his party platform. He is a former president of the Federation of Canadian Municipalities and a former Toronto city councillor who regularly advocates for more spending on urban issues. Hans Cunningham, the current FCM president, said ending the P3 fund won't help cities deal with pressing issues like traffic gridlock. "We can't go back to robbing Peter to pay Paul in our communities," he said in a statement to The Globe. "Any change to any program - P3 or otherwise - must come with a guarantee that protects every dollar intended for local roads, public transit and other municipal infrastructure." The P3 fund was created in the 2008 Conservative budget as a Crown corporation with $1.25-billion to spend. So far, it has contributed $25-million toward a road extension in Winnipeg, $50-million project in the Maritimes to expand emergency radio services and $25-million to a commuter-train maintenance centre in Montreal. Next story | Learn More Discover content from The Globe and Mail that you might otherwise not have come across. Here we’ll provide you with fresh suggestions where we will continue to make even better ones as we get to know you better. | Mid | [
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Evaluation of virulence factors profiles and antimicrobials resistance of Escherichia coli isolated from bulk tank milk and raw milk filters. Data on the presence of pathogenic Escherichia coli in bulk tank milk (BTM) and raw milk filters (RMF) are not available in Italy and there are few studies worldwide. Therefore, a study under field condition was conducted to assess the presence of E.coli pathogenic and commensal (CoEC) strains in BTM and RMF samples and their associated AMR pattern. One hundred forty-nine E.coli isolates were characterized. Among all the isolates, 53 (35.6%) were classified as pathogenic while the other ones were classified as CoEC. Among the pathogenic ones, 23 (54.7%) were classified as enterotoxigenic E.coli (ETEC), 6 (11.3%) as enteroinvasive E.coli (EIEC), 2 (3.8%) as enteroaggregative E.coli (EAEC), 12 (22.6%) harboured virulence factors (VF) common to ETEC+EIEC, and 2 (3.8%) common to ETEC+EAEC. To our knowledge, it is the first time that ETEC isolates harboring VF associated with EAEC or EIEC are observed in raw milk. These data support the presence of transmission of VFs genes among isolates. None of the isolates showed resistance to three or more antimicrobials. The CoEC role as a vector of AMR was confirmed by the presence of 18% ampicillin- and cephalexin-resistant isolates. The presence of AMR in CoEC supports the role of these bacteria as source of resistance genes. Monitoring raw milk by either BTM or RMF analysis, and the relatively cheap procedure applied to identify E.coli pathotypes can be useful to identify hazards related to the spread of enteric diseases and antimicrobial resistance. | Mid | [
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Recent editorials from Mississippi newspapers: ___ Sept. 18 The Greenwood Commonwealth on two Mississippi lieutenant governor candidates’ stances on flying the state flag that contains a Confederate emblem: Delbert Hosemann and Jay Hughes are both fine candidates to be Mississippi’s next lieutenant governor. Despite the growing testiness of their race, they actually have some things in common, such as bringing greater transparency to the Legislature and putting heavier emphasis on vocational training in the high schools. Unfortunately, another stance they share in common is chickening out on replacing the racially divisive state flag. Both say, if elected, they would only consider dropping the flag and its Confederate emblem if the question were put to the people in a referendum. More than likely, that means no change. If Mississippi is going to adopt a new, unifying flag, it will take courage in the Legislature to vote the change through, and not pawn it off to a popular vote. A test of leadership is to do what you know is best for the public good, especially when the majority of the public is not yet able to recognize it. It’s disappointing that neither Hosemann nor Hughes is willing to show leadership on this point. Online: https://www.gwcommonwealth.com ___ Sept. 17 The Vicksburg Post on the payoff of a program aimed at expanding preschool access in a Mississippi county: When Mississippi Attorney General Jim Hood made a trip to Warren County to learn more about the Vicksburg Warren School District’s pre-K program, he shed light on a community treasure. In his visit to Dana Road Elementary School, where he visited with pre-K students and marveled at how much they learned in six short weeks of school, he brought attention to a community treasure. When he interacted with the students, shook their hands and engaged them in questions and answers, he brought focus to a community treasure. Over the past few years, the number of students seeking pre-K education in Warren County outnumbered the number of spots available at the few schools where the program was offered. But through strong leadership by district administrators and the district’s board of trustees, their investment and focus on increasing the number of pre-K classrooms is paying off. Today, at nine of the 10 elementary schools in the district, pre-K students fill 17 classrooms across the district. Today, 4-year-olds are getting a start on their education very few before had ever had the chance. Much in the way we focused on the seniors at River City Early College being trendsetters, these 4-year-olds, these “babies” as some of their teachers and principals might call them, are really the next wave of educational advancement and improvement in our community. Today, these children are learning their letters, their numbers and the fundamentals of reading to put them on the path for a strong education down the road. Tomorrow, when these students enter kindergarten, they will have the head start many children before did not have. Already, district leaders have studies and scores showing pre-K students, as they move through the grades, are having stronger test scores and better results in the classroom. And by being a part of the classroom at such an early age, they are developing the social skills - through the exposure with Leader in Me - needed to be successful down the road. There are a lot of things going on in the Vicksburg Warren School District to be excited about; the dual enrollment programs, the career academies and the new construction. But the investment made in these children, the youngest among us, is an investment that will undoubtedly pay huge dividends in the future. These students - and this program - are a community treasure. Online: https://www.vicksburgpost.com ___ Sept. 13 The (Tupelo) Daily Journal on tackling high rates of childhood obesity: Each month of the year has its own health observations to bring light to the wellness issues that impact our society. With children back in school, September is National Childhood Obesity Awareness Month. Growing obesity rates affect 17% of all children and adolescents in the United States, which is three times the prevalence from just one generation ago, according to the National Institute of Child Health and Human Development (NICHD). Nearly 32% of children and adolescents are either overweight or obese. With increasing obesity rates, an increase is seen in related health conditions such as heart disease and diabetes. Not only are obese children at a higher risk to become obese adults, but the risk factors associated with weight are more likely to be severe. These children also have a higher risk of being the target of bullying, having lower self-esteem and potential depression and behavioral issues. When parents are busy at work all day, early care and education providers play a critical role in maintaining a child’s health and safety. By modeling healthy eating and physically active lifestyles, early care and education providers can set children on the road to a lifetime of good habits. To help ensure that children have a healthy weight, parents can make sure children get adequate sleep, follow recommendations on daily screen time, take part in regular physical activity, and eat the right amount of calories. The U.S. Department of Health and Human Services provides fitness information at https://www.hhs.gov/fitness . No challenge is more urgent than protecting the health and safety of our children - now, and as they grow. The fight against childhood obesity can start in the home, but also requires the support of communities. The results can last a lifetime. All children deserve a healthy start in life; it’s our responsibility to make that possible. Online: https://www.djournal.com Sign up for Daily Newsletters Manage Newsletters Copyright © 2020 The Washington Times, LLC. | Mid | [
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package javax.sip.message; import java.io.Serializable; import java.text.ParseException; import java.util.ListIterator; import javax.sip.SipException; import javax.sip.header.ContentDispositionHeader; import javax.sip.header.ContentEncodingHeader; import javax.sip.header.ContentLanguageHeader; import javax.sip.header.ContentLengthHeader; import javax.sip.header.ContentTypeHeader; import javax.sip.header.ExpiresHeader; import javax.sip.header.Header; public interface Message extends Cloneable, Serializable { void addFirst(Header header) throws SipException, NullPointerException; void addHeader(Header header); void addLast(Header header) throws SipException, NullPointerException; @Override // java.lang.Object Object clone(); boolean equals(Object obj); Object getApplicationData(); Object getContent(); ContentDispositionHeader getContentDisposition(); ContentEncodingHeader getContentEncoding(); ContentLanguageHeader getContentLanguage(); ContentLengthHeader getContentLength(); ExpiresHeader getExpires(); Header getHeader(String str); ListIterator getHeaderNames(); ListIterator getHeaders(String str); byte[] getRawContent(); String getSIPVersion(); ListIterator getUnrecognizedHeaders(); int hashCode(); void removeContent(); void removeFirst(String str) throws NullPointerException; void removeHeader(String str); void removeLast(String str) throws NullPointerException; void setApplicationData(Object obj); void setContent(Object obj, ContentTypeHeader contentTypeHeader) throws ParseException; void setContentDisposition(ContentDispositionHeader contentDispositionHeader); void setContentEncoding(ContentEncodingHeader contentEncodingHeader); void setContentLanguage(ContentLanguageHeader contentLanguageHeader); void setContentLength(ContentLengthHeader contentLengthHeader); void setExpires(ExpiresHeader expiresHeader); void setHeader(Header header); void setSIPVersion(String str) throws ParseException; String toString(); } | Mid | [
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God doesn't give children with special needs to strong people; He gives children with special needs to ordinary, weak people and then gives them strength. Raising a child with special needs doesn't TAKE a special family, it MAKES a special family. Saturday, December 26, 2009 Update on Steve Steve got out his heart cath at around 11 am. We have great news!! Steve has no blockage in his arteries. He got a clean bill of health. Steve has had pericarditis after a viral infection in the past(about three years ago, I think). This puts him at increased risk for this again. And Christmas Eve, he told me that his chest pain felt the same as it did before when he previously had pericarditis. But in the ER, when they drew blood, his cardiac enzymes were elevated; just barely elevated. Cardiac enzymes are a indicator of cadiac muscle damage. They were concerned because of his family history or heart problems that it would be good to investigate further. So, hence the reason for the heart cath. When the doctor came and talked to us after the procedure he said his arteries were perfect, but that there was a little inflammation of the heart muscle (myocarditis). This is essentially the same as pericarditis, but with further involvement. And when you have myocarditis, you will "leak enzymes" in the blood. So hence the reason for the increased cardiac enzymes. His ejection fraction of his heart (that tells the strength of the hearts ability to pump blood) was minimally decreased but the doctor said that was due to the infection and when he has a checkup in a couple months, it will most likely be back to normal. Steve will go home today with a anti-inflammatory to take for 3 weeks. The hardest part for Steve will be the fact that he cannot lift more than 10 pounds for 5 days; which puts him out of work for 5 days. He is NOT happy about that. It takes a lot to make Steve sit still. But the fear of his artery opening back up and excessive bleeding from lifting too much weight scares him enough that he'll sit (or at least not lift more than 10 pounds) for 5 days. Maybe it will a blessing in disquise. This gives us 5 days as a family together. About Me We have four beautiful children: Micah, Megan,Mason, and Matthew Owen who was born with congenital hydrocephalus, epilespy, septo-optic dysplasia and other anomalies. In spite of all these diagnosis, Matthew is thriving and is a delight and a blessed part of our family. Come, if you wish, and join our journey. This blog contains events of our real life, full of up and downs, good days and bad. | Mid | [
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In the Generation I and II games and their remakes, wild Snorlax can be found sleeping in inconvenient locations throughout Kanto. In order to catch one, a Trainer must first awaken it with music from either a Poké Flute or Pokégear set to the Poké Flute channel. A sleeping Snorlax makes a return in Pokémon X and Y, in which it is blocking the player's way on Route 7. Biology Snorlax is a huge, bipedal, dark blue-green Pokémon with a cream-colored face, belly, and feet. Its body is composed of mostly its belly, where most of its fat reserves accumulate. Its head is large, with small, pointed ears and two pointed teeth protruding from its lower jaw. It has large, hind feet with three claws and a circular brown paw pad, and its arms and five foreclaws are short. Snorlax is often found in mountains and forests. It wakes up only to eat and seldom for exercises. It is not a picky eater, as its strong stomach allows it to eat even moldy food without feeling any ill effects, even being able to handle Muk's poison. When hungry, it is not satisfied until it consumes 900 lbs. (400 kg) of food, and can eat in its sleep. Snorlax is docile enough to let children and small Pokémon bounce on its large stomach. In The Garden of Eatin', a Snorlax was causing trouble for a man named Marcel by eating the bananas in his Slakoth Banana Garden. Marcel's newly evolved Vigoroth defeated the Snorlax, allowing him to capture it. Afterwards, Marcel made an attraction around his new Snorlax: a relaxation room. A Snorlax appeared in PK13, in which it ate Corphish's bananas that were on sale. In Pokémon Origins Red encountered a Snorlax in File 3: Giovanni by playing the Poké Flute. He was able to catch it and later used it in his Gym battle against Giovanni, where it was quickly defeated by Giovanni's Rhyhorn's Horn Drill. Snorlax does the same maneuver as it did in the previous game, but covers a smaller area. Snorlax is also a Poké Float. It is lying down asleep and so fighting occurs on its head and belly. Melee trophy information Snorlax love to sleep and love to eat: these portly Pokémon get grumpy if they don't get 888 pounds of food per day. After snacking out, they always nap. They have cast-iron stomachs and can eat moldy and even rotten food with no digestion problems. They are the heaviest Pokémon on record, weighing in at over 1,000 pounds. Brawl trophy information "A Sleeping Pokémon. It's the ultimate loafer. Sometimes children like to play on top its big belly. Once in a slumber, not even the hardest rain or the fiercest wind will wake it. Snorlax recovers health and restores its physical state by sleeping, and it proves daunting with its damaging Snore attack. Snorlax is the king of Sleeping Pokémon." Snorlax reappears as a Poké Ball summon in these games, behaving the same way as before. Trophy information NA: This sleepy, Normal-type Pokémon is huge! It eats more than 900 lb. of food every day. Most of the time not spent eating is spent sleeping. That big, round body comes in handy when it's brought onto a Smash Bros. battlefield—the Body Slam attack will send anyone who gets hit flying into the air! PAL: Snorlax is often referred to as the Sleeping Pokémon, and there's a good reason for that! This giant loafer spends almost all its time snoozing, getting up for just long enough each day to scoff up a tidy 400kg of food. In this game, it soars into the air and uses its Body Slam attack, smacking into fighters like a giant wrecking ball. Game data NPC appearances Pokémon Ranger: Snorlax will be seen sleeping throughout the game, effectively cutting off certain areas until later on. It will eventually remain in a cave in the Sekra Range. Once the rest of the Ranger Browser has been completed, it will wake up and can be captured. Trivia In HeartGold and SoulSilver, if the player interacts with a Snorlax that is walking with them while at Mt. Silver, the message "SNORLAX is feeling very eager" will appear. This is due to Red, who is also at Mt. Silver, owning a Snorlax as well. While the player is on Mt. Silver, unique messages will also appear if the player interacts with a walking Pikachu or Charizard. Snorlax has the highest base stat total of all Pokémon that can hatch from an Egg. Origin Snorlax may be loosely based on hibernatingbears or teddy bears. It may also be based on the cave bear. It may also be based on a food coma, as it eats large quantities of food, then takes a nap (symptoms of a food coma). Snorlax also shares traits with sloths, who are often portrayed as lazy and sleepy creatures. Name origin Snorlax is a combination of snore and lax or relax. Kabigon may come from an alternate reading of sleep, 寐 bi, and a corruption of 鼾酔 kansui (snoring) or 憩う ikou (rest). It may also incorporate 黴 kabi (mold), noting the fact that Snorlax will eat anything, even moldy food. Kabigon is also based on the nickname of Game Freak programmer Kōji Nishino, which is the reason his game appearance uses Snorlax as his highest-leveled Pokémon in Black 2 and White 2. In other languages Language Title Meaning Japanese カビゴン Kabigon Kabigon may come from an alternate reading of sleep, 寐 bi, and a corruption of 鼾酔 kansui or 憩う ikou. | Mid | [
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Q: grep --after-context in perl The code below works exactly as I want it to in my perl script. However, it takes forever to run through very large files. Would someone know a perl alternative to my grep command? my $print = `grep --after-context=3 $line $inputfile`; print OUTFILE $print To explain the code above: it simply finds a line (called $line) in the input file (called $inputfile) and prints the match it found and the three lines following the match (from the $inputfile) to my outfile (called OUTFILE). Cheers! A: While there's some overhead in launching a grep subprocess, it's a fixed amount, unrelated to the size of the file. Unless you've got a very bad implementation of grep, you're not going to be able to improve the search time in pure Perl. In fact, searching a large file using Perl is likely to be slower than grep, which is optimized solely for searching files. If you're only looking for the first match, you might want to add --max-count=1 to your grep command. This will cause grep to quit immediately, instead of reading the rest of the file to find additional matches. | Low | [
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(module JST_SUR_BM15B-SURS-TF_1x15-1MP_P0.80mm_Vertical (layer F.Cu) (tedit 5B78AD88) (descr "JST SUR series connector, BM15B-SURS-TF (http://www.jst-mfg.com/product/pdf/eng/eSUR.pdf), generated with kicad-footprint-generator") (tags "connector JST SUR side entry") (attr smd) (fp_text reference REF** (at 0 -2.6) (layer F.SilkS) (effects (font (size 1 1) (thickness 0.15))) ) (fp_text value JST_SUR_BM15B-SURS-TF_1x15-1MP_P0.80mm_Vertical (at 0 2.6) (layer F.Fab) (effects (font (size 1 1) (thickness 0.15))) ) (fp_line (start -7.1 0.9) (end 7.1 0.9) (layer F.Fab) (width 0.1)) (fp_line (start -7.21 0.56) (end -7.21 1.01) (layer F.SilkS) (width 0.12)) (fp_line (start -7.21 1.01) (end -6.11 1.01) (layer F.SilkS) (width 0.12)) (fp_line (start -6.11 1.01) (end -6.11 1.4) (layer F.SilkS) (width 0.12)) (fp_line (start 7.21 0.56) (end 7.21 1.01) (layer F.SilkS) (width 0.12)) (fp_line (start 7.21 1.01) (end 6.11 1.01) (layer F.SilkS) (width 0.12)) (fp_line (start -6.04 -1.21) (end 6.04 -1.21) (layer F.SilkS) (width 0.12)) (fp_line (start -7.1 -1.1) (end 7.1 -1.1) (layer F.Fab) (width 0.1)) (fp_line (start -7.1 0.9) (end -7.1 -1.1) (layer F.Fab) (width 0.1)) (fp_line (start 7.1 0.9) (end 7.1 -1.1) (layer F.Fab) (width 0.1)) (fp_line (start -8 -1.9) (end -8 1.9) (layer F.CrtYd) (width 0.05)) (fp_line (start -8 1.9) (end 8 1.9) (layer F.CrtYd) (width 0.05)) (fp_line (start 8 1.9) (end 8 -1.9) (layer F.CrtYd) (width 0.05)) (fp_line (start 8 -1.9) (end -8 -1.9) (layer F.CrtYd) (width 0.05)) (fp_line (start -6.1 0.9) (end -5.6 0.192893) (layer F.Fab) (width 0.1)) (fp_line (start -5.6 0.192893) (end -5.1 0.9) (layer F.Fab) (width 0.1)) (pad 1 smd roundrect (at -5.6 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 2 smd roundrect (at -4.8 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 3 smd roundrect (at -4 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 4 smd roundrect (at -3.2 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 5 smd roundrect (at -2.4 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 6 smd roundrect (at -1.6 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 7 smd roundrect (at -0.8 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 8 smd roundrect (at 0 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 9 smd roundrect (at 0.8 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 10 smd roundrect (at 1.6 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 11 smd roundrect (at 2.4 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 12 smd roundrect (at 3.2 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 13 smd roundrect (at 4 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 14 smd roundrect (at 4.8 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad 15 smd roundrect (at 5.6 0.85) (size 0.5 1.1) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.25)) (pad MP smd roundrect (at -6.9 -0.55) (size 1.2 1.7) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.208333)) (pad MP smd roundrect (at 6.9 -0.55) (size 1.2 1.7) (layers F.Cu F.Mask F.Paste) (roundrect_rratio 0.208333)) (fp_text user %R (at 0 -0.4) (layer F.Fab) (effects (font (size 1 1) (thickness 0.15))) ) (model ${KISYS3DMOD}/Connector_JST.3dshapes/JST_SUR_BM15B-SURS-TF_1x15-1MP_P0.80mm_Vertical.wrl (at (xyz 0 0 0)) (scale (xyz 1 1 1)) (rotate (xyz 0 0 0)) ) ) | Mid | [
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Changes in tissue concentrations of 14C-doxorubicin caused by mitoxantrone, mithramycin A and vinblastine in the rat. The purpose of this study was to determine if mitoxantrone (a new antineoplastic drug) and two other anticancer agents (mithramycin A and vinblastine) could result in changes in the tissue distribution and disposition of doxorubicin in rats. Each of 16 male rats received 1 mg/kg of 14C-labeled doxorubicin on day one and received either saline, or doses of 4 mg/kg of mitoxantrone, 1.7 mg/kg of mithramycin A or 2.9 mg/kg of vinblastine on day three. All rats were sacrificed on day eight. Concentrations of radioactivity in the heart, lung, kidney and muscle were higher in the mitoxantrone treated rats than in the controls. Mithramycin A decreased the concentrations of radioactivity in liver, kidney and fatty tissues, while vinblastine increased the concentrations in heart, liver, lung, muscle and skin. In summary, mithramycin A, vinblastine and mitoxantrone caused a change in tissue concentrations of radioactivity of doxorubicin and/or its metabolites following a single I.V. dose of 14C-labeled doxorubicin in rats. This may cause elevated plasma concentrations of doxorubicin. These findings in the rat could theoretically have implications regarding doxorubicin therapy in man. | Mid | [
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1. Field of the Invention This invention relates to a two-part electrical socket contact. 2. Description of the Prior Art In many applications of electrical contacts such as in the automotive industry, one of the requirements is that the electrical contact can be inserted through a family seal into a cavity within a housing. Inside the cavity, such an electrical socket contact can, for instance, be secured by means of a flexible contact securing element provided in the cavity. One fundamental problem is that the family seal must not be damaged by the socket contact when inserted through the seal. It is standard practice to produce electrical contacts from sheet metal by stamping and forming with the electrical contacts being of one or two parts. The electrical contacts feature contact springs to make contact with a complementary contact pin or blade. The contact springs are often supported by supporting elements in order to increase the spring action. EP-A-727 842 for instance, discloses a single piece socket contact produced by stamping and forming that is designed to be inserted into the cavity of a housing. Inside the cavity, the contact is secured by a flexible contact securing element provided in the cavity. The socket contact features a contact body with a contact making section for making contact with a complementary contact pin or blade and a connecting section for making connection with an electrical conductor. The contact making section is provided with a contact spring on each of the two opposite sides. The contact making section of the contact body is surrounded by an outer, cantilever spring which has been formed out of one piece of sheet metal. The outer cantilever spring is typically box-shaped with a top, a bottom and two sides, the top and bottom each being provided with a support element to support the contact spring of the contact body. In addition, one of the sides is provided with an opening to accommodate the contact securing element. The outer cantilever spring is without any outwardly protruding sharp edges to assure that the contact will be inserted through a seal without damaging the seal. If the contact securing element of the housing is disposed on a side of the socket contact on which the support element is also located, then the contact discussed in EP 727 842-A2 cannot be inserted into such a cavity or be altered for such a cavity. U.S. Pat. No. 5,295,875 discloses a two-part electrical socket contact which can be inserted through a family seal without difficulties. This contact is also intended to be inserted into a housing provided with a cavity having a flexible contact securing element. The contact consists of a contact body having a contact making section and a connection end with. The contact making section is provided, on at least two opposite sides, with a contact spring. The electrical socket contact is further provided with an outer cantilever spring which surrounds the contact making section of the contact body. The outer cantilever spring is of a cylindrical shape and is provided with a circumferential shoulder which the contact securing element positively engages. | Mid | [
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The CandidateDonna Edwards, an accomplished public servant who has dedicated her career to service. A single mother who overcame challenging circumstances herself, Donna has worked tirelessly to make a real, lasting difference in the lives of others – from co-founding the National Network to End Domestic Violence and leading the fight for the landmark Violence Against Women Act, to spearheading campaign finance and lobbying reform efforts at Public Citizen and working to strengthen protections for labor rights as executive director of the Arca Foundation. The ChallengeDonna faced the district’s 16-year incumbent Democratic Congressman, Al Wynn, who started the race with a disproportionate share of resources and the backing of several prominent Democratic leaders and institutions. The OutcomeLake Research Partners’ research – along with Donna’s message of progressive change and the groundswell of grassroots and institutional support that her message generated – propelled her to a stunning 25-point victory. The MethodologyDonna first challenged Wynn in 2006. With LRP guiding the research on messaging and targeting, Donna managed to pull within three points of victory despite being outspent by a wide margin. Riding a wave of enthusiasm from her 2006 race, Donna challenged Wynn again in 2008. LRP’s research helped Donna develop essential contrasts in her message by identifying the most persuasive elements of her candidacy, and helped upend the conventional wisdom about Al Wynn by uncovering the core vulnerabilities in his profile. LRP identified critical GOTV and persuasion targets, and found the messages that inspired Democrats to brave the sleet and snow and vote for Donna on Election Day. | High | [
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Barrie’s Riley Leech is ready for the big time, even if he wasn’t expected to get there just yet. The Barrie North Collegiate and K-Bay Wrestling Club athlete will represent Canada at the Pan Am Games in Brazil, starting next weekend. “I was pretty shocked when I made the team. I wasn’t expecting to make it.” Leech, who is in Grade 10, will compete in the FILA Cadet Pan American Championships, for teens in Grade 9, 10 and 11. He flies out April 30 and competes May 2. This is the 16-year-old athlete’s first international competition. “I had to place top three at a national event, then compete again the next day. I placed third at that match so I made the team,” he said. “There aren’t any other Barrie North or K-Bay wrestlers going. There are only four wrestlers from Ontario and 14 from Canada going. It’s an honour.” Susie Rowe, Leech’s Barrie North Collegiate coach and one of his K-Bay coaches, said Leech’s success was a surprise. “He works hard and he puts in a lot of extra time off the mat,” she said. “He’s still so young. We thought he’d do well, but making the team was a big surprise. He’s been working hard with his head coach, Nick Cryer. He’s earned it.” Leech didn’t set out to be a wrestler. | High | [
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/* [auto_generated] boost/numeric/odeint/integrate/integrate_times.hpp [begin_description] Integration of ODEs with observation at user defined points [end_description] Copyright 2009-2011 Karsten Ahnert Copyright 2009-2011 Mario Mulansky Distributed under the Boost Software License, Version 1.0. (See accompanying file LICENSE_1_0.txt or copy at http://www.boost.org/LICENSE_1_0.txt) */ #ifndef BOOST_NUMERIC_ODEINT_INTEGRATE_INTEGRATE_TIMES_HPP_INCLUDED #define BOOST_NUMERIC_ODEINT_INTEGRATE_INTEGRATE_TIMES_HPP_INCLUDED #include <boost/type_traits/is_same.hpp> #include <boost/range.hpp> #include <boost/numeric/odeint/stepper/stepper_categories.hpp> #include <boost/numeric/odeint/iterator/integrate/null_observer.hpp> #include <boost/numeric/odeint/iterator/integrate/detail/integrate_times.hpp> namespace boost { namespace numeric { namespace odeint { /* * the two overloads are needed in order to solve the forwarding problem */ template< class Stepper , class System , class State , class TimeIterator , class Time , class Observer > size_t integrate_times( Stepper stepper , System system , State &start_state , TimeIterator times_start , TimeIterator times_end , Time dt , Observer observer ) { typedef typename odeint::unwrap_reference< Stepper >::type::stepper_category stepper_category; return detail::integrate_times( stepper , system , start_state , times_start , times_end , dt , observer , stepper_category() ); } /** * \brief Solves the forwarding problem, can be called with Boost.Range as start_state. */ template< class Stepper , class System , class State , class TimeIterator , class Time , class Observer > size_t integrate_times( Stepper stepper , System system , const State &start_state , TimeIterator times_start , TimeIterator times_end , Time dt , Observer observer ) { typedef typename odeint::unwrap_reference< Stepper >::type::stepper_category stepper_category; return detail::integrate_times( stepper , system , start_state , times_start , times_end , dt , observer , stepper_category() ); } /** * \brief The same function as above, but without observer calls. */ template< class Stepper , class System , class State , class TimeRange , class Time , class Observer > size_t integrate_times( Stepper stepper , System system , State &start_state , const TimeRange × , Time dt , Observer observer ) { return integrate_times( stepper , system , start_state , boost::begin( times ) , boost::end( times ) , dt , observer ); } /** * \brief Solves the forwarding problem, can be called with Boost.Range as start_state. */ template< class Stepper , class System , class State , class TimeRange , class Time , class Observer > size_t integrate_times( Stepper stepper , System system , const State &start_state , const TimeRange × , Time dt , Observer observer ) { return integrate_times( stepper , system , start_state , boost::begin( times ) , boost::end( times ) , dt , observer ); } /********* DOXYGEN ***********/ /** * \fn size_t integrate_times( Stepper stepper , System system , State &start_state , TimeIterator times_start , TimeIterator times_end , Time dt , Observer observer ) * \brief Integrates the ODE with observer calls at given time points. * * Integrates the ODE given by system using the given stepper. This function * does observer calls at the subsequent time points given by the range * times_start, times_end. If the stepper has not step size control, the * step size might be reduced occasionally to ensure observer calls exactly * at the time points from the given sequence. If the stepper is a * ControlledStepper, the step size is adjusted to meet the error bounds, * but also might be reduced occasionally to ensure correct observer calls. * If a DenseOutputStepper is provided, the dense output functionality is * used to call the observer at the given times. The end time of the * integration is always *(end_time-1). * * \param stepper The stepper to be used for numerical integration. * \param system Function/Functor defining the rhs of the ODE. * \param start_state The initial condition x0. * \param times_start Iterator to the start time * \param times_end Iterator to the end time * \param dt The time step between observer calls, _not_ necessarily the * time step of the integration. * \param observer Function/Functor called at equidistant time intervals. * \return The number of steps performed. */ } // namespace odeint } // namespace numeric } // namespace boost #endif // BOOST_NUMERIC_ODEINT_INTEGRATE_INTEGRATE_TIMES_HPP_INCLUDED | Mid | [
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Tax strategies that go hand-in-hand with charitable giving It’s the most wonderful time of the year (cue the holiday music) – and as 2017 comes to an end, many people will expand their giving season by making charitable contributions. American donors gave an estimated $390 billion to charity in 2016. This year, as we support the missions of our favorite charities, we can do so with potential financial and tax implications in mind. QCD: FOR THOSE 70½ AND OLDER An often overlooked philanthropic strategy available to people 70½ or older, the qualified charitable distribution allows donors to transfer individual retirement account assets to a charity tax free while simultaneously satisfying their required minimum distribution. Normally, distributions from an IRA result in a taxable event, increasing taxable income and inflating adjusted gross income. Those who take the standard deduction and donate directly to a charity receive no tax benefit from giving. A QCD allows donors who itemize as well as those who take the standard deduction to reduce adjusted gross income while benefiting their favorite cause – a successful outcome for all. A couple of rules that apply to QCDs: <The QCD must transfer directly from the IRA to a qualified charity as defined by the Internal Revenue Service. The IRA owner cannot take possession of the distribution and subsequently donate it to a charity. Charitably inclined people whose IRA distributions would push them into the 15 percent federal capital gains bracket might benefit most from this strategy. By donating via QCD, they are able to exclude the charitable IRA distribution from taxable income and pay no federal capital gains tax. OTHER WAYS TO GIVE For donors of all ages, the simplest technique for charitable giving is to donate cash, for which tax filers who itemize can take a deduction. Another giving strategy is to donate appreciated assets, such as stocks or real estate. Donors can deduct the current value of the asset without owing capital gains tax. Many charities will facilitate the donation of a car, truck or boat – and it need not be in working order. To streamline, charities use a third-party clearinghouse to pick up and haul the vehicle, eliminating the need for the donor to sell it. This creates a tax deduction while helping the charity. Consult your tax adviser or financial adviser for special rules that apply to vehicle donations. DONOR-ADVISED FUNDS Another method for charitable giving is donating through a donor-advised fund, such as a local community foundation. A donor-advised fund is a private fund administered by a third party for the purpose of overseeing and managing donations on behalf of individuals, families or organizations. Through this fund, a taxpayer can receive an immediate tax benefit of up to $100,000 and later recommend grants from the fund over time. A number of irrevocable trusts exist to reduce income tax, give to charity and provide an income. Two of the most common are the charitable remainder annuity trust and the charitable remainder unitrust. The annuity trust pays a set amount annually to noncharitable beneficiaries (for example, your children) for a fixed term or for the duration of the beneficiaries’ lives. The remainder unitrust differs slightly in that the trust pays the actual income or a set percentage of the current value of the trust’s assets to the noncharitable beneficiaries. Both trusts then distribute the remaining assets to a qualified charity. TAX REFORM It is possible that tax reform, if implemented, could affect charitable giving. While the existing version of the Republican tax plan leaves the charitable deduction as is, the proposed doubling of the standard deduction will inevitably result in fewer taxpayers itemizing deductions – and it’s possible that those taking the higher standard deduction might be less inclined to donate. For now, at least, donors continue to receive significant tax benefits for their generosity. Carrie L. Fellon is a financial strategist at JoycePayne Partners of Bethlehem and Richmond, Va., responsible for client financial strategy and counsel, comprehensive financial planning and investment management. A Certified Financial Planner and chartered retirement plans specialist, she can be reached at [email protected]. | Mid | [
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Q: Aerospike ACID - How to know the final result of the transaction on timeouts? I'm new to Aerospike. I would like to know that in all possible timeout scenarios, as stated in this link: https://discuss.aerospike.com/t/understanding-timeout-and-retry-policies/2852 Client can’t connect by specified timeout (timeout=). Timeout of zero means that there is no timeout set. Client does not receive response by specified timeout (timeout=). Server times out the transaction during it’s own processing (default of 1 second if client doesn’t specify timeout). To investigate this, confirm that the server transaction latencies are not the bottleneck. Client times out after M iterations of retries when there was no error due to a failed node or a failed connection. Client can’t obtain a valid node after N retries (where retries are set from your client). Client can’t obtain a valid connection after X retries. The retry count is usually the limiting factor, not the timeout value. The reasoning is that if you can’t get a connection after R retries, you never will, so just timeout early. Of all timeout scenarios mentioned, under which circumstances could I be absolute certain that the final result of the transaction is FAILED? Does Aerospike offer anything i.e. to rollback the transaction if the client does not respond? In the worst case, If I could’t be certain about the final result, how would I be able to know for certain about the final state of the transaction? Many thanks in advance. Edit: We came up with a temporary solution: Keep a map of [generation -> value read] for that record (maybe a background thread constantly reading the record etc.) and then on timeouts, we would periodically check the map (key = the generation expected) to see if the true written value is actually the one put to the map. If they are the same, it means the write succeeded, otherwise it means the write failed. Do you guys think it's necessary to do this? Or is there other way? A: First, timeouts are not the only error you should be concerned with. Newer clients have an 'inDoubt' flag associated with errors that will indicate that the write may or may not have applied. There isn't a built-in way of resolving an in-doubt transaction to a definitive answer and if the network is partitioned, there isn't a way in AP to rigorously resolve in-doubt transactions. Rigorous methods do exist for 'Strong Consistency' mode, the same methods can be used to handle common AP scenarios but they will fail under partition. The method I have used is as follows: Each record will need a list bin, the list bin will contain the last N transaction ids. For my use case, I gave each client an unique 2 byte identifier - each client thread a unique 2 byte identifier - and each client thread had a 4 byte counter. So a particular transaction-id would look like would mask an 8 byte identifier from the 2 ids and counter. * Read the records metadata with the getHeader api - this avoids reading the records bins from storage. Note - my use case wasn't an increment so I actually had to read the record and write with a generation check. This pattern should be more efficient for a counter use case. Write the record using operate and gen-equal to the read generation with the these operations: increment the integer bin, prepend to the list of txns, and trim the list of txns. You will prepend you transaction-id to your txns list and then trim the list to the max size of the list you selected. N needs to be large enough such that a record can be sure to have enough time to verify its transaction given the contention on the key. N will affect the stored size of the record so choosing too big will cost disk resource and choosing too small will render the algorithm ineffective. If the transaction is successful then you are done. If the transaction is 'inDoubt' then read the key and check the txns list for your transaction-id. If present then your transaction 'definitely succeeded'. If your transaction-id isn't in txns, repeat step 3 with the generation returned from the read in step 5. Return to step 3 - with the exception that on step 5 a 'generation error' would also need to be considered 'in-doubt' since it may have been the previous attempt that finally applied. Also consider that reading the record in step 5 and not finding the transaction-id in txns does not ensure that the transaction 'definitely failed'. If you wanted to leave the record unchanged but have a 'definitely failed' semantic you would need to have observed the generation move past the previous write's gen-check policy. If it hasn't you could replace the operation in step 6 with a touch - if it succeeds then the initial write 'definitely failed' and if you get a generation-error you will need to check if you raced the application of the initial transaction initial write may now have 'definitely succeeded'. Again, with 'Strong Consistency' the mentions of 'definitely succeeded' and 'definitely failed' are accurate statements, but in AP these statements have failure modes (especially around network partitions). A: Recent clients will provide an extra flag on timeouts, called "in doubt". If false, you are certain the transaction did not succeed (client couldn't even connect to the node so it couldn't have sent the transaction). If true, then there is still an uncertainty as the client would have sent the transaction but wouldn't know if it had reached the cluster or not. You may also consider looking at Aerospike's Strong Consistency feature which could help your use case. | Mid | [
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Q: How do I revert sys.stdout.close()? In the interactive console: >>> import sys >>> sys.stdout <open file '<stdout>', mode 'w' at 0xb7810078> >>> sys.stdout.close() >>> sys.stdout # confirming that it's closed (...) ValueError: I/O operation on closed file Attempting to revert: >>> sys.stdout.open() (...) AttributeError: 'file' object has no attribute 'open' >>> sys.stdout.write('foo') (...) ValueError: I/O operation on closed file I agree that it's a frivolous question, but I'm curious how sys.stdout.close() can be reverted in Python (without restarting the interactive console, of course) and why sys.stdout.open() does not make sense. A: Okay, so I hope you are on a unix system... Basically sys.stdout is just a variable containing any writable object. So we can do magic like sys.stdout = open("file", "w") and now we can write to that file as if it was stdout. Knowing unix is just one big box of files. Unix is kind enough to give us /dev/stdout So to re-open stdout its simple sys.stdout = open("/dev/stdout", "w") Job done, you now have a new stdout opened up. Edit >>> os.fstat(1) posix.stat_result(st_mode=8592, st_ino=7, st_dev=11L, st_nlink=1, st_uid=1000, st_gid=5, st_size=0, st_atime=1374230552, st_mtime=1374230552, st_ctime=1374230434) >>> sys.stdout.close() >>> sys.stdout = open("/dev/stdout", "w") >>> sys.stdout.fileno() 3 >>> os.fstat(3) posix.stat_result(st_mode=8592, st_ino=7, st_dev=11L, st_nlink=1, st_uid=1000, st_gid=5, st_size=0, st_atime=1374230576, st_mtime=1374230576, st_ctime=1374230434) >>> os.fstat(1) posix.stat_result(st_mode=8592, st_ino=7, st_dev=11L, st_nlink=1, st_uid=1000, st_gid=5, st_size=0, st_atime=1374230576, st_mtime=1374230576, st_ctime=1374230434) >>> A: In your case, you can get the sys.stdout back by sys.stdout = os.fdopen(1, 'w', 0). But, in truth, you do not close the sys.stdout really. If you want to close it completely, you have to use os.close(sys.stdout.fileno()). You can read Why doesn’t closing sys.stdout (stdin, stderr) really close it? for why. In this case, I don't know how to reopen it. The above method or even open('/dev/stdout', 'w') have failed on my Linux. | Low | [
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{ "language": "Solidity", "sources": { "A": { "content": "//SPDX-License-Identifier: GPL-3.0\npragma solidity >=0.0; contract C { function f() public pure {} }" } }, "settings": [ { "optimizer": { "enabled": true, "runs": 200 }, "evmVersion": "byzantium", "metadata": { "useLiteralContent": true } } ] } | Mid | [
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Catching a Shooting Star Scientists announced that for the first time they have successfully detected and tracked an asteroid as it collided with earth. It was a very small asteroid and what was left of it after passing through earth’s atmosphere landed in the Sudanese desert, having posed no danger to the United States Congress. | Low | [
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Parents from across the country explain the benefits of medical cannabis for epilepsy that doesn’t respond to pharmaceutical medications and the need for rescheduling and legalization of medical marijuana. Tennesseans United Board member, Paul Kuhn gave this speech to a meeting of the Nashville Kiwanis Club. It contains a wealth of information. And, judging by the reactions of the crowd and the gentleman sitting to Paul’s left, it was very well-received! Five minutes is all it takes to learn about the issues facing many TN families who choose to leave everything behind and move to Colorado for the sake of their child’s survival. Please watch this video. Dr. David Allen, retired cardiac surgeon on the discovery of the Endocannabinoid System: “It is critically important for doctors to understand this new science. The discovery of the endocannabinoid system is the single most important medical scientific discovery ever and will save more lives than the discovery and application of sterile surgical technique.” Read that again, keeping in mind that this is a SURGEON saying it. Three minute video to share with everyone you know, especially Medical Doctors. Huffington Post had a wonderful feature on Seth Green, who suffers from both Cerebral Palsy and Multiple Sclerosis. For many people, marijuana has changed their life in the most positive ways imaginable. Most of us can’t imagine a life where our speech and movement is limited, a life where one of your greatest desires is to be less of a burden on those you love. | High | [
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Pill testing to go ahead at Australian music festival Mum Adriana Buccianti talks about her son's death at a music festival in Unharm video2:55 Adriana Buccianti's son died from a drug overdose at a music festival. Now she wants the authorities to allow drug testing so festival goers can check their stash is not contaminated. November 24th 2016 2 years ago /display/newscorpaustralia.com/Web/NewsNetwork/Network News/National/ If drugs are tested at festivals, fewer people might take them.Source:News Corp Australia A CANBERRA music festival will become Australia’s first to provide pill testing for festival goers. The ACT government has decided to allow pill testing at the Spilt Milk festival to go ahead on November 25. Attendees will be able to access the free service provided by the Safety Testing and Advisory Service at Festivals and Events (STA-SAFE) consortium. The testing facility, to be positioned alongside medical services, will be enclosed to ensure privacy. A small “scraping” of the pill will be analysed, and information about the result, and the risks of drug-taking, will be provided to the user. Amnesty bins containing bleach will also be supplied for those who wish to dump their drugs. ACT Health Minister Meegan Fitzharris signalled her support for the scheme at a press conference in Canberra on Friday. “This is a really good measure to make sure that young people stay safe,” she told reporters. Ms Fitzharris insisted taking illicit drugs was illegal, but added the government is being realistic in recognising that young people do take them. A small ‘scraping’ of the pill would be taken and tested. Picture: Shaney BalcombeSource:News Corp Australia She cited evidence from New Zealand which showed that 63 per cent of people who have their pills tested, and were told the substance wasn’t what they thought it was, decided not to take them. Harm Reduction Australia’s David Caldicott said the decision was a long time coming. “I think our opponents would probably try to portray this as new and dangerous,” he said. “We represent a safety net.” At music festivals people were already committed to using drugs and there are already best-practice guidelines for such tests in Europe, Dr Caldicott said. The testing data will be collated and presented to the territory government. Advocates for pill testing have long been calling for the practice to be introduced in Australia following success in Europe. Parents and family members of drug overdose victims have been among the most vocal supporters of pill testing. Adriana Buccianti, whose son Daniel died at Victoria’s 2012 Rainbow Serpent music festival after taking a tab of “bad acid”, has been a leading voice in the controversial calls for testing stations to be set up at all Australian music festivals. “The bottom line is people will take drugs, irrespective of the law,” she said at a campaigning event last year. “If pill testing was implemented, people might not take their drugs because no one want to come out of a festival or nightclub in a body bag if they think their drugs might kill them.” Results from the testing data at the Spilt Milk music festival will be collated and presented to the ACT government. | Mid | [
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DVD/CD return policy A DVD or Audio CD is returnable within 30 days for a refund or exchange of a different item only if it is returned with the hologram seal intact (i.e. unopened). An open case (a broken seal) is not returnable for a refund or exchange. A DVD or Audio CD is exchangeable for the exact same title only if it is defective. In this episode of "On Court with USPTA," USPTA Professional Otis Sadler shows you how to take control of the match and put your opponent in pressure situations. Take full advantage of your serve by applying the serve-and-volley tactic, attack your opponents' service game by hitting a return winner or by chipping deep and charging to the net. These tactics aim to either end the rally or induce a weak response allowing you to put the point away. Technique and court position are discussed along with other helpful tips to strengthen your offense. In today's game of huge forehands and even bigger serves, an attacking game might be just what you need to take your game to the next level. In this DVD you will learn - how and when to use the serve and volley - how and when to use the first strike - how and when to use the chip and charge Bonus Features - Serve-and-volley lesson with interviews - First-strike lesson with interviews - Otis Sadler on driving Appox. 75 minutes If your complete order has only 1 or 2 DVDs and is being shipped in the United States, you may choose delivery by U.S. First Class Mail for $4. If your complete order has 3 to 6 DVDs and is being shipped in the United States, you may choose delivery by U.S. Priority Mail for $7.20. Indicate that you want shipping by U.S. Mail in the “Additional Instructions” section of the Billing & Shipping page when checking out. | Mid | [
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Complex amplitude reconstruction for dynamic beam quality M<sup>2</sup> factor measurement with self-referencing interferometer wavefront sensor. A real-time complex amplitude reconstruction method for determining the dynamic beam quality M<sup>2</sup> factor based on a Mach-Zehnder self-referencing interferometer wavefront sensor is developed. By using the proposed complex amplitude reconstruction method, full characterization of the laser beam, including amplitude (intensity profile) and phase information, can be reconstructed from a single interference pattern with the Fourier fringe pattern analysis method in a one-shot measurement. With the reconstructed complex amplitude, the beam fields at any position z along its propagation direction can be obtained by first utilizing the diffraction integral theory. Then the beam quality M<sup>2</sup> factor of the dynamic beam is calculated according to the specified method of the Standard ISO11146. The feasibility of the proposed method is demonstrated with the theoretical analysis and experiment, including the static and dynamic beam process. The experimental method is simple, fast, and operates without movable parts and is allowed in order to investigate the laser beam in inaccessible conditions using existing methods. | High | [
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Jerry Sandusky sentenced to at least 30 years Credit: Getty Images BELLEFONTE, PA - OCTOBER 09: Former Penn State assistant football coach Jerry Sandusky walks into the Centre County Courthouse before being sentenced in his child sex abuse case on October 9, 2012 in Bellefonte, Pennsylvania. Sandusky was sentenced Tuesday to at least 30 years in prison - effectively a life sentence - in the child sexual abuse scandal that brought shame to Penn State and led to coach Joe Paterno's downfall. (Photo by Patrick Smith/Getty Images) | Mid | [
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As a number of devices using a wireless network increased, a method of simplifying an authentication process required to register a device in an access point (AP) has become an issue. Accordingly, a Wifi Protective Setup Specification (WPS spec.) was defined. FIG. 1 is a flowchart illustrating a conventional method of authenticating a device. [Various methods may be used to register a device in an AP in a wireless network, but the conventional method of FIG. 1 uses a push button configuration (PBC) according to WPS spec. In operation 110, a button of an unregistered device to be registered in an AP is clicked. In operation 120, a button of the AP is clicked within a predetermined time. For example, the button of the AP may be clicked after 120 seconds from clicking the button of the unregistered device. In operation 130, the AP performs an authentication operation on the unregistered device. According to WPS spec., by performing operations 110 through 130, the unregistered device is registered in the AP. Meanwhile, the unregistered device may be registered in the AP by using a third device registered in the AP. In this case, the third device requires a register for performing an authentication operation. When the register is included in the third device, the unregistered device is registered in the AP by the third device, the AP, and the unregistered device exchanging messages related to registration of the unregistered device. | Mid | [
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Detailed assessment of cleft lip scar following straight line repair. Minimizing upper lip skin scarring is one of the most important factors in cleft lip repair. Currently, Millard's procedure or one of its modifications is the most commonly used surgical repair procedure, yet several surgeons continue to prefer a more natural-looking straight scar. Some publications concerning the resultant scarring after Millard's procedure are available; on the other hand, those concerning that after straight line repair are limited. This study aimed to evaluate and analyse upper lip skin scarring following straight line repair in order to further refine our surgical procedure. Twenty-six patients with ages ranging from 4 years and 11 months to 6 years and 10 months (17 boys and nine girls) participated in this study. Each upper lip skin scar was divided into three portions and evaluated by three board-certified plastic surgeons who calculated the evaluation score. The score for each portion of the scar was analysed to determine the correlation of the score with the five following factors: type of cleft, age at operation, length of operation, skin texture regularity and skin brightness; the last two were determined using a facial-measurement instrument. Taking all the results into consideration together with practical experience, the quality of scars of the upper lip skin was thought to be correlated with the skin brightness and length of the operation, particularly in the case of the upper and middle third portions of the upper lip. In the lower third portion, the scar quality appeared to be more influenced by the age at operation. It is suggested that early surgical intervention may help minimize scarring because lip motion is weaker in younger babies than in older ones. | Mid | [
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// *************************************************************************** // * // * Copyright (C) 2006 International Business Machines // * Corporation and others. All Rights Reserved. // * Tool: com.ibm.icu.dev.tool.cldr.LDML2ICUConverter.java // * Source File:<path>/common/collation/ar.xml // * // *************************************************************************** /** * ICU <specials> source: <path>/xml/collation/ar.xml */ ar{ Version{"1.20"} collations{ standard{ Sequence{"&ة=ت"} Version{"1.4"} } } } | Low | [
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The selective antiproliferative effects of alpha-tocopheryl hemisuccinate and cholesteryl hemisuccinate on murine leukemia cells result from the action of the intact compounds. In the present study we have established that the antitumor activity of alpha-tocopheryl succinate (TS, vitamin E succinate) and cholesteryl succinate (CS) result from the action of the intact TS and CS compounds and not from the release of alpha-tocopherol, cholesterol, or succinate. We report that treatment of murine leukemia cell lines C1498 (myeloid) and L1210 (lymphocytic), with the tris salts of TS or CS, but not alpha-tocopherol and tris succinate or cholesterol and tris succinate, significantly inhibit the growth of these tumor cells and significantly enhance doxorubicin-induced tumor cell kill in a similar fashion. In contrast, the treatments mentioned above did not adversely affect the growth of murine normal bone marrow cells (colony-forming unit-granulocyte-macrophage). In fact, colony-forming unit granulocyte-macrophage cell growth was stimulated by exposure to CS and TS (as well as their ether analogues) at concentrations above 100 microM. Furthermore, pretreatment of colony-forming unit granulocyte-macrophage cells with TS or CS appears to protect these normal cells from the lethal effect of doxorubicin exposure. Selective inhibition of leukemia cell proliferation (identical to that noted for CS and TS) was also observed following the treatment of cells with the nonhydrolyzable ether forms of CS (cholesteryloxybutyric acid) and TS (alpha-tocopheryloxybutyric acid). These findings suggest that TS, alpha-tocopheryloxybutyric acid, CS, and cholesteryloxybutyric acid may prove clinically useful as selective antitumor agents when administered alone or in combination with doxorubicin by a route that ensures tissue accumulation of the intact compound. | High | [
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Experimental 'scramjet' sets hypersonic record as it flies at six times the speed of sound Arcing through the hazy air above California, this is the incredible sight of a scramjet as it flies at six times the speed of sound. The experimental aircraft set a record for hypersonic flight, blazing through the air for more than three minutes at Mach 6, or more than 4,500 mph. The X-51A Waverider scramjet was released from a B-52 bomber last week before its engine took it to Mach 6 and it flew autonomously for 200 seconds. Scramjets work by using oxygen rushing in through the engine at supersonic speeds to ignite hydrogen fuel. [caption] In a conventional jet engine, spinning blades suck air into the engine and compress it for combustion. The next step up is the ramjet engine, powered by fuel burning after subsonic air is forced into the engine by the speed of the aircraft. But in scramjets, so-called because they are 'supersonic combustion ramjets', airflow throughout the engine remains supersonic - using the oxygen in the incoming air to ignite hydrogen fuel. The expanding hot gases from combustion accelerate the exhaust air to create tremendous thrust. The engines could slash satellite launch costs, because there is no need for liquid oxygen as fuel. The U.S. space shuttle has to carry more than a million pounds of liquid oxygen each time it lifts off. [caption] [caption] The U.S Air Force said the previous record for a hypersonic scramjet burn was 12 seconds. ‘We are ecstatic to have accomplished many of the X-51A test points during its first hypersonic mission,’ said Charlie Brink, an X-51A program manager with the Air Force Research Laboratory. ‘We equate this leap in engine technology as equivalent to the post-World War II jump from propeller-driven aircraft to jet engines,’ Mr Brink said. A passenger plane traveling at Mach 6 would cut the flight time from London to Sydney to little more than two hours. Dr Andrew Coates, of the Mullard Space Science Lab at University College London, said the effects for passengers aboard a scramjet-powered plane would be 'more akin to space travel than airline travel'. They would need protective clothing to counteract the effects of the G-forces pressing on the body during acceleration to 5,000mph. British scientists have worked on designs for scramjets but do not expect one to be available for commercial flights until at least 2020. | High | [
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Project Sponsor Secondary Contact info Name: N/A Wiki Name: Fedora Account Name: Group: Project Info Project Name: Public Cobbler Server Target Audience: All users of Fedora Expiration/Delivery Date (required): 4/31/2007 Description/Summary: Cobbler is a Linux installation server. By hosting a cobbler cobbler server, we can allow people to remotely browse (via "yum install koan") the list of "profiles" a server offers and then allow them to install these profiles in various virtual machines (Xen PV, qemu/KVM) with a single command line command. Project plan (Detailed): Install a Cobbler server on a Fedora hosted machine and configure it for public access, with a set of kickstarts that point at Fedora mirrors. Disk space needs will be minimal as all content will be hosted later. Construct kickstarts for base installs of various useful profiles (base Fedora, minimal virt image, possibly a spin or two) and advertise to public lists how to try it out. As people come up with other useful spins/kickstarts, add them to the public server so they can be browsed. Initially I would offer up for distros F8 and F9 (with the update repo configured in kickstart) for x86 and x86_64. Cobbler's public XMLRPC would be enabled (TCPIP port 25151 by default) as koan would need it though the read-write port would be disabled. Apache proxies the XMLRPC over port 80. This would allow for folks to use koan to install virtual machines painlessly for various hosted external profiles, and also do reinstalls of existing Linux systems. Furthermore, if they want to use the koan Live CD (I'd build one for this purpose), we could also allow them to use this server for PXE-like baremetal installation in ways that do not even require PXE. (The koan Live CD works by erasing an HDD, setting up grub, and running koan). Goals: (1) Set up a public cobbler server and have people use it, to determine if there are any scaling issues regarding public cobbler servers (2) Get people using koan (3) Work on getting this into something that is a permanent fixture for Fedora virt/bare-metal deployment (4) Make virtualization ubiquitous by reducing user barriers to entry (5) Encourage exploration of community spins in easy to consume ways (6) (secondary goal) Encourage cobbler adoption within organizations by offering up a public instance for people to try out Specific resources needed Virtual machine that is publically accessible for network traffic on port 80, with root access for configuration. Virtual machine is not picky on requirements, I'd suggest 20 GB disk and 2 GB RAM, though it will not be hosting content. In lieu of a virtual machine, real hardware is also accessible. I will need to be able to SSH into the virtual machine to configure it. Additional Info (Optional) Let me know if you have any other questions -- mpdehaan on #cobbler, mdehaan AT redhat.com, etc. | Mid | [
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Q: Must I declare own wxFrame class? I'm creating simple c++ application with user interface. I have written own classes with needed mechanics, and now I must display some of its components using wxWidgets. MyApp contains objects of that classes, but they are also needed in MyFrame when handling events. It would be much more comfortable without passing pointers to that objects to MyFrame and implement everything in MyApp::OnInit function. Is that possible? // should contain informations about game state, players, gameboard, etc class MyApp : public wxApp { GameBoard gb; Player player; bool lightTheme; public: virtual bool OnInit(); }; // should contain only window layout, button events, etc class MyFrame : public wxFrame { GameBoard *gb; Player *player; bool *lightTheme; std::vector<wxStaticBitmap*> cardImages; // some events here void displayImages(wxGridSizer*); public: MyFrame(GameBoard*, Player*, bool*); }; A: To answer your title question, you don't have to declare MyFrame and can just create and directly use wxFrame and use Bind() to connect the different event handlers. In all but the simplest situations, it's typically convenient to have a MyFrame class centralizing the data and event handlers for the window, but it is not required by any means. If you decide to keep everything in MyApp instead, you may find wxGetApp() useful for accessing it from various places in your code. | Mid | [
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Introduction {#Sec1} ============ The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in late 2019 to cause coronavirus disease (COVID-19). The rapid global spread and exponential growth of the pandemic wave have stretched the limits of the available healthcare and intensive care unit capacity. Since the initial notification of an outbreak on December 31st, the global response has transitioned from the initial policy of active case finding and containment to an increasingly complex package of confinement measures including closures of schools, implementation of travel restrictions, and physical distancing measures. At present, given the global circulation of SARS-CoV-2, the consensus is that elimination of the virus is no longer feasible, and that longer-term strategies are needed that strike a balance between the economically and socially damaging (near) lockdown approaches and full release of any control measures. There is wide agreement that, in the latter situation, rapid resurgence would be very likely, with modeled epidemic peaks potentially exceeding the current healthcare capacity^[@CR1]^. The so-called exit strategy is defined as the transition from the current approach, which focuses entirely on flattening the peak of the COVID-19 emergence curve, to the transition phase in which restrictions are gradually lifted. The gradual lifting of control measures will require active surveillance to allow early detection of new cases or clusters, coupled with contact tracing and quarantine, most likely combined with continued physical distancing recommendations and enhanced protection of those at-risk from most severe disease. A key knowledge gap is the level and duration of protective immunity in the population at large and in specific groups, including persons with different clinical severity^[@CR1],[@CR2]^. To assess the extent of virus circulation in the community, and the likelihood of protection against a re-infection, there is a crucial need to add serology to the testing algorithms. The required performance of a serological assay will depend on the specific aim of testing, which may be either population screening (in the general population or at-risk populations) or diagnostic support. We recently showed that antibodies directed against the S1 subunit of the SARS-CoV-2 spike protein and specifically to the receptor binding domain (RBD) within the S1 subunit strongly correlate with virus neutralization^[@CR3]^. The likelihood of predicting protective antibody responses will thus increase when using either S1 antigens or RBD in the assay. The specificity of serological tools detecting antibodies against SARS CoV-2 might be hampered by the presence of antibodies against other circulating coronaviruses in the population, and thus testing for cross reactivity is crucial. When selecting an appropriate assay for a specific purpose, decision making should include the available knowledge on antibody specificities, kinetics, and functions^[@CR4]^. The limited knowledge on antibody kinetics in emerging virus infections is always a challenge for design and validation of serological assays during an outbreak. Recent studies in COVID-19 patients have shown that in both hospitalized patients and patients with mild disease, seroconversion rates reach 100% after 10--14 days, and that antibody levels may correlate with clinical severity^[@CR2],[@CR3],[@CR5]^. This is in line with observations in Middle East Respiratory Syndrome coronavirus (MERS-CoV) infection, in which antibody responses varied depending on disease severity, with mild and asymptomatic infections resulting in weaker immune responses^[@CR6]^. Therefore, for meaningful interpretation of serological assays and extrapolation of results to population screening, sufficient samples from persons with mild and asymptomatic disease should be included in validation studies. In our study we compare three platforms, which are widely used in diagnostic laboratories (three rapid tests, four ELISAs, and a high throughput chemiluminescent assay (CLIA)), which can be used to address different needs: for individualized (home) testing, as supplement to diagnostics and in population screening. We analyze their performance in correlation to an in-house virus neutralization assay^[@CR3]^, which is currently the gold standard when assessing protective immunity against SARS CoV-2. Results {#Sec2} ======= Patient diagnostics {#Sec3} ------------------- Serological testing to support clinical diagnostic work-up is mostly requested in hospitalized patients. This can be for example when SARS CoV-2 RNA diagnostic testing remains negative in a patient despite a strong clinical suspicion or for patients whose samples during the symptomatic phase were not collected. Other patients in whom antibody testing can be very valuable are those who have been hospitalized for weeks and in whom a PCR test continues to be positive with increasing cycle threshold values. In these patients, the detection of virus neutralizing antibodies can help with the decision to stop using personal protective equipment. In these patients usually the serological results are interpreted by laboratory staff and there is a possibility to test follow-up sera or perform confirmation serological testing. When comparing the laboratory assays in patients with different severity and stages of disease (overall), and in patients tested more than 14 days post-onset of disease, the RBD antigen based Wantai total Ig assay performed best (Fig. [1](#Fig1){ref-type="fig"}, Table [1](#Tab1){ref-type="table"}). Both IgG assays targeting the S antigen (Euroimmun and Liaison) lacked sensitivity in hospitalized patients as the sample set included early time-points. The S1 based IgA assay by Euroimmun, in contrast, had a good sensitivity, and showed the best quantitative relationship, specifically once neutralizing titers were higher than 80 (PRNT50 units), upon which the RBD Ig assay becomes non-linear. IgA testing will detect both early and memory IgA responses and will thus be a useful addition to IgG assays. The possible relevance of quantitative antibody measurements will need to be assessed when results of longer-term patient follow-up studies become available. An alternative of the PRNT50 can be the use of a surrogate virus neutralization test for SARS CoV-2 (as recently produced by Genscript, USA) which allows direct quantification. Extensive studies on the performance have however not yet been published.Fig. 1Performance of commercial assays for the detection of SARS-CoV-2-specific antibodies.Correlation of SARS-CoV-2 neutralizing antibody titers tested by a plaque reduction neutralization assay (PRNT50) to antibodies measured by selected assays. (**a**) Wantai Ig total ELISA, (**b**) Wantai IgM ELISA, (**c**) Euroimmun IgG ELISA, (**d**) Euroimmun IgA ELISA, (**e**) DiaSorin Liaison XL IgG chemiluminescence immunoassay, (**f**) Cellex IgM/IgG, (**g**) InTec IgM/IgG, (**h**) Orient gene/Healgen IgM/IgG. Turquoise dots indicate patient specimen collected ≤7 days post onset of symptoms (dps), magenta dots indicate samples collected from 8--14 dps, gray dots indicate specimen collected more than 14 dps. Dotted lines indicate the cut-off for positivity of each assay, as indicated by the manufacturer: Wantai ELISAs, OD ratio \> 1; Euroimmun ELISAs, OD ratio \> 1.1; DiaSorin Liaison IgG \>15 AU/ml. OD: optical density, AU: arbitrary units, r: correlation coefficient. (**i**) Percentages of specificities and sensitivities of the various platforms tested. The arrow bar indicates the upper and lower limit of the 95% CI. Source data are provided as a Source Data file.Table 1A summary of the performance characteristics of eight commercial COVID-19 serology assays.AssayWantai IgWantai IgMEuroimmun IgGEuroimmun IgALiaisonCellexIntecOrient/HealgenPlatformELISAELISAELISAELISACLIARDTRDTRDTAntigenRBDRBDS1S1S1 and S2S and NNS and NSpecificityn/N145/146144/146156/157147/157119/13297/9883/9887/98Value0.990.990.990.940.900.990.850.8895% CI0.96--1.00.951--1.00.97--1.00.89--0.970.84--0.950.95--1.00.76--0.910.80--0.94SensitivityOveralln/N186/187167/18561/7573/75134/165101/113102/113113/113Value0.990.900.810.970.810.890.901.095% CI0.97--1.00.85--0.940.71--0.890.91--1.00.74--0.870.82--0.940.83--0.950.97--1.0\>14 dpsn/N117/117100/11526/2727/2795/10463/6755/6567/67Value1.00.870.961.00.910.940.841.095% CI0.97--1.00.79--0.930.81--1.00.87--1.00.84--0.960.85--0.980.74--0.920.95--1.0Mildn/N64/6454/621/33/346/5533/3726/3637/37Value1.00.870.331.00.840.890.721.095% CI0.94--1.00.76--0.940.0084--0.910.29--1.00.71--0.920.75--0.970.55--0.860.91--1.0Overall PPVPopulation prevalence4%0.860.730.840.390.260.780.200.2650%0.990.990.990.940.890.990.860.8995%1.01.01.01.00.991.00.990.99Overall NPVPopulation prevalence4%1.01.00.991.00.991.01.01.050%0.990.910.840.970.830.90.91.095%0.910.350.220.650.200.330.311.0Sensitivity of the assays was determined by comparing the outcome to virus neutralization (PRNT\> 20). Patients were considered mild if they have not been admitted to a hospital. The PPV was calculated for 3 scenarios: 4 % seroprevalence in a general population. 50% seroprevalence in a high risk sub-population and 90% seroprevalence in hospitalized patients suspect for COVID-19. Ig: immunoglobulin, ELISA: enzyme linked immunosorbent assay, CLIA: chemiluminescence immune assay, RDT: rapid diagnostic test, n:number of positives, N: total number tested, CI: confidence interval, dps: days post onset of symptoms, PPV: positive predictive value, NPV: negative predictive value, PRNT: plaque reduction neutralization test. Despite the differences in sensitivity, all laboratory assays had sufficient positive predictive value (PPV) in COVID-19 hospitalized patients when assuming an expected seroprevalence in this population of ≥50% (Table [1](#Tab1){ref-type="table"}), or when using serology as an adjunct to RT-PCR testing to monitor the clinical course of illness. Their application as sole diagnostic, however---for instance in primary care, where the seroprevalence will be much lower---will be more challenging as illustrated by the variation in PPV of the assays with a seroprevalence estimate of 4%, which is the level currently observed in the Netherlands^[@CR7]^. In addition to specialized ELISA assays used in laboratory settings, a wide range of rapid diagnostic tests (RDT) has been put on the market, triggering the question whether they can be used in patient care or for triage in a medical care facility. We selected three RDTs by following criteria (1) preferably targetting the spike of SARS-CoV-2 (2) at least European Conformity (CE) marking or other authorization, and (3) sufficient production capacity. The RDTs provide qualitative (yes/no) results, which does not allow quantification or the definition of a cut-off for neutralization (Fig. [1f--h](#Fig1){ref-type="fig"}). All three RDTs had a sufficient PPV in high seroprevalence scenarios, which implies that there might be a role for the RDTs when used for the individual patient with a sufficiently high pretest probability as an add on to PCR based diagnostics. The high negative predictive value (NPV) of the RDTs in a low seroprevalence scenario could offer opportunities for the use of the test in the general population, if the aim is to rule out the presence of SARS CoV-2 antibodies (Table [1](#Tab1){ref-type="table"}). Population screening {#Sec4} -------------------- Population screening during a pandemic phase requires a highly specific assay, to assure an acceptable PPV in populations with a low sero-prevalence^[@CR3]^, and additionally a reasonable sensitivity (Table [1](#Tab1){ref-type="table"}). This condition was met for the Wantai ELISAs and Euroimmun IgG ELISA. The Euroimmun IgA and Liaison CLIA analyzer performed less well, with specificities \<95% when testing serum samples from persons exposed to a range of viruses (Table [1](#Tab1){ref-type="table"})^[@CR8]^. This led to very low PPV's of respectively 39% and 26% for the Euroimmun IgA and the CLIA analyzer in low prevalence settings, while the Wantai total Ig continued to perform reasonably well. Tested specimen were obtained from patients with mild, moderate, and severe disease. All patients had detectable antibodies by PRNT50 from day 18 ([supplementary data](#MOESM3){ref-type="media"}). The severity of disease did not affect the range of detected neutralizing titers or sensitivity of selected assays (Table [1](#Tab1){ref-type="table"}, [supplementary data](#MOESM3){ref-type="media"}). Due to limitations in sample volumes of mild patients, these were not equally tested in all assays. In addition, future studies are recommended to address the performance of alternative high throughput assays like the Roche Elecsys Anti-SARS-CoV-2 or Abbott SARS-CoV-2 IgG, in correlation to neutralization. For the RDTs the specificities varied from 85 to 99% (Table [1](#Tab1){ref-type="table"}), although the overall performance of the Cellex assay with 99% specificity was hampered by its low sensitivity of 80%. Generally, the use of the selected RDT is not recommended in population screening where estimated seroprevalence is mostly \<5% and the PPV will be too low for a reliable interpretation (Table [1](#Tab1){ref-type="table"}). A final question in population screening is whether the antibody measurements correlate with functional antibodies that can protect a population during a subsequent exposure. In our analyses, samples testing positive in the Wantai Ig ELISA with an OD ratio \> 10 all had detectable levels of neutralizing antibodies which suggests that---using a cut-off- in this assay could be used to indicate presence of neutralizing antibodies. The exact kinetics and functionality of these antibodies in offering protection remains to be determined. In conclusion, our presented data support decision making for the use of serology in either individual patient care or population-level serological testing. We conclude that for the aim of detecting protective antibodies, the RBD based Wantai ELISA had the best overall performance including the potential to set a cut-off indicating the presence of protective antibodies. The global performance of the selected RDTs is not robust enough for over the counter personalized testing in the population. Methods {#Sec5} ======= Blood samples {#Sec6} ------------- All specimen used in the study have been collected and delivered to our diagnostic laboratory for patient diagnostics, and not following a predefined COVID-19 research protocol. To determine specificity of the assays, we used a well-defined panel of 147 serum and plasma samples from 147 individuals exposed to human coronaviruses (HCoV-229E, NL63 or OC43), SARS, MERS), or with a range of other respiratory viruses (adenovirus, human metapneumovirus, influenza A/B, RSV A/B, rhinovirus, Bocavirus, parainfluenzavirus 1 and 3, enterovirus). Specimen from patients with recent cytomegalovirus (CMV), Epstein Barr virus (EBV) or M. pneumoniae infection were included as these have a high likelihood of causing cross reactivity. Sera were collected from 2--3 weeks upon the respiratory infection, and during the acute phase of CMV or EBV. The variation in the number of samples tested per assay was caused by limited sample volume and by the limited availability of RDTs during the study period. Sensitivity was calculated by using a total of 187 sera from 107 individuals in the Netherlands, in whom COVID-19 was confirmed by RT-PCR and antibodies were detected by PRNT50. Disease severity varied from (1) Mild, non-hospitalized, (2) Moderate, hospitalized, and (3) Severe, admitted to the intensive care unit. Specimen were taken at different time-points post-onset of disease ([supplementary data](#MOESM3){ref-type="media"}, Fig. [1](#MOESM1){ref-type="media"}). All specimen were stored at −20 °C until use. The variation in the number of samples tested per assay is caused by the fact that validation was part of the acute diagnostic response during the first phase of the COVID-19 pandemic. Initially, a set of 75 patient sera was tested in all assays. These sera were mostly collected from hospitalized patients and involved only three sera from mild patients. To assess the performance of the assays in population screening it is important to involve sera from mild patients so we increased the number of tested sera in the Wantai ELISAs, Liaison, and RDTs. The selection of these assays was based on the best overall performance of Wantai ELISAs in the first analyses and the likely application of Liaison and RDTs in population screening. The exact number of specimen tested per assay varied due to availability of serum. Figure [1](#Fig1){ref-type="fig"} depicts the outcome of the assays per time interval, analyses in mild patients are shown in Table [1](#Tab1){ref-type="table"}, source data can be found in the Supplementary Data [1](#MOESM4){ref-type="media"}. Ethics declarations {#Sec7} ------------------- The use of specimen was approved by the Erasmus MC medical ethical committee (MEC approval: 2014--414), which allows the use of clinical data and left-over material from the specimen delivered to our laboratory for diagnostics, unless patients have declared they opted out of this scheme. In addition, the Erasmus MC institutional research committee regulated that all COVID-19 patients admitted to Erasmus MC are asked for permission to use their clinical data and left-over patient material for COVID-19 research purposes. All patients who refused have been excluded from the analyses. ELISA {#Sec8} ----- Four selected ELISAs were performed according to manufacturer's protocol: (1) Wantai SARS-CoV-2 total Ig and IgM ELISAs from Beijing Wantai Biological Pharmacy Enterprise Co., Ltd., China. The ELISAs are coated with RBD antigen. (2) Euroimmun Anti-SARS-CoV-2 IgG and IgA ELISA assays from EUROIMMUN Medizinische Labordiagnostika AG, Lübeck, Germany. The Euroimmun ELISAs are coated with S1 antigen. DiaSorin Liaison XL {#Sec9} ------------------- The Liaison XL by DiaSorin (Saluggia, Italy), is a semi-automated system using chemiluminescent immunoassay (CLIA) technology for detection of Ab in human samples. The assay is based on S1 and S2 coating antigens. The assays were performed following manufacturer's protocol. Rapid antibody test {#Sec10} ------------------- The rapid tests we evaluated are (1) Rapid SARS -CoV-2 Antibody (IgM/IgG) Test from InTec utilizing the nucleocapsid protein as antigen (Test lots S2020021505 and GJ20030288), (2) the qSARS-CoV-2 IgG/IgM Cassette Rapid Test (GICA) from Cellex Inc. utilizing both the spike and the nucleocapsid protein (Test lot 20200416WI5513C) and (3) the COVID-19 IgG/IgM Rapid Test Cassette (Whole Blood/Serum/Plasma) from Orient Gene / Healgen (Test lot 2003309), utilizing both the spike and the nucleocapsid protein. All three tests are based on immunochromatography for detection of IgG and IgM specific to SARS CoV-2 in human whole blood (venous and fingerstick) serum or plasma. We performed the tests following the manufacturers' instructions. Each sample was tested by one test and readout (positive/negative) interpreted by two operators in parallel. PRNT 50 {#Sec11} ------- An in-house plaque-reduction neutralization test (PRNT50) was used as a reference for this study, because virus neutralization assays are the gold standard in coronavirus serology. We tested serum and plasma samples for their neutralizing capacity against SARS-CoV-2 (German isolate; GISAID ID EPI_ISL 406862; European Virus Archive Global \# 026V-03883) by PRNT50 as previously described by Okba et al.^[@CR3]^. Statistical analysis {#Sec12} -------------------- The outcome of commercial testing was correlated to functional antibody measurements, to assess likelihood of predicting protective antibody responses. The results of the different ELISAs and RDTs were compared with those detected by PRNT50. For sensitivity calculations only the PRNT50 positive samples were used for the calculations. Specificity was calculated by using the cross reactive panel of non-SARS CoV-2 sera. Graphs were made by using GraphPad Prism version 8 (<https://www.graphpad.com>). The predictive values were calculated for three scenarios 4% seroprevalence in a general population, 50% seroprevalence in a high-risk sub-population and 95% seroprevalence in confirmed or highly suspect COVD-19 hospitalized patients. Reporting summary {#Sec13} ----------------- Further information on research design is available in the [Nature Research Reporting Summary](#MOESM2){ref-type="media"} linked to this article. Supplementary information ========================= {#Sec14} Peer Review File Reporting Summary Description of Additional Supplementary Files Supplementary Data 1 Source data {#Sec15} =========== Source Data **Peer review information** *Nature Communications* thanks the anonymous reviewers for their contribution to the peer review of this work. **Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. These authors contributed equally: Corine H. GeurtsvanKessel, Nisreen M.A. Okba. Supplementary information ========================= **Supplementary information** is available for this paper at 10.1038/s41467-020-17317-y. Sandra Scherbeijn and Zain Abdel-Karem Abou-Nouar are acknowledged for excellent technical assistance. This work partially was funded through EU COVID-19 grant RECOVER 101003589. C.G., N.O., Z.I., B.H. and M.K. contributed to the conception and design of the study; C.G., C.R., B.R., J.R., J.A., J.K., A.E. were involved in COVID-19 patient care, data, and specimen collection; N.O., Z.I., S.B., C.E., B.L., L.L. were involved in data acquisition; C.G., N.O., Z.I., S.B., B.H., M.K. were involved in data analysis and drafting a significant proportion of the paper or figures; C.G., R.B. and M.K. critically revised the paper. Source data are provided with this paper. Other data are available from the corresponding author upon reasonable requests. Source data are provided with this paper. The authors declare no competing interests. | Mid | [
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Related literature {#sec1} ==================== For related structures, see: Abdul Ajees *et al.* (2002[@bb1]); Usha *et al.* (2003[@bb12]). For background to the biological properties of spiro-pyrrolidine derivatives, see: Chande *et al.* (2005[@bb3]); Dandia *et al.* (2003[@bb5]); Cravotto *et al.* (2001[@bb4]); Winfred *et al.* (2000[@bb13]); Metwally *et al.* (1998[@bb9]); Suenaga *et al.* (2001[@bb11]). For the synthesis of the title compound, see: Kumar *et al.* (2008*a* [@bb6],*b* [@bb7]); Liang *et al.* (2009[@bb8]). Experimental {#sec2} ============== {#sec2.1} ### Crystal data {#sec2.1.1} C~33~H~25~F~2~NO~2~*M* *~r~* = 505.54Orthorhombic,*a* = 17.728 (13) Å*b* = 12.272 (9) Å*c* = 12.094 (8) Å*V* = 2631 (3) Å^3^*Z* = 4Mo *K*α radiationμ = 0.09 mm^−1^*T* = 293 K0.45 × 0.38 × 0.27 mm ### Data collection {#sec2.1.2} Bruker SMART CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2002[@bb2]) *T* ~min~ = 0.641, *T* ~max~ = 1.00012188 measured reflections2500 independent reflections2072 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.123 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.055*wR*(*F* ^2^) = 0.126*S* = 1.022500 reflections344 parameters13 restraintsH-atom parameters constrainedΔρ~max~ = 0.24 e Å^−3^Δρ~min~ = −0.32 e Å^−3^ {#d5e486} Data collection: *SMART* (Bruker, 2002[@bb2]); cell refinement: *SAINT* (Bruker, 2002[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb10]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb10]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb10]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== ###### Click here for additional data file. Crystal structure: contains datablock(s) I, global. DOI: [10.1107/S1600536812051550/pk2458sup1.cif](http://dx.doi.org/10.1107/S1600536812051550/pk2458sup1.cif) ###### Click here for additional data file. Structure factors: contains datablock(s) cd20184. DOI: [10.1107/S1600536812051550/pk2458Isup2.hkl](http://dx.doi.org/10.1107/S1600536812051550/pk2458Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?pk2458&file=pk2458sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?pk2458sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?pk2458&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [PK2458](http://scripts.iucr.org/cgi-bin/sendsup?pk2458)). This work was supported by the Zhejiang Provincial Natural Science Foundation of China (grant Nos. LY12H16003 and Y4110197) and the Project of Wenzhou Science & Technology Bureau (Y20100273). The X-ray crystallographic facility at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, is gratefully acknowledged for the data collection. Comment ======= Spiro-pyrrolidine compounds find applications in the synthesis of biologically active compounds. The synthesis of spiro compounds has drawn considerable attention of chemists, in view of their wide spectrum of pharmacological properties (Chande *et al.*, 2005; Dandia *et al.*, 2003; Cravotto *et al.*, 2001; Winfred *et al.*, 2000; Metwally *et al.*, 1998; Suenaga *et al.*, 2001). In the present study, the 1,3-dipolar cycloaddition of an azomethine ylide generated *in situ* from acenaphthenequinone and sarcosine to novel mono-carbonyl analogue of curcumin containg cyclopentanone afforded the title compound (Kumar *et al.*, 2008; Liang *et al.*, 2009). With this background, and in continuation of our structural analysis of spiro-pyrrolidine derivatives, the X-ray crystal structure determination of the title compound, (I), was undertaken. The bond lengths and angles in the pyrrolidine ring are slightly larger than normal values because of bulky substituents on the pyrrolidine moiety. A similar effect has been observed in related reported structures (Abdul Ajees *et al.*, 2002; Usha *et al.*, 2003). The sum of the angles at atom N1 \[339.1 (11)°\] is in accordance with *sp*^3^-hybridization. The dihedral angles between the acenaphthene ring system and phenyl rings C21---C26 and C27---C32 are 50.93 (14)° and 36.89 (14)° respectively, while that between the two phenyl-ring substituents is 87.55 (17)°. The pyrrolidine and cyclopentanone ring both adopt an envelope conformation. In addition to van der Waals interactions, the crystal structure is stabilized by C---H···O and C---H···F intramolecular interactions. In the present study, the 1,3-dipolar cycloaddition of an azomethine ylide generated *in situ* from acenaphthenequinone and sarcosine to novel mono-carbonyl analogue of curcumin containg cyclopentanone afforded title compound. Experimental {#experimental} ============ A mixture of (2E,5E)-2,5-bis(2-fluorobenzylidene)cyclopentanone (1 mmol), (Liang *et al.*, 2009), acenaphthenequinone (0.182 g, 1 mmol), and sarcosine (0.089 g, 1 mmol) was dissolved in methanol (10 mL) and refluxed for 1 h. After completion of the reaction as evident from TLC, the mixture was cooled to room temperature and poured into cold water (50 mL). The precipitate was filtered and washed with water to obtain pure product as a yellow solid (79.6% yield, mp 93.2--95.0°C). Single crystals were grown in an ethyl acetate/CH~2~Cl~2~ mixture (2:1ν/ν). Refinement {#refinement} ========== The H(C) atom positions were calculated. The H atoms bound to C were positioned geometrically and allowed to ride on their parent atoms at distances of 0.96 Å (RCH~3~), 0.97 Å (R~2~CH~2~), 0.98 Å (R~3~CH), 0.93 Å (R~2~CH), and with U~iso~(H) values set to either 1.2U~eq~ or 1.5U~eq~ (RCH~3~) of the attached atom. Figures ======= {#Fap1} Crystal data {#tablewrapcrystaldatalong} ============ ------------------------- --------------------------------------- C~33~H~25~F~2~NO~2~ *F*(000) = 1052 *M~r~* = 505.54 *D*~x~ = 1.274 Mg m^−3^ Orthorhombic, *Pca*2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2c -2ac Cell parameters from 3224 reflections *a* = 17.728 (13) Å θ = 4.6--41.9° *b* = 12.272 (9) Å µ = 0.09 mm^−1^ *c* = 12.094 (8) Å *T* = 293 K *V* = 2631 (3) Å^3^ Prismatic, yellow *Z* = 4 0.45 × 0.38 × 0.27 mm ------------------------- --------------------------------------- Data collection {#tablewrapdatacollectionlong} =============== ------------------------------------------------------------ -------------------------------------- Bruker SMART CCD area-detector diffractometer 2500 independent reflections Radiation source: fine-focus sealed tube 2072 reflections with *I* \> 2σ(*I*) Graphite monochromator *R*~int~ = 0.123 φ and ω scans θ~max~ = 25.5°, θ~min~ = 1.7° Absorption correction: multi-scan (*SADABS*; Bruker, 2002) *h* = −21→20 *T*~min~ = 0.641, *T*~max~ = 1.000 *k* = −14→10 12188 measured reflections *l* = −14→13 ------------------------------------------------------------ -------------------------------------- Refinement {#tablewraprefinementdatalong} ========== ------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.055 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.126 H-atom parameters constrained *S* = 1.02 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0837*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2500 reflections (Δ/σ)~max~ \< 0.001 344 parameters Δρ~max~ = 0.24 e Å^−3^ 13 restraints Δρ~min~ = −0.32 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------- Special details {#specialdetails} =============== ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ------ -------------- -------------- ------------ -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ F1 0.1562 (3) 0.1946 (2) 0.9893 (3) 0.1212 (15) F2 0.37848 (15) 0.7382 (2) 1.1356 (2) 0.0723 (8) O1 0.20514 (17) 0.54755 (19) 1.1294 (2) 0.0503 (7) O2 0.08624 (18) 0.9035 (2) 0.9244 (3) 0.0656 (9) N1 0.0970 (2) 0.7803 (3) 1.1430 (3) 0.0494 (8) C1 0.1917 (2) 0.5827 (3) 1.0368 (3) 0.0351 (8) C2 0.1848 (2) 0.5181 (3) 0.9340 (3) 0.0367 (8) C3 0.1787 (2) 0.5964 (3) 0.8387 (3) 0.0390 (8) H3A 0.1272 0.6007 0.8120 0.047\* H3B 0.2113 0.5745 0.7783 0.047\* C4 0.2041 (2) 0.7055 (2) 0.8874 (3) 0.0351 (8) H4A 0.1802 0.7655 0.8486 0.042\* H4B 0.2583 0.7135 0.8812 0.042\* C5 0.18001 (19) 0.7045 (2) 1.0097 (3) 0.0329 (7) C6 0.2244 (2) 0.7800 (3) 1.0916 (3) 0.0376 (8) H6 0.2461 0.7324 1.1483 0.045\* C7 0.1640 (2) 0.8486 (3) 1.1487 (3) 0.0515 (10) H7A 0.1777 0.8636 1.2249 0.062\* H7B 0.1562 0.9170 1.1103 0.062\* C8 0.0945 (2) 0.7332 (3) 1.0318 (3) 0.0376 (8) C9 0.0633 (2) 0.8121 (3) 0.9403 (3) 0.0460 (9) C10 0.0007 (2) 0.7571 (4) 0.8828 (3) 0.0520 (11) C11 −0.0125 (2) 0.6583 (3) 0.9373 (3) 0.0501 (10) C12 0.0375 (2) 0.6408 (3) 1.0259 (3) 0.0467 (9) C13 0.0260 (3) 0.5518 (4) 1.0922 (4) 0.0690 (13) H14 0.0563 0.5400 1.1538 0.083\* C14 −0.0322 (4) 0.4789 (5) 1.0659 (6) 0.0884 (17) H14A −0.0390 0.4182 1.1109 0.106\* C15 −0.0788 (3) 0.4923 (4) 0.9792 (6) 0.093 (2) H15 −0.1158 0.4407 0.9646 0.112\* C16 −0.0713 (3) 0.5851 (4) 0.9099 (4) 0.0718 (14) C17 −0.1165 (3) 0.6177 (6) 0.8195 (6) 0.094 (2) H17 −0.1559 0.5731 0.7967 0.113\* C18 −0.1034 (3) 0.7133 (7) 0.7648 (5) 0.098 (2) H18 −0.1339 0.7309 0.7048 0.118\* C19 −0.0455 (3) 0.7867 (4) 0.7954 (4) 0.0719 (15) H19 −0.0387 0.8523 0.7582 0.086\* C20 0.1819 (2) 0.4093 (3) 0.9397 (3) 0.0430 (8) H21 0.1849 0.3811 1.0109 0.052\* C21 0.1747 (2) 0.3280 (3) 0.8532 (3) 0.0452 (9) C22 0.1803 (3) 0.3482 (3) 0.7384 (3) 0.0562 (11) H22 0.1859 0.4196 0.7140 0.067\* C23 0.1776 (3) 0.2659 (4) 0.6621 (4) 0.0689 (14) H23 0.1820 0.2824 0.5873 0.083\* C24 0.1685 (3) 0.1603 (4) 0.6939 (5) 0.0726 (14) H24 0.1678 0.1048 0.6415 0.087\* C25 0.1604 (4) 0.1365 (4) 0.8058 (5) 0.0829 (18) H25 0.1528 0.0652 0.8294 0.099\* C26 0.1639 (3) 0.2197 (3) 0.8797 (4) 0.0676 (14) C27 0.2887 (2) 0.8456 (3) 1.0442 (3) 0.0374 (8) C28 0.2768 (3) 0.9352 (3) 0.9739 (3) 0.0533 (11) H28 0.2278 0.9556 0.9559 0.064\* C29 0.3368 (3) 0.9934 (3) 0.9313 (4) 0.0632 (12) H29 0.3274 1.0522 0.8849 0.076\* C30 0.4090 (3) 0.9666 (4) 0.9558 (4) 0.0647 (13) H30 0.4485 1.0070 0.9263 0.078\* C31 0.4239 (3) 0.8797 (4) 1.0239 (4) 0.0614 (11) H31 0.4731 0.8598 1.0412 0.074\* C32 0.3623 (2) 0.8225 (3) 1.0661 (3) 0.0457 (9) C33 0.0275 (3) 0.8304 (4) 1.1823 (4) 0.0793 (15) H33A 0.0325 0.8479 1.2593 0.119\* H33B −0.0136 0.7805 1.1724 0.119\* H33C 0.0179 0.8958 1.1410 0.119\* ------ -------------- -------------- ------------ -------------------- -- Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ F1 0.251 (5) 0.0477 (15) 0.0652 (18) −0.031 (2) −0.035 (2) 0.0173 (15) F2 0.0645 (19) 0.0727 (17) 0.0798 (18) 0.0172 (13) 0.0031 (14) 0.0249 (15) O1 0.078 (2) 0.0374 (14) 0.0354 (13) −0.0033 (12) −0.0117 (13) 0.0106 (11) O2 0.073 (2) 0.0410 (16) 0.082 (2) 0.0067 (14) −0.0102 (17) 0.0123 (16) N1 0.050 (2) 0.060 (2) 0.0389 (16) −0.0045 (15) 0.0072 (14) −0.0143 (15) C1 0.041 (2) 0.0303 (17) 0.0343 (18) −0.0005 (14) 0.0016 (15) 0.0056 (15) C2 0.043 (2) 0.0327 (18) 0.0347 (17) −0.0015 (14) 0.0011 (15) 0.0035 (15) C3 0.057 (3) 0.0307 (18) 0.0296 (16) −0.0015 (15) 0.0021 (16) 0.0000 (14) C4 0.045 (2) 0.0305 (17) 0.0303 (16) 0.0003 (14) 0.0002 (14) 0.0042 (14) C5 0.039 (2) 0.0298 (17) 0.0298 (16) 0.0002 (14) −0.0024 (14) −0.0003 (14) C6 0.046 (2) 0.0338 (17) 0.0326 (16) −0.0041 (14) −0.0044 (16) −0.0004 (14) C7 0.058 (3) 0.054 (2) 0.043 (2) −0.0043 (18) 0.0014 (18) −0.0198 (19) C8 0.041 (2) 0.0350 (18) 0.0366 (17) −0.0028 (14) −0.0019 (16) −0.0044 (15) C9 0.052 (3) 0.039 (2) 0.046 (2) 0.0113 (17) 0.0017 (19) −0.0034 (17) C10 0.049 (3) 0.063 (3) 0.045 (2) 0.0167 (19) −0.0042 (19) −0.0184 (19) C11 0.044 (2) 0.054 (2) 0.053 (2) −0.0005 (16) 0.0025 (19) −0.024 (2) C12 0.043 (2) 0.045 (2) 0.052 (2) −0.0027 (16) 0.0068 (19) −0.0049 (18) C13 0.057 (3) 0.068 (3) 0.082 (3) −0.012 (2) 0.017 (2) 0.017 (3) C14 0.075 (4) 0.076 (4) 0.114 (5) −0.032 (3) 0.013 (4) 0.007 (3) C15 0.078 (4) 0.069 (3) 0.133 (5) −0.038 (3) 0.027 (4) −0.028 (4) C16 0.047 (3) 0.086 (4) 0.082 (3) −0.005 (2) 0.001 (2) −0.043 (3) C17 0.067 (4) 0.115 (5) 0.101 (5) −0.001 (3) −0.019 (3) −0.060 (4) C18 0.077 (4) 0.149 (6) 0.069 (4) 0.031 (4) −0.037 (3) −0.055 (4) C19 0.071 (4) 0.094 (4) 0.050 (2) 0.031 (3) −0.014 (2) −0.018 (2) C20 0.055 (2) 0.0339 (19) 0.0407 (18) −0.0037 (15) −0.0023 (17) 0.0052 (16) C21 0.048 (2) 0.035 (2) 0.053 (2) −0.0003 (16) −0.0060 (18) −0.0006 (17) C22 0.073 (3) 0.043 (2) 0.052 (2) −0.016 (2) 0.004 (2) −0.0028 (19) C23 0.080 (4) 0.068 (3) 0.058 (3) −0.020 (2) 0.009 (2) −0.018 (2) C24 0.081 (4) 0.057 (3) 0.080 (4) 0.011 (2) −0.018 (3) −0.032 (3) C25 0.131 (5) 0.032 (2) 0.085 (4) 0.004 (2) −0.040 (3) −0.004 (3) C26 0.109 (4) 0.035 (2) 0.059 (3) −0.004 (2) −0.024 (3) 0.008 (2) C27 0.048 (2) 0.0332 (18) 0.0313 (16) −0.0048 (14) −0.0008 (15) −0.0074 (15) C28 0.067 (3) 0.040 (2) 0.052 (2) −0.0045 (18) −0.006 (2) 0.0060 (18) C29 0.090 (4) 0.038 (2) 0.061 (3) −0.022 (2) −0.003 (3) 0.002 (2) C30 0.083 (4) 0.061 (3) 0.050 (3) −0.037 (2) 0.009 (2) −0.011 (2) C31 0.050 (3) 0.073 (3) 0.061 (3) −0.005 (2) 0.004 (2) −0.009 (2) C32 0.053 (3) 0.040 (2) 0.044 (2) −0.0025 (17) 0.0018 (18) −0.0059 (17) C33 0.058 (3) 0.106 (4) 0.074 (3) 0.000 (3) 0.014 (3) −0.039 (3) ----- ------------- ------------- ------------- -------------- -------------- -------------- Geometric parameters (Å, º) {#tablewrapgeomlong} =========================== ----------------------- ------------ ----------------------- ------------ F1---C26 1.368 (6) C14---H14A 0.9300 F2---C32 1.362 (5) C15---C16 1.421 (8) O1---C1 1.224 (4) C15---H15 0.9300 O2---C9 1.209 (5) C16---C17 1.413 (9) N1---C7 1.455 (5) C17---C18 1.367 (9) N1---C33 1.456 (6) C17---H17 0.9300 N1---C8 1.465 (5) C18---C19 1.415 (8) C1---C2 1.478 (5) C18---H18 0.9300 C1---C5 1.545 (5) C19---H19 0.9300 C2---C20 1.338 (5) C20---C21 1.451 (5) C2---C3 1.505 (5) C20---H21 0.9300 C3---C4 1.530 (5) C21---C26 1.380 (6) C3---H3A 0.9700 C21---C22 1.414 (6) C3---H3B 0.9700 C22---C23 1.369 (6) C4---C5 1.539 (5) C22---H22 0.9300 C4---H4A 0.9700 C23---C24 1.361 (7) C4---H4B 0.9700 C23---H23 0.9300 C5---C6 1.568 (5) C24---C25 1.392 (8) C5---C8 1.580 (5) C24---H24 0.9300 C6---C27 1.508 (5) C25---C26 1.359 (6) C6---C7 1.527 (5) C25---H25 0.9300 C6---H6 0.9800 C27---C32 1.362 (5) C7---H7A 0.9700 C27---C28 1.405 (5) C7---H7B 0.9700 C28---C29 1.381 (6) C8---C12 1.520 (5) C28---H28 0.9300 C8---C9 1.571 (5) C29---C30 1.353 (7) C9---C10 1.473 (6) C29---H29 0.9300 C10---C19 1.386 (6) C30---C31 1.373 (7) C10---C11 1.400 (6) C30---H30 0.9300 C11---C12 1.408 (6) C31---C32 1.395 (6) C11---C16 1.415 (6) C31---H31 0.9300 C12---C13 1.370 (6) C33---H33A 0.9600 C13---C14 1.402 (7) C33---H33B 0.9600 C13---H14 0.9300 C33---H33C 0.9600 C14---C15 1.344 (10) C7---N1---C33 115.6 (3) C13---C14---H14A 118.3 C7---N1---C8 107.2 (3) C14---C15---C16 120.1 (5) C33---N1---C8 116.1 (4) C14---C15---H15 120.0 O1---C1---C2 126.6 (3) C16---C15---H15 120.0 O1---C1---C5 124.1 (3) C17---C16---C11 114.8 (6) C2---C1---C5 109.3 (3) C17---C16---C15 129.1 (5) C20---C2---C1 119.7 (3) C11---C16---C15 116.0 (5) C20---C2---C3 132.3 (3) C18---C17---C16 121.4 (5) C1---C2---C3 107.9 (3) C18---C17---H17 119.3 C2---C3---C4 104.1 (3) C16---C17---H17 119.3 C2---C3---H3A 110.9 C17---C18---C19 122.9 (5) C4---C3---H3A 110.9 C17---C18---H18 118.6 C2---C3---H3B 110.9 C19---C18---H18 118.6 C4---C3---H3B 110.9 C10---C19---C18 117.5 (6) H3A---C3---H3B 109.0 C10---C19---H19 121.3 C3---C4---C5 106.3 (3) C18---C19---H19 121.3 C3---C4---H4A 110.5 C2---C20---C21 130.8 (3) C5---C4---H4A 110.5 C2---C20---H21 114.6 C3---C4---H4B 110.5 C21---C20---H21 114.6 C5---C4---H4B 110.5 C26---C21---C22 113.9 (4) H4A---C4---H4B 108.7 C26---C21---C20 120.5 (4) C4---C5---C1 100.0 (3) C22---C21---C20 125.5 (4) C4---C5---C6 117.6 (3) C23---C22---C21 122.1 (4) C1---C5---C6 111.8 (3) C23---C22---H22 119.0 C4---C5---C8 115.3 (3) C21---C22---H22 119.0 C1---C5---C8 108.0 (3) C24---C23---C22 121.0 (5) C6---C5---C8 104.1 (3) C24---C23---H23 119.5 C27---C6---C7 114.1 (3) C22---C23---H23 119.5 C27---C6---C5 117.0 (3) C23---C24---C25 119.2 (4) C7---C6---C5 105.1 (3) C23---C24---H24 120.4 C27---C6---H6 106.7 C25---C24---H24 120.4 C7---C6---H6 106.7 C26---C25---C24 118.4 (5) C5---C6---H6 106.7 C26---C25---H25 120.8 N1---C7---C6 103.5 (3) C24---C25---H25 120.8 N1---C7---H7A 111.1 C25---C26---F1 117.6 (4) C6---C7---H7A 111.1 C25---C26---C21 125.3 (4) N1---C7---H7B 111.1 F1---C26---C21 117.1 (4) C6---C7---H7B 111.1 C32---C27---C28 115.1 (3) H7A---C7---H7B 109.0 C32---C27---C6 122.6 (3) N1---C8---C12 110.9 (3) C28---C27---C6 122.2 (3) N1---C8---C9 114.5 (3) C29---C28---C27 120.9 (4) C12---C8---C9 101.2 (3) C29---C28---H28 119.5 N1---C8---C5 102.4 (3) C27---C28---H28 119.5 C12---C8---C5 117.6 (3) C30---C29---C28 121.4 (4) C9---C8---C5 110.9 (3) C30---C29---H29 119.3 O2---C9---C10 127.2 (4) C28---C29---H29 119.3 O2---C9---C8 124.4 (4) C29---C30---C31 120.1 (4) C10---C9---C8 108.4 (3) C29---C30---H30 119.9 C19---C10---C11 119.2 (5) C31---C30---H30 119.9 C19---C10---C9 133.2 (5) C30---C31---C32 117.4 (4) C11---C10---C9 107.5 (3) C30---C31---H31 121.3 C10---C11---C12 112.7 (3) C32---C31---H31 121.3 C10---C11---C16 124.2 (4) C27---C32---F2 118.7 (3) C12---C11---C16 123.1 (4) C27---C32---C31 125.0 (4) C13---C12---C11 118.3 (4) F2---C32---C31 116.3 (4) C13---C12---C8 131.8 (4) N1---C33---H33A 109.5 C11---C12---C8 109.9 (3) N1---C33---H33B 109.5 C12---C13---C14 119.1 (5) H33A---C33---H33B 109.5 C12---C13---H14 120.5 N1---C33---H33C 109.5 C14---C13---H14 120.5 H33A---C33---H33C 109.5 C15---C14---C13 123.4 (5) H33B---C33---H33C 109.5 C15---C14---H14A 118.3 O1---C1---C2---C20 10.5 (6) C16---C11---C12---C13 −3.8 (6) C5---C1---C2---C20 −170.2 (3) C10---C11---C12---C8 −3.1 (5) O1---C1---C2---C3 −172.3 (4) C16---C11---C12---C8 179.1 (4) C5---C1---C2---C3 7.0 (4) N1---C8---C12---C13 −49.0 (5) C20---C2---C3---C4 −168.1 (4) C9---C8---C12---C13 −170.8 (4) C1---C2---C3---C4 15.2 (4) C5---C8---C12---C13 68.3 (6) C2---C3---C4---C5 −32.0 (4) N1---C8---C12---C11 127.7 (3) C3---C4---C5---C1 34.8 (4) C9---C8---C12---C11 5.8 (4) C3---C4---C5---C6 156.0 (3) C5---C8---C12---C11 −115.1 (3) C3---C4---C5---C8 −80.6 (3) C11---C12---C13---C14 3.4 (6) O1---C1---C5---C4 153.6 (4) C8---C12---C13---C14 179.9 (5) C2---C1---C5---C4 −25.7 (3) C12---C13---C14---C15 −1.0 (9) O1---C1---C5---C6 28.4 (5) C13---C14---C15---C16 −1.3 (10) C2---C1---C5---C6 −150.9 (3) C10---C11---C16---C17 1.4 (6) O1---C1---C5---C8 −85.5 (4) C12---C11---C16---C17 178.9 (4) C2---C1---C5---C8 95.2 (3) C10---C11---C16---C15 −176.1 (4) C4---C5---C6---C27 −1.6 (4) C12---C11---C16---C15 1.5 (6) C1---C5---C6---C27 113.3 (3) C14---C15---C16---C17 −175.9 (6) C8---C5---C6---C27 −130.4 (3) C14---C15---C16---C11 1.0 (8) C4---C5---C6---C7 126.1 (3) C11---C16---C17---C18 −0.4 (8) C1---C5---C6---C7 −119.0 (3) C15---C16---C17---C18 176.6 (6) C8---C5---C6---C7 −2.7 (3) C16---C17---C18---C19 −1.2 (9) C33---N1---C7---C6 −174.1 (4) C11---C10---C19---C18 −1.0 (6) C8---N1---C7---C6 −42.8 (4) C9---C10---C19---C18 −177.1 (4) C27---C6---C7---N1 155.9 (3) C17---C18---C19---C10 1.9 (8) C5---C6---C7---N1 26.4 (4) C1---C2---C20---C21 179.5 (4) C7---N1---C8---C12 166.6 (3) C3---C2---C20---C21 3.0 (7) C33---N1---C8---C12 −62.4 (5) C2---C20---C21---C26 −172.3 (4) C7---N1---C8---C9 −79.7 (4) C2---C20---C21---C22 9.8 (7) C33---N1---C8---C9 51.3 (5) C26---C21---C22---C23 −2.1 (7) C7---N1---C8---C5 40.4 (4) C20---C21---C22---C23 175.8 (4) C33---N1---C8---C5 171.4 (4) C21---C22---C23---C24 0.7 (7) C4---C5---C8---N1 −151.9 (3) C22---C23---C24---C25 1.3 (8) C1---C5---C8---N1 97.2 (3) C23---C24---C25---C26 −1.7 (9) C6---C5---C8---N1 −21.7 (3) C24---C25---C26---F1 −179.6 (6) C4---C5---C8---C12 86.3 (4) C24---C25---C26---C21 0.2 (9) C1---C5---C8---C12 −24.6 (4) C22---C21---C26---C25 1.7 (7) C6---C5---C8---C12 −143.5 (3) C20---C21---C26---C25 −176.4 (5) C4---C5---C8---C9 −29.4 (4) C22---C21---C26---F1 −178.5 (5) C1---C5---C8---C9 −140.2 (3) C20---C21---C26---F1 3.4 (7) C6---C5---C8---C9 100.8 (3) C7---C6---C27---C32 128.5 (4) N1---C8---C9---O2 51.8 (5) C5---C6---C27---C32 −108.3 (4) C12---C8---C9---O2 171.1 (4) C7---C6---C27---C28 −51.5 (4) C5---C8---C9---O2 −63.4 (4) C5---C6---C27---C28 71.7 (4) N1---C8---C9---C10 −125.9 (3) C32---C27---C28---C29 0.3 (5) C12---C8---C9---C10 −6.6 (4) C6---C27---C28---C29 −179.7 (4) C5---C8---C9---C10 118.9 (3) C27---C28---C29---C30 −0.2 (7) O2---C9---C10---C19 4.0 (7) C28---C29---C30---C31 0.2 (7) C8---C9---C10---C19 −178.4 (4) C29---C30---C31---C32 −0.4 (6) O2---C9---C10---C11 −172.4 (4) C28---C27---C32---F2 178.6 (3) C8---C9---C10---C11 5.2 (4) C6---C27---C32---F2 −1.4 (5) C19---C10---C11---C12 −178.4 (4) C28---C27---C32---C31 −0.6 (5) C9---C10---C11---C12 −1.4 (5) C6---C27---C32---C31 179.5 (3) C19---C10---C11---C16 −0.7 (6) C30---C31---C32---C27 0.6 (6) C9---C10---C11---C16 176.4 (4) C30---C31---C32---F2 −178.5 (3) C10---C11---C12---C13 174.0 (4) ----------------------- ------------ ----------------------- ------------ Hydrogen-bond geometry (Å, º) {#tablewraphbondslong} ============================= ----------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C3---H3*B*···O1^i^ 0.97 2.35 3.317 (5) 172 C14---H14*A*···F2^ii^ 0.93 2.43 3.212 (7) 141 C25---H25···O2^iii^ 0.93 2.58 3.458 (7) 158 ----------------------- --------- --------- ----------- --------------- Symmetry codes: (i) −*x*+1/2, *y*, *z*−1/2; (ii) *x*−1/2, −*y*+1, *z*; (iii) *x*, *y*−1, *z*. ###### Hydrogen-bond geometry (Å, °) *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- --------- ------- ----------- ------------- C3---H3*B*⋯O1^i^ 0.97 2.35 3.317 (5) 172 C14---H14*A*⋯F2^ii^ 0.93 2.43 3.212 (7) 141 C25---H25⋯O2^iii^ 0.93 2.58 3.458 (7) 158 Symmetry codes: (i) ; (ii) ; (iii) . | Mid | [
0.6255924170616111,
24.75,
14.8125
]
|
Yourwellness Magazine Gives CPR Advice for Remote Locations Share Article With a new drone being invented to reach heart attack victims before the emergency services, Yourwellness Magazine outlined how to administer CPR. Yourwellness, the gateway to living well London, UK (PRWEB UK)9 September 2013 An autonomous octocopter that can carry a defibrillator, aiming to get to patients faster than an ambulance, could help save the lives of heart attack victims, it was announced August 25th. Developed by Height Tech – a company that creates drones for such tasks as movie production, surveying, aerial photography and signal mast inspection – the drone can be called through a smartphone app that automatically sends GPS coordinates, and parachutes its payload when it arrives at the patient. Marco König from the German emergency services union commented that it’s still early days and “We'll have to see how much these drones can help.” (http://www.wired.co.uk/news/archive/2013-08/25/drone-defibrillators) As the device was designed to help heart attack victims in isolated areas, Yourwellness Magazine outlined what to do in the case of a cardiac arrest. Yourwellness Magazine explained, “When someone's heart stops and when they stop receiving oxygen there's only a matter of time before serious damage is done to the organs. In cases like this it's always best to call the emergency services but sometimes it'll be a while before they arrive and if a patient has stopped breathing and/or they've not got a pulse, it might be time to use CPR.” (http://www.yourwellness.com/2012/12/in-case-of-cardiac-arrest/#sthash.QdQkxF4I.dpuf) Yourwellness Magazine outlined how to administer CPR, noting it should only be used on people who are unconscious, aren’t breathing and don't have a pulse: 1. Gently lift the person’s chin while pressing on the forehead to tilt the head back slowly. 2. The person giving CPR should cover the person’s open mouth with theirs, making sure no air can escape. 3. Gently hold the patients nose close so that air doesn't escape when CPR is started. 4. Breathe deeply into the patients mouth twice, their chest should rise a bit if the CPR is done correctly. 5. With the heel of the hands, quickly compress the chest around 30 times, do this at on top of the breastbone. 6. Repeat steps four and five until the emergency services arrive and give further instructions. | Mid | [
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Introduction {#s1} ============ The intratumoral phenotypic heterogeneity results from the genetic variation but also from the plasticity of tumor cells that is observed in response to microenvironmental stimuli. Among diverse functional phenotypes within a tumor, a subpopulation of cancer stem-like cells (CSCs) capable of self-renewal and the bulk of a tumor consisting of fast-cycling cells and more differentiated cells could be distinguished [@pone.0090783-Fang1]--[@pone.0090783-Hermann1]. As the phenotypic heterogeneity was shown to be highly dynamic in many tumors including melanoma [@pone.0090783-Quintana1]--[@pone.0090783-Kumar1] and the therapeutic eradication of CSC subpopulation may be followed by its regeneration from non-CSCs, both CSCs and the bulk population should be considered in developing the anticancer therapy [@pone.0090783-Clevers1]--[@pone.0090783-GomezCabrero1]. Therefore, a drug combination causing a complete eradication of all kinds of cells within a tumor might be necessary to achieve durable cures. In the selection process of highly potent drug candidates, there is a substantial problem in creating experimental *in vitro* models that reliably predict drug activity in patients. In the present study, melanoma cells obtained directly from pathologically distinct specimens, nodular melanoma and superficial spreading melanoma, were grown in an anchorage-independent manner in stem cell medium and were enriched with cells exerting self-renewing capacity in comparison to serum-driven monolayers [@pone.0090783-SztillerSikorska1]. This *in vitro* three-dimensional model has also been shown to preserve the heterogeneity of the original tumor more accurately than two-dimensional monolayer cultures [@pone.0090783-Perego1]--[@pone.0090783-Thurber1] and was an important element of novelty in the present *in vitro* screening of the natural compound library. Natural compounds are widely used in anticancer therapy and can exert considerable biological activity [@pone.0090783-Gu1]--[@pone.0090783-DIncalci1]. Although their mechanisms of action are often not well defined, most of therapeutic agents derived from natural products are mainly effective at eliminating cancer cells with a high proliferation rate. Compounds that affect cell division may fail, however, to eradicate the subpopulation of slow-cycling cancer stem-like cells, leading eventually to tumor relapse. In the present study, although several approaches have been used in the selection process, priority was given to those compounds that were capable of reducing the number of clonogenic cells. A reduction in clonogenicity was interpreted as a direct effect on the self-renewing potential of the cancer stem-like cells. In addition, apoptosis, label-retention, frequency of ABCB5-positive cells and the expression of Wnt/β-catenin signaling target genes, *MITF* and *c-MYC*, were assessed in melanoma populations treated with compounds selected as either highly anti-clonogenic or highly cytotoxic. We investigated the influence of selected compounds on stemness-associated molecules and pathways. Slow-cycling cells considered as cancer stem-like cells (CSCs) can be marked as label-retaining cells [@pone.0090783-Bragado1]. In the present study, we used a fluorescent dye CFSE to identify compounds that left the label-retaining melanoma cells unaffected. ABCB5 transporter protein, a mediator of chemoresistance in melanoma, is also recognized as a potential marker for melanoma stem-like cells [@pone.0090783-Schatton1], [@pone.0090783-Chartrain1]. Melanoma cells that express ABCB5 protein could selectively survive when exposed to dacarbazine, vemurafenib and other drugs [@pone.0090783-Chartrain1]. It was demonstrated that anti-ABCB5 antibody or siRNA gene silencing reversed melanoma resistance to anticancer drugs [@pone.0090783-Frank1], [@pone.0090783-Elliott1]. We investigated whether the proportion of cells carrying this transporter was altered upon the treatment with selected natural compounds. Wnt signaling plays a crucial role in preserving the pluripotency of embryonic stem cells and cancer development [@pone.0090783-Valkenburg1]. Recent report suggested a role for the Wnt/β-catenin signaling pathway in maintaining the viability and/or sustaining the self-renewal of breast tumor initiating cells *in vitro* [@pone.0090783-Hallett1]. In melanoma, β-catenin signaling increases during tumor progression and it promotes chemoresistance [@pone.0090783-Sinnberg1]. Our recent study revealed that the Wnt/β-catenin signaling pathway is suppressed in melanoma populations with the low frequency of clonogenic cells (Hartman et al., submitted). The influence of selected natural compounds on two Wnt/β-catenin target genes, *MITF* and *c-MYC* was investigated. Transcription factor MITF acts as a rheostat determining the phenotypic identity among different subpopulations of melanoma cells [@pone.0090783-Goding1]. Although amplified only in about 20% of melanomas, MITF has been proposed as a lineage addiction oncogene contributing to melanoma chemoresistance [@pone.0090783-Garraway1], [@pone.0090783-Haq1]. The proto-oncogene c-MYC plays a crucial role in the development of a large number of human tumors [@pone.0090783-Dang1]. Most recently, it has been shown that over-expression of c-MYC within the tumor can be targeted with specific T-cells [@pone.0090783-Helm1]. Compounds inducing apoptosis and/or inhibiting proliferation in a c-MYC-specific manner act on distinct cellular targets [@pone.0090783-Frenzel1], [@pone.0090783-Soucek1]. c-MYC inhibition in melanoma cells results in reduced proliferation through mechanisms involving several enzymes of nucleotide biosynthesis [@pone.0090783-Mannava1]. To our knowledge, there are no previous studies exploring so many factors in parallel in the initial selection process for active compounds from The Natural Products Set II (NCI). Based on the created activity profiles, each of the selected compounds can be further investigated for its potential applicability as a part of anticancer therapy or as a tool in the laboratory work. The natural products selected as active compounds against melanoma cells can also provide novel leads for conversion into clinically useful agents. Materials and Methods {#s2} ===================== Compounds {#s2a} --------- The Natural Products Set II was obtained from the US National Cancer Institute (NCI, <http://www.dtp.nci.nih.gov>). The compounds were in 96-well plates with 60 compounds per plate. Plates were stored dry at −20°C. Each well contained 0.02 µmol of compound in 1 µl of glycerol. 10 mM solution (20 µl) of each compound was obtained by the addition of 19 µl of DMSO to each well. Immediately after solubilization the drug solutions were aliqouted into several testing plates to avoid possible precipitation of the compound. All experiments were performed using compounds provided by NCI. Tumor Tissues and Ethics Statement {#s2b} ---------------------------------- DMBC cells were obtained in [D]{.ul}epartment of [M]{.ul}olecular [B]{.ul}iology of [C]{.ul}ancer from surgical specimens of melanoma in advanced stages. Patient characteristics of melanoma specimens were published previously [@pone.0090783-SztillerSikorska1], [@pone.0090783-Czyz1], [@pone.0090783-Koprowska1]. The study was approved by the Ethical Commission of the Medical University of Lodz and written informed consent was obtained from all patients. Cell Cultures {#s2c} ------------- Cells were maintained in stem cells medium (SCM) in an anchorage-independent manner as described previously [@pone.0090783-Czyz1]. Measurement of Viable Cell Number {#s2d} --------------------------------- Melanoma cells were counted after staining with Trypan blue (Sigma-Aldrich) and plated at a density of 4 × 10^3^ viable cells per well in 96-well plates. Cells were cultured for 45 h with vehicle (0.05% DMSO) or the compounds from The Natural Products Set II at 5 µM. An acid phosphatase activity (APA) assay was used to measure viable cell number. Briefly, the plates were centrifuged, the medium was discarded and replaced with 100 µl assay buffer containing 0.1 M sodium acetate (pH = 5), 0.1% Triton X-100 and 5 mM p-nitrophenyl phosphate, pNPP (Sigma-Aldrich) and incubated for additional 2 h at 37°C. The reaction was stopped with 10 µl/well of 1 M NaOH, and the absorbance values were measured at the wavelength of 405 nm using a microplate reader (Infinite M200Pro, Tecan, Austria). Melanoma cells did not respond to 0.05% DMSO with reduced viability. Viability Assay {#s2e} --------------- Drug-induced changes in cell viability after 45 h treatment were also assessed by flow cytometry after propidium iodide (PI) staining or by using an automated cell viability analyzer according to standard procedures. In both assays, cells were analyzed using a FACSVerse flow cytometer (Becton Dickinson, San Jose, California, USA), and results were processed by using FACSuite software (Becton Dickinson). Cell Cycle Analysis {#s2f} ------------------- Melanoma cells were treated with the vehicle or the compounds at the indicated concentrations for 30 h or 45 h, then collected and fixed with 70% (w/v) ethanol at −20°C. Cells were washed twice with PBS and resuspended in PI Staining Buffer containing RNAse (Becton Dickinson, San Jose, CA, USA). Following incubation for 30 min at room temperature in the dark, cells were analyzed using a FACSVerse flow cytometer (Becton Dickinson). ModFit LT 3.0 software (Verify Software, Topsham, MN, USA) was used to calculate the percentages of cells in each cell cycle phase, and FACSuit software (Becton Dickinson) was used to calculate the percentages of dead cells in subG~1~. Clonogenic Assay {#s2g} ---------------- Melanoma cells were first incubated with compounds at indicated concentrations for 4 h. Then, viability was determined by Trypan blue staining and 1000 single, viable melanoma cells were transferred to 700 µl top agar medium mixture (SCM, 0.35% (w/v) agar) and the obtained cell suspensions were overlaid onto 12-well culture plates coated with 700 µl solidified bottom agar mixture (SCM, 0.5% (w/v) agar). The plates were then incubated at 37°C in a humidified incubator for 2 weeks, and in some cases also for 3 weeks. Cells were stained with 500 µl of 0.005% crystal violet for 2 h, and colonies at least 50 µm in diameter were counted under the microscope. The influence of the compounds on the clonogenicity was expressed as percent of control according to the formula: number colonies generated after treatment with the compounds/number of colonies in control with the vehicle × 100. Flow Cytometric Analysis of Apoptosis {#s2h} ------------------------------------- Detection of cell death was carried out by dual staining with Annexin V-FITC and PI (Roche Diagnostics, Manheim, Germany). Melanoma cells were seeded into 12-well plates and treated for 45 h with the compounds at indicated concentrations. After treatment, cells were collected, centrifuged at 400×g for 5 min and stained with Annexin V-FITC and PI for 15 min at room temperature in the dark. 15,000 events were analyzed for each sample by flow cytometer FACSVerse (Becton Dickinson), and results were processed by using FACSuite software (Becton Dickinson). Assessment of ABCB5-Positive Cells {#s2i} ---------------------------------- The frequency of cells expressing ABCB5 was assessed by flow cytometry. Unconjugated anti-ABCB5 primary antibody from Sigma-Aldrich and FITC-conjugated goat anti-rabbit secondary antibody (BD Pharmingen) were used in this study. Typically, 30,000 cells were analyzed per sample. Isotype controls were included in each experiment. To exclude dead cells from the analysis, 7-aminoactinomycin D staining (7-AAD; eBiosciences) was used. Flow cytometric acquisition was performed using a FACSVerse flow cytometer (Becton Dickinson) and analyzed using FACSuite software. Changes in the frequency of ABCB5-positive cells after drug treatment for 45 h were expressed as percentages of control with vehicle. CFSE Staining {#s2j} ------------- For CFSE analysis, melanoma cells were stained with 1.5 µM CFSE (the prodrug carboxyfluorescein diacetate succinimidyl ester) for 30 min at 37°C, washed twice, seeded in twelve-well plates at 1.25×10^5^/well, and exposed to the compounds for 5 days at indicated concentrations. Then, medium was exchanged and cells were incubated in drug-free medium for additional 6 days, and assessed by flow cytometry. Green fluorescence emission was measured using a FACSVerse flow cytometer (Becton Dickinson) and analyzed using FACSuite software. RNA Isolation, cDNA Synthesis and Real-Time PCR {#s2k} ----------------------------------------------- RNA was isolated and purified using Total RNA Isolation kit with mini column system (A&A Biotechnology, Gdynia, Poland). The RNA concentration and purity were measured with a Tecan NanoQuant Plate reader (Tecan, Austria). cDNA was synthesized by using 300 ng of random primers and SuperScript II Reverse Transcriptase (Invitrogen Life Technologies, Carlsbad, CA, USA). The Rotor-Gene 3000 Real-Time DNA analysis system (Corbett Research, Morklake, Australia) was used to evaluate the gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). The amplification was performed by using KAPA SYBR FAST qPCR Kit Universal 2X qPCR Master Mix (Kapa Biosystems, Cape Town, South Africa), 200 nM of each primer and 25 ng cDNA template per reaction. The primers used for Real-Time PCR were as following: MITF: 5′-ACC GTC TCT CAC TGG ATT GG-3′ and 5′-TAC TTG GTG GGG TTT TCG AG-3′; C-MYC: 5′-AAT GAA AAG GCC CCC AAG GTA GTT ATC C-3′ and 5′-GTC GTT TCC GCA ACA AGT CCT CTT C-3′; SOX2: 5′-GCT AGT CTC CAA GCG ACG-3′ and 5′-GCA AGA AGC CTC TCC TTG-3′. The annealing temperature for all genes was 56°C. The relative expression of target genes was calculated versus a reference gene RPS17 (with primers: 5′-AAT CTC CTG ATC CAA GGC TG-3′ and 5′-CAA GAT AGC AGG TTA TGT CAC G-3′), and a mathematical model including an efficiency correction for Real-Time PCR was used. Statistical Analysis {#s2l} -------------------- Data represent means ± SD from three separate experiments unless otherwise specified. The significance of an apparent difference in mean values for any tested parameter was validated by a Student\'s paired t test. P\<0.05 was considered significant. Results {#s3} ======= Selection Strategy of Natural Compounds in Melanoma Cells Grown in an Anchorage-Independent Manner {#s3a} -------------------------------------------------------------------------------------------------- The Natural Products Set II, consisting of 120 compounds (Table S1 in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}) derived from the DTP Open Repository collection of 140,000 compounds, was screened to identify compounds effective against melanoma cells. In the pre-screen of compounds, two cell lines derived from advanced melanoma were used, one from nodular melanoma (DMBC12) [@pone.0090783-SztillerSikorska1] and one from superficial spreading melanoma (DMBC11) [@pone.0090783-Koprowska1]. Both populations were grown in SCM in an anchorage-independent manner as multicellular 3-dimensional spheroids. In the primary screening, melanoma cells from dissociated spheroids were exposed to each compound at a single concentration of 5 µM. Both, non-clonogenic and clonogenic assays were used in parallel ([Fig. 1](#pone-0090783-g001){ref-type="fig"}). {#pone-0090783-g001} Short-Term Cytotoxic and Cytostatic Effects of Natural Compounds on Melanoma Cells {#s3b} ---------------------------------------------------------------------------------- Four non-clonogenic methods were chosen for the initial screening. Changes in the viable cell numbers were determined based on the quantification of cytosolic acid phosphatase activity (APA assay) (Fig. S1A in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}) and by flow cytometry using an automated cell viability analyzer (volumetric assay) (Fig. S1B in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}). Cytoxicity of the compounds was measured by flow cytometry after PI staining, either as the frequency of PI-positive cells ([Fig. 2](#pone-0090783-g002){ref-type="fig"} and Fig. S2 in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}) or as percentage of cells in subG~1~ fraction. Histograms for those compounds that accumulated more than 40% of melanoma cells in subG~1~ fraction are included in [Fig. 3](#pone-0090783-g003){ref-type="fig"} and Fig. S3A in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}. All these assays were used to assess drug activity after short incubation, either after 45 h for the quantification of fractions of viable and PI-positive cells, or after 30 h for percentages of cells in subG~1~ fractions. In parallel, natural compounds at 5 µM were assessed in drug-resistant, p53-deficient leukemic cell line K562 ([Fig. 2](#pone-0090783-g002){ref-type="fig"}, Fig. S1-S2 in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}). The comparison of cytotoxicity of natural products against melanoma and leukemia cells ([Fig. 2](#pone-0090783-g002){ref-type="fig"}) revealed that several compounds active against melanoma cells were not active in K562 cells. For example, streptonigrin (32), crassin (68) and geldanamycin analog (72) reduced viability of melanoma cells to less than 3% of control, but the reduction of viability of K562 cells did not reach 50% of control. Melanoma cells were also much more sensitive to fastigilin B (63), bactobolin (84), didemnin B (104), siomycin A (107), toyocamycin (108), geldanamycin (110) and tubulosine (119) among others ([Fig. 2](#pone-0090783-g002){ref-type="fig"}). K562 cells, in turn, were much more sensitive to lapachone (20) than melanoma cells. {ref-type="supplementary-material"}) are put in the first raw and the first column. See Figure S2 in [File SI](#pone.0090783.s001){ref-type="supplementary-material"} for quantitative data.](pone.0090783.g002){#pone-0090783-g002} {ref-type="supplementary-material"}. Effects of lower concentrations for the most cytotoxic compounds or of longer exposure for compounds ineffective at 30 h are included in Figure S3B in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}.](pone.0090783.g003){#pone-0090783-g003} In cell cycle analysis, several compounds at the concentration of 5 µM accumulated melanoma cells either in different cell cycle phases or generated damaged cells collected in subG~1~ ([Fig. 3](#pone-0090783-g003){ref-type="fig"} for DMBC11 cells and Fig. S3A in [File SI](#pone.0090783.s001){ref-type="supplementary-material"} for DMBC12 cells). Colchicine (1), rotenone (19), vincristine (39), maytansine (60) and rhizoxin (86) arrested the majority of melanoma cells in G~2~/M phase. Resorufin (12), michellamine B (101) and fumagillin (120), among others arrested cells in S phase, whereas brefeldin A (47) and camptothecin (48) accumulated cells in G~0~/G~1~ or subG~1~ depending on the drug and cell line. Several compounds, which at 5 µM caused no effects on cell cycle after treatment for 30 h, were used in the subsequent experiment for 45 h, whereas compounds causing accumulation of cells in subG~1~ were tested at 1 µM, and in case of the most potent compounds at 0.1 µM (Fig. S3B in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}). Streptonigrin (32) generating a large population of cells in subG~1~ at 5 µM, accumulated DMBC12 cells in S phase when used at 0.1 µM. Pre-screen of Clonogenic Capacity as a Long-Term Effect of Natural Compounds on Melanoma Cells {#s3c} ---------------------------------------------------------------------------------------------- A clonogenic assay was employed to investigate effects of natural compounds on self-renewing capacity of melanoma cells. Cells were incubated with the compounds only for 4 h, and long-term effects of this incubation were assessed as capability of forming spheres in soft agar after 2 weeks. Forty eight and forty six compounds at 5 µM reduced the numbers of clones formed in agar to ≤1% of control in DMBC11 and DMBC12 populations, respectively ([Fig. 4](#pone-0090783-g004){ref-type="fig"} and Fig. S4 in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}). As clonogenic cells might divide more slowly, and the colony might not reach the appropriate size within 2 weeks, for several compounds the colony counting was done one week later. There were no substantial discrepancies between the number of clones obtained after two and three weeks (data not shown). {ref-type="supplementary-material"} for quantitative data.](pone.0090783.g004){#pone-0090783-g004} Comparison of Short- and Long-Term Effects of Active Natural Compounds on Melanoma Cells {#s3d} ---------------------------------------------------------------------------------------- After the initial screening performed at 5 µM, each compound from The Natural Products Set II could be assigned to one of five categories ([Fig. 5](#pone-0090783-g005){ref-type="fig"}). Forty six compounds at 5 µM were not active in any of employed assays in both tested populations. They were excluded from further analyses. Some of those non-active compounds such as curcumine (27) or rapamycin (69) are well-characterized for their anticancer activity but apparently at 5 µM they were not active against anchorage-independent melanoma cells. Several compounds were capable of inducing cell death within the first two days, and in addition they efficiently eradicated cells with clonogenic potential. Those compounds were considered as very potent, and their activities, both non-clonogenic and clonogenic, were measured at lower concentrations in the following experiments. Two drugs, actinomycin D (105) and cyclophosphamide (117), were excluded from further analysis, as they are very well-characterized for their *in vitro* and *in vivo* anticancer activity. In addition, parthenolide (61) was also excluded as our detailed report describing its effects on anchorage-independent melanoma cells, was published recently [@pone.0090783-Czyz1]. As priority was given to compounds that reduced the number of melanoma cells showing self-renewing capacity, selected compounds from the group of anti-clonogenic but not highly cytotoxic were also further analyzed. {ref-type="supplementary-material"} for the names of the compounds corresponding to numbers shown in the Figure.](pone.0090783.g005){#pone-0090783-g005} First, the cytotoxic effects of potent natural compounds were confirmed in six patient-derived cell lines, including four additional cell lines derived from surgical specimens of nodular melanoma, DMBC2, DMBC8, DMBC10 [@pone.0090783-SztillerSikorska1] and DMBC9 [@pone.0090783-Czyz1]. Concentrations of the compounds were lowered to 1 µM and 0.1 µM, and in some cases to 0.01 µM or even 0.001 µM, until IC~50~ effect was reached (Table S2 in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}). In general, only small differences between responses of melanoma cells from different DMBC populations were visible at drug concentrations of 1 µM and 0.1 µM. DMBC8 cells seemed to be less sensitive to several compounds than other populations. Next, dose--response curves were prepared for 45 compounds exerting strong anti-clonogenic and/or cytotoxic potentials ([Fig. 6](#pone-0090783-g006){ref-type="fig"} and Fig. S5 in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}). Based on the dose-response curves, the ranking list of the most potent compounds from the Natural Products Set II was prepared ([Table 1](#pone-0090783-t001){ref-type="table"}). Anti-clonogenic activity was ranked above cytotoxic activity. IC~50~ values of seven compounds were below 0.1 µM when the drug influence on the capacity of forming clones in soft agar was evaluated. Among those compounds, maytansine (60) exerted a stronger overall cytotoxic effect than anti-clonogenic effect, streptonigrin (32), toyocamycin (108), colchicine (1) and echinomycin A (102) had similar potency in both activities, whereas nanaomycin A (74) and illudin M (114) were more potent in eradicating cells with the clonogenic potential than in reducing viability within the short-term incubation. Similar phenomena were observed for several compounds that were effective at higher concentrations. For instance, the IC~50~ values for anti-clonogenic compounds, bryostatin 1 (112), siomycin A (107), fumitremorgin C (118), fumagallin (120) michellamine B (101) and pentoxifylline (100) were in the range 0.1 -- 1 µM in the clonogenic assay but in the range 1 -- 5 µM in the viability assay. {ref-type="supplementary-material"}.](pone.0090783.g006){#pone-0090783-g006} 10.1371/journal.pone.0090783.t001 ###### Comparison of cytotoxic and anti-clonogenic activities of highly potent natural compounds from Natural Products Set II. {#pone-0090783-t001-1} A. 'anti-clonogenic drugs': more potent against clonogenic cells than fast-cycling ------------------------------------------------------------------------------------ ----- ------------------- ----------------- ---------- 267461 74 nanaomycin A **0.01 -- 0.1** 0.1 -- 1 400978 114 illudin M **0.01 -- 0.1** 0.1 -- 1 122750 110 geldanamycin **0.1 -- 1** 1 -- 5 339555 112 bryostatin 1 **0.1 -- 1** 1 -- 5 285116 107 siomycin A **0.1 -- 1** 1 -- 5 719655 118 fumitremorgin C **0.1 -- 1** 1 -- 5 9168 120 fumagillin **0.1 -- 1** 1 -- 5 661755 101 michellamine B **0.1 -- 1** 1 -- 5 637086 100 pentoxifylline **0.1 -- 1** 1 -- 5 338250 89 croton Factor F1 **0.1 -- 1** 1 -- 5 302289 81 helenin **0.1 -- 1** 1 -- 5 376248 95 nordracorubin **0.1 -- 1** 1 -- 5 375294 94 confertifoline **0.1 -- 1** 1 -- 5 221019 111 wortmannin **0.1 -- 1** 1 -- 5 349438 113 4-ipomeanol **0.1 -- 1** 1 -- 5 210236 68 crassin **0.1 -- 1** 1 -- 5 614552 116 castanospermine **0.1 -- 1** 1 -- 5 307981 83 lonchocarpic acid **0.1 -- 1** 1 -- 5 401005 115 pleurotin **0.1 -- 1** \> 5 B. 'cytotoxic drugs': equally or more potent against fast-cycling cells than against clonogenic cells ------------------------------------------------------------------------------------------------------- ----- --------------------- ------------- ------------------- 153858 60 maytansine 0.01 -- 0.1 **0.001 -- 0.01** 45383 32 streptonigrin 0.01 -- 0.1 0.01 -- 0.1 63701 108 toyocamycin 0.01 -- 0.1 0.01 -- 0.1 757 1 colchicine 0.01 -- 0.1 0.01 -- 0.1 526417 102 echinomycin A 0.01 -- 0.1 0.01 -- 0.1 106399 109 cucurbitacin E 0.1 -- 1 0.1 -- 1 325319 104 didemnin B 0.1 -- 1 0.1 -- 1 131547 119 tubulosine 0.1 -- 1 0.1 -- 1 333856 106 tetrocarcin A 0.1 -- 1 0.1 -- 1 67574 39 vincristine 0.1 -- 1 0.1 -- 1 325014 84 bactobolin 0.1 -- 1 0.1 -- 1 85236 44 helenalin 0.1 -- 1 0.1 -- 1 305222 82 cytochalasin H 0.1 -- 1 0.1 -- 1 82151 43 daunorubicin 0.1 -- 1 0.1 -- 1 332876 87 hispanolone 0.1 -- 1 1 -- 5 255109 72 geldanamycin analog ∼ 1 0.1 -- 1 332598 86 rhizoxin 1 -- 5 **0.1 -- 1** 330753 85 baccatin III 1 -- 5 1 -- 5 62709 38 imidazoquinoline 1 -- 5 1 -- 5 26258 19 rotenone 1 -- 5 1 -- 5 345647 90 chaetochromin 1 -- 5 1 -- 5 176503 63 fastigilin B 1 -- 5 1 -- 5 287088 78 physalin B 1 -- 5 1 -- 5 85239 45 parthenin 1 -- 5 1 -- 5 122819 55 teniposide 1 -- 5 1 -- 5 122023 103 valinomycin 1 -- 5 1 -- 5, \>5 Induction of Apoptosis in Melanoma Cells Exposed to Selected Compounds {#s3e} ---------------------------------------------------------------------- Flow cytometric analysis of Annexin V/PI-stained cells revealed that highly cytotoxic compounds induced apoptosis in melanoma cells, whereas compounds eradicating mainly cells with the capacity to form clones ([Table 1](#pone-0090783-t001){ref-type="table"}) did not trigger apoptosis at concentrations effective for their anti-clonogenic activity ([Fig. 7](#pone-0090783-g007){ref-type="fig"}). For example, maytansine (60) induced apoptosis in the majority of cells at the concentration as low as 0.01 µM. On the contrary, nanaomycin A (74), which at 0.1 µM almost completely eradicated cells with clonogenic potential did not induce apoptosis at this concentration. {#pone-0090783-g007} Influence of Selected Compounds on Cell Division of Fast- and Slow-Cycling Subpopulations {#s3f} ----------------------------------------------------------------------------------------- We further characterized the top-ranked anti-clonogenic and/or cytotoxic compounds ([Table 1](#pone-0090783-t001){ref-type="table"}) for their impact on cell division. To analyze their effects on subpopulations of fast-dividing and slow-cycling cells, the CFSE assay was employed. CFSE is a prodrug for an intracellular vital green-fluorescent dye that is partitioned evenly between daughter cells upon cell division. It had no effect on cell viability and proliferation rates (data not shown). Over the course of eleven days, five days of drug treatment followed by six days of recovery period, dividing cells diluted out CFSE and decreased in fluorescence intensity ([Fig. 8](#pone-0090783-g008){ref-type="fig"}). At 11^th^ day, however, in cultures of melanoma cells treated with maytansine (60) at 0.01 µM and streptonigrin (32), toyocamycin (108) and colchicine (1) at 0.1 µM, a small fraction of viable, label-retaining cells (LRCs) was still present indicating that a distinct subpopulation of slow-dividing cells remained unaffected by these compounds ([Fig. 8](#pone-0090783-g008){ref-type="fig"}). The fractions of LRCs were also observed when maytansine at higher concentration of 0.1 µM and streptonigrin at lower concentration of 0.01 µM were used (data not shown). On the contrary, no LRCs were left in the populations treated with compounds such as nanaomycin A (74), illudin M (114), bryostatin 1 (112), siomycin A (107), fumitremorgin C (118), fumagillin (120), michellamine B (101) and pentoxifylline (100) ([Fig. 8](#pone-0090783-g008){ref-type="fig"}) at the concentrations not substantially affecting overall cell viability, but sufficient to eliminate most cells with clonogenic potential ([Table 1](#pone-0090783-t001){ref-type="table"}). {#pone-0090783-g008} Influence of Natural Compounds on Stemness-Associated Molecules and Pathways {#s3g} ---------------------------------------------------------------------------- Drug resistance is considered as an element of cancer stem cell characteristics, and the ABCB5 transporter closely associated with melanoma-initiating cell phenotype is responsible for the efflux of multiple chemotherapeutic agents [@pone.0090783-Schatton1], [@pone.0090783-Chartrain1], [@pone.0090783-Frank1]. Flow cytometry was used, and the representative dot plots obtained after 45 h exposure of DMBC12 cells to selected compounds are shown in [Fig. 9](#pone-0090783-g009){ref-type="fig"}. Maytansine (60) at 0.01 µM and colchicine (1) at 0.1 µM increased the proportion of ABCB5-positive cells, whereas 0.4 µM illudin M (114) and 2 µM bryostatin 1 (112), siomycin A (107), fumagillin (120), michellamine B (101) and pentoxifylline (100) preferentially killed those cells. Pentoxifylline (100) was the most efficient in reducing the proportion of ABCB5-positive cells. The drug influence on the expression of two targets of Wnt/β-catenin signaling, *MITF* and *c-MYC*, was analyzed by qRT-PCR. Two primary melanoma cultures, DMBC8 and DMBC12, showing the highest difference in *MITF* expression were chosen. For investigations of the influence of drug on gene expression, concentrations resulting in viability above 40% of control were chosen ([Fig. 10A](#pone-0090783-g010){ref-type="fig"}). *MITF* expression was significantly inhibited by 0.1 µM maytansine (60), toyocamycin (108) and colchicine (1), whereas its expression was significantly higher in melanoma cells treated with 0.1 µM streptonigrin (32) and 0.4 µM geldanamycin analog (72) for 24 h ([Fig. 10B](#pone-0090783-g010){ref-type="fig"}). This tendency was well preserved when cells were treated for 48 h with these compounds at lower concentrations (not shown), despite the marked influence on cell viability. When compounds exerting low effects on *MITF* expression after 24 h were tested at higher concentrations (2 µM) for 48 h, a significant increase in *MITF* expression was observed for most of those compounds. *MITF* expression was more enhanced in DMBC12 than in DMBC8 cells after treatment with the majority of compounds. This may be due to the difference in the basal level of *MITF* expression between DMBC8 and DMBC12 cells; DMBC8 cells had 18-fold higher basal level of the MITF transcript than DMBC12 cells (data not shown). *c-MYC* expression was significantly reduced after 24 h of treatment mainly by compounds markedly affecting proliferation. No substantial changes were induced in *SOX2* expression (data not shown). {#pone-0090783-g009} {#pone-0090783-g010} Discussion {#s4} ========== The present study re-evaluated compounds from The Natural Products Set II with a view to determining their potential against melanoma cells grown as anchorage-independent spheroids. These 3-dimentional cultures exhibit a more heterogeneous phenotype than monolayers maintained in the presence of serum [@pone.0090783-Perego1], [@pone.0090783-Thurber1]. The idea was to select compounds most potent in affecting the self-renewing capacity in the populations with the high enough content of melanoma cells exerting this property [@pone.0090783-SztillerSikorska1]. Those compounds might be overlooked when more uniform populations such as monolayers are used. Those compounds might be also disregarded in the selection process when assays measuring exclusively cytotoxic or cytostatic short-term effects are employed. In our study a broad spectrum of screening methods was used to rank 120 natural compounds not only according to their cytotoxic effects but mainly according to their potential to eradicate melanoma stem-like cells. Compounds that were selected as highly anti-clonogenic and/or cytotoxic were further investigated for their potential to affect slow-cycling cells, to influence the frequency of ABCB5-positive cells and to alter the expression of *MITF* and *c-MYC*. The present screening re-identified a number of compounds that have already been tested against melanoma cells, and streptonigrin, bryostatin 1, siomycin A and pentoxifylline were among the compounds classified as the top ranked ones in this study. Streptonigrin was previously found to be active against multiple cancer cells [@pone.0090783-Bolzn1], however, its clinical usage in cancer treatment is limited by severe and prolonged side effects. Streptonigrin is converted by NAD(P)H:quinine oxidoreductase (NQO1) to the more active hydroquinone form. Therefore, tumors containing high levels of this enzyme might be sensitive to streptonigrin at concentrations that do not generate severe side effects [@pone.0090783-Gavriil1]. It was also shown that streptonigrin at 0.05 µM markedly decreased clonogenic survival of pancreatic cancer cells expressing NQO1 at elevated levels but not of colorectal cancer cells with lower levels of this enzyme [@pone.0090783-Lewis1]. Streptonigrin has been shown to inhibit β-catenin/TCF signaling by suppression of TCF-mediated DNA binding and to reduce the level of nuclear β-catenin [@pone.0090783-Park1]. Its growth inhibitory properties were observed mainly in β-catenin-activated embryonic cells and cancer cells, and were associated with decreased expression of c-MYC, cyclin D and AXIN2 [@pone.0090783-Park1]. Results from the present study support some of those findings. For example, streptonigrin was more cytotoxic against melanoma cells than against leukemia K562 cells which might indicate a cancer type specificity, probably connected with the NQO1 level. As NQO1 is over-expressed in most melanoma cell lines in comparison with normal melanocytes [@pone.0090783-Garate1], even low concentration of streptonigrin might be sufficient to kill melanoma cells. Secondly, streptonigrin at the concentration as low as 0.04 µM was highly effective against melanoma cells with clonogenic potential which is in line with the previous finding for pancreatic cancer cells [@pone.0090783-Lewis1]. Streptonigrin significantly reduced the expression of *c-MYC*, but it increased the expression of *MITF*, and this interesting result needs to be further investigated. Compounds less cytotoxic than streptonigrin, bryostatin 1, siomycin A and pentoxifylline, were selected based on their activity against melanoma cells exerting high self-renewing capacity. In addition, all of them were more cytotoxic to melanoma cells than to K562 cells. Those compounds substantially decreased the frequency of ABCB5-positive melanoma cells and removed the slow-cycling label-retaining cells at concentrations that did not trigger apoptosis. In a previous study [@pone.0090783-Zhao1], bryostatin 1 increased HLA class II protein levels crucial for the stimulation of CD4+ T cells. It also enhanced the expression of costimulatory molecules (CD80 and CD86) in melanoma cells and induced melanoma cell differentiation. It was implied that this drug could be used as a chemo-immunotherapeutic agent for reducing tumorigenic potential and preventing melanoma recurrence. Our present data suggest that bryostatin 1 is either capable of stimulating melanoma cell differentiation or selectively eradicates more primitive stem-like melanoma cells. The next compound, siomycin A was shown previously to reduce viability in melanoma cell lines [@pone.0090783-Bhat1]. Treatment of stem-like glioblastoma multiforme cells with siomycin A resulted in arrested self-renewal [@pone.0090783-Nakano1]. In the present study, the reduction of cells with clonogenic capacity, ABCB5-positive and slow-cycling cells indicates that siomycin A at 1 µM is more effective against melanoma stem-like cells than against fast-cycling cells. Pentoxifylline, the next compound selected in our study, is clinically used in patients with chronic peripheral arterial disease to increase blood flow and to enhance tissue oxygenation. In melanoma cell lines, pentoxifylline combined with irradiation significantly increased radiotoxicity in a *TP53* mutant cell line, effectively suppressed DNA double-strand break repair [@pone.0090783-Theron1], inhibited in G~1~-S phase transition [@pone.0090783-Dua1], caused glutathione depletion and increased glutathione-S-transferase activity [@pone.0090783-Shukla1]. In *in vivo* experiments, it showed anti-metastatic activity [@pone.0090783-Jain1], and significantly inhibited subcutaneous melanoma xenograft growth and angiogenesis without any toxicity [@pone.0090783-Kamran1], [@pone.0090783-Kamran2]. In the present study, pentoxifylline was more efficient in reducing percentages of cells with clonogenic potential than in affecting overall cell viability. More importantly, pentoxifylline might be also considered as capable of reducing availability of ABCB5 transporter in the cell membrane. Several other natural compounds not considered previously as anti-melanoma agents were selected in the present study. From this group comprising toyocamycin, nanaomycin A, illudin M, fumitremorgin C, fumagillin and michellamine B, geldanamycin and its analog, two natural agents: toyocamycin and nanaomycin A were capable of eradicating clonogenic melanoma cells at the concentration as low as 0.1 µM. Interestingly, toyocamycin was also highly cytotoxic at this concentration. Nanaomycin A was less cytotoxic, and at 0.1 µM it reduced the overall viability to about 80% of control and did not increased the percentages of Annexin V-positive cells. Toyocamycin blocks RNA synthesis and ribosome function [@pone.0090783-Suhadolnik1], [@pone.0090783-Tavitian1]. Most recently, it has been shown that it binds to the ATP-binding site of Rio1 kinase, an enzyme involved in the maturation of 40S RNA [@pone.0090783-Kiburu1]. Toyocamycin was also recognized as a potent inhibitor of ER stress-induced XBP1 mRNA splicing [@pone.0090783-Ri1]. At nanomolar concentrations, it induced apoptosis of multiple myeloma cells including bortezomib-resistant cells and inhibited growth of xenografts [@pone.0090783-Ri1]. The clinical application of toyocamycin is limited because of its toxicity. There have not yet been any *in vivo* preclinical studies or clinical trials with nanaomycin A, and the number of *in vitro* studies is limited. Nanaomycin A was found to selectively inhibit DNA (cytosine-5-)-methyltransferase (DNMT3B) and reactivate silenced tumor suppressor genes in human cancer cells [@pone.0090783-Kuck1], [@pone.0090783-Caulfield1]. Most recently, it was reported that hepatocellular carcinoma side population cells enriched with cancer stem-like cells, possessed a differential DNA methylation status as compared with non-side population cells suggesting that DNA methylation might play a significant role in maintaining the CSC-like status [@pone.0090783-Zhai1]. As our study strongly suggests that nanaomycin A preferentially eradicates cells with self-renewing capacity, it would be interesting to find out whether this drug could eliminate melanoma cells with stem cells characteristics *via* epigenetic regulation. Illudin M exerts anti-proliferative and pro-apoptotic activity by alkylating DNA, RNA and proteins. It has a poor therapeutic index [@pone.0090783-McMorris1], which was improved by structural modification of this compound with ferrocene [@pone.0090783-Knauer1]. The new derivative showed increased apoptotic potential. The esters of illudin M with demethylcantharidinic acid (endothall) and 2,2′-bipyridyl dicarboxylic acid retained the cytotoxicity of the parent compound while displaying significantly improved specificity for tumor cells over normal fibroblasts [@pone.0090783-Schobert1]. In the present study, illudin M at 1 µM markedly reduced cell viability and the frequency of ABCB5-positive cells. At 0.1 µM, illudin M reduced clonogenicity below 40% of control, whereas cell viability decreased to about 80% of control indicating that this compound preferentially eradicated cells with self-renewing capacity. This suggests that illudin M might be further studied *in vivo* at subtoxic concentrations. Geldanamycin and its analog (17-aminogeldanamycin) exert various cellular effects including destabilization of Hsp90 target proteins [@pone.0090783-Toyomura1]. In the present study, both compounds were more efficient in reducing viability of melanoma cells than of leukemia cells. Interestingly, the geldanamycin analog showed higher cytotoxic activity than original geldanamycin, however, it was much less potent in eradicating melanoma cells with self-renewing capacity. The geldanamycin analog induced the expression of *MITF*, which is in agreement with a recently published report showing that it caused an increase in MITF protein level [@pone.0090783-vanderKraan1]. Interestingly, it has been demonstrated that agents increasing *MITF* expression can be exploited in anti-melanoma therapeutic strategies [@pone.0090783-SezAyala1]. The next natural drug candidate, fumitremorgin C at micromolar concentrations inhibited expression of the breast cancer resistant protein (BCRP/ABCG2) that mediates transport of chemotherapeutic agents [@pone.0090783-Rabindran1]. In the present study, however, fumitremorgin C did not alter the frequency of cells expressing another transporter, ABCB5. It was also shown previously that fumitremorgin C blocked the appearance of side population (SP) phenotype in non-small cell lung cancer cultures [@pone.0090783-Singh1]. Our study confirmed this finding in melanoma as 1 µM fumitremorgin C very efficiently eradicated primitive cells, which was clearly visible in clonogenic and label retention assays. Fumagillin has been shown to inhibit angiogenesis [@pone.0090783-Chen1], [@pone.0090783-Kilarski1] and irreversibly block methionine aminopeptidase-2 (MetAP-2) through covalent modification [@pone.0090783-Sheen1]. In addition, it significantly reduced cholangiocarcinoma cell proliferation in a dose-dependent manner and the degree of growth inhibition was dependent on the amount of cellular MetAP2 [@pone.0090783-Sawanyawisuth1]. In the present study, fumagillin at 1 µM was more efficient in eradicating clonogenic cells than in reducing overall cell viability. Michellamine B, known for its anti-yeast and anti-HIV activity, was not yet recognized as having anticancer potential. The present study revealed that it is not highly cytotoxic but markedly reduced the frequency of slow-cycling melanoma cells and ABCB5-positive melanoma cells. The impact on ABCB5-positive melanoma cells was quite different for two other drugs, maytansine and colchicine. Both compounds were highly cytotoxic but they substantially increased the frequency of ABCB5-positive cells suggesting that these two compounds might be efficiently effluxed from cells expressing this transporter. Maytansine has been tested in several clinical trials involving different tumors but the results of these trials were discouraging due to dose-limiting toxicity and lack of efficacy [@pone.0090783-Blum1], [@pone.0090783-Borden1]. Studies performed on NCI\'s panel of 60 cancer cell lines revealed that maytansine inhibits the assembly of microtubules by binding to tubulin and has the same binding site as rhizoxin [@pone.0090783-Cassady1]. In the present study, maytansine was highly cytotoxic and cell viability was below 22% of control after 48 h treatment in a broad range of concentrations from 0.004 µM to 5 µM. However, when cells were exposed to 0.1 µM maytansine for 24 h, viability was reduced only to 70% of control. This suggests strong time-dependent effects of this compound. Indeed, after the first 30 h of treatment with maytansine at 1 µM or even at 5 µM, the majority of cells were not collected in subG~1~ but in G~2~/M phase, but 18 h later more than 70% of cells were Annexin V-positive at the concentration as low as 0.01 µM. At this concentration, however, maytansine had already lost its anti-clonogenic potential. Probably, the short exposure to the drug (4 h) used in clonogenic assay was not sufficient to obtained long-term effects on cells exerting self-renewing capacity. More interestingly, maytansine did not affect slow-cycling label-retaining cells. Thus, the length of time required to induce anticancer effects and the lack of ability to eradicate all types of melanoma cells, especially those considered as melanoma stem-like cells, could partially explain why maytansine failed in clinical trials. More recently, phase II trials of Her2- and CD19-based antibody conjugates containing a maytansine derivative (maytansine-DM1) have shown good clinical efficacy in breast and B-cell malignancies, respectively [@pone.0090783-Burris1], [@pone.0090783-Blanc1]. It would be interesting to evaluate this new derivative against melanoma cells, especially against those cells with cancer stem-like characteristics. The next compound, colchicine is used in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever, pericarditis, and Behçet\'s disease. It inhibits microtubule polymerization by binding to tubulin [@pone.0090783-Skoufias1]. In the present study, colchicine-induced cell death was preceded by G~2~/M arrest of the cell cycle, however, at 0.1 µM colchicine had a limited influence on both fast- and slow-cycling cells. At this concentration it was also not highly effective against clonogenic cells. It has been shown recently that colchicine exerted anti-proliferative effect in hepatocellular carcinoma cell lines [@pone.0090783-Lin1], but the significance of this finding is diminished by observation that it also reduced viability in normal liver cells [@pone.0090783-Chen2]. Given these results, colchicine is probably not a good drug candidate for the treatment of melanoma. Its high capacity to select ABCB5-positive and slow-cycling cells could however be used in *in vitro* experiments to enrich melanoma population with cells potentially exhibiting stem-cell characteristics. Conclusions {#s5} =========== In the present study, numerous agents across different therapeutic categories and modes of action (Table S3 in [File SI](#pone.0090783.s001){ref-type="supplementary-material"}) have been selected from The Natural Products Set II as highly potent against melanoma cells. As some of natural compounds were capable of targeting melanoma stem-like cells, a subpopulation of tumor cells responsible for cancer initiation, propagation and maintenance, results of our screen represent possible opportunities to repurpose these drugs for the treatment of patients with melanoma. Moreover, because in the clonogenic assay, melanoma cells were not continuously exposed to tested compounds but only for short periods of time, the probability of exceeding the plasma/serum half-life was reduced and the observed long-term effects might be clinical relevant. If we consider that the phenotypic plasticity may facilitate escape of melanoma cells from anti-cancer therapies [@pone.0090783-Leder1], selected anti-clonogenic drugs should rather be used in combination with highly cytotoxic and/or targeted agents to prevent the regeneration of the heterogeneous pool of cancer cells from a subpopulation that remains unaffected. Nevertheless, our results position bryostatin 1, siomycin A, pentoxifylline, illudin M and michellamine B as drugs against melanoma stem-like cells and potentially resistance-reversing agents capable of reducing ABCB5 expression. Streptonigrin and nanaomycin A, which were even more effective against cells with self-renewing capacity, were not capable of affecting ABCB5-positive cells. It is, however, unclear whether melanoma stem-like cells can be identified through the expression of this transporter [@pone.0090783-Schatton1], [@pone.0090783-Quintana1], [@pone.0090783-Murphy1]. Thus, our results emphasize the need to better understand the role of diverse subpopulations in tumor maintenance and response to therapy. Another noteworthy aspect of the present study was the demonstration that the most cytotoxic compounds might serve as agents selecting a cancer stem-like cell subpopulation. Maytansine was highly cytotoxic even at 0.01 µM but it did not reduce clonogenicity at this concentration, it selected ABCB5-positive cells and a small subpopulation of slow-cycling cells remained unaffected. This indicates that maytansine and probably also colchicine might be considered as a valuable biochemical tool for future studies of melanoma stem-like cells and certainly warrants further investigation. Supporting Information {#s6} ====================== ###### **Figure S1. The influence of natural compounds used at a single concentration of 5 µM on viable cell numbers in melanoma (DMBC11 and DMBC12) and leukemia (K562) cell cultures.** Viable cells were assessed by acid phosphatase activity assay (A) or by flow cytometry using an automated cell viability analyzer (B). Data are the mean ± SD of two independent experiments performed in triplicates. **Figure S2. Effects of natural compounds (5 µM) on viability of melanoma cells (DMBC11 and DMBC12) and leukemia cells (K562).** Changes in cell viability were assessed by PI staining and flow cytometry and they are expressed as % of vehicle control. Data are the mean ± SD of two independent experiments performed in triplicates. **Figure S3. The influence of natural compounds on cell distribution in cell cycle and cell death shown as accumulation in subG~1~.** (A) Representative histograms of DMBC12 cells treated with natural compounds at a single concentration of 5 µM for 30 h are shown. When accumulation of melanoma cells in subG~1~ did not exceed 40%, histograms were analyzed using ModFit software to calculate the percentages of cells in each cell cycle phase. Histograms showing cell cycle arrest were marked with green (G~0~/G~1~ phase), blue (S phase) and red (G~2~/M) frames, and percentages of melanoma cells accumulated in each phase are included. When accumulation of melanoma cells in subG~1~ exceeded 40%, FACSuit software was used and the percentages of dead cells are indicated. Results obtained for DMBC11 cells are shown in [Figure 3](#pone-0090783-g003){ref-type="fig"}. (B) Effects of lower concentrations for the most cytotoxic compounds or of longer exposure for compounds that were ineffective at 30 h. **Figure S4. The influence of natural compounds used at a single concentration of 5 µM on the clonogenic growth of melanoma cells.** Cells were incubated in drug-containing medium for 4 h and then they were grown on agar for 14 days in drug-free medium. Cell colonies were stained and counted. Anti-clonogenic activity was expressed as percentage of control treated with vehicle. At least two independent experiments were performed in duplicates. **Figure S5. Dose-response curves prepared for compounds exerting anti-clonogenic and/or cytotoxic potentials.** Blue curves, anti-clonogenic activity; black curves, cytotoxic activity. The graphs summarize the results of at least 3 independent experiments performed in triplicates using DMBC11 (filled square) and DMBC12 (open square) cell lines. Chemical formulas of compounds are included. Dose-response curves for more potent compounds are shown in [Figure 6](#pone-0090783-g006){ref-type="fig"}. **Table S1. The Natural Products Set II Consisting of 120 compounds.** Table contains names of all compounds and the numbers (underlined) that could be used to get detailed information about compounds from available databases. The upper numbers were given to compounds in the present study, and they appear in brackets in the text and also in some Figures. **Table S2. Viability assessed after 45 h of treatment with selected compounds at indicated concentrations in six different melanoma cell lines derived from surgical specimens.** Cell viability was assessed by flow cytometry after PI staining. Data expressed as % of control treated with vehicle are means ± SD of two independent experiments conducted in triplicates. **Table S3. Activity profiles of natural compounds selected in this study prepared based on a literature search.** Only the main biological activities of compounds are included. (PDF) ###### Click here for additional data file. The authors wish to thank Dr. Jennifer Wilding from University of Oxford for reviewing the manuscript and Dr. Markus Duchler for stimulating discussion. The authors gratefully acknowledge the excellent technical and administrative assistance of M.Sc. Karolina Niewinna. This work was financially supported by a grant 2011/01/B/NZ4/04921 from the National Science Centre. [^1]: **Competing Interests:**The authors have declared that no competing interests exist. [^2]: Conceived and designed the experiments: MC. Performed the experiments: MSS KK KM MH MC. Analyzed the data: MC KK. Contributed reagents/materials/analysis tools: MC MSS. Wrote the paper: MC. | High | [
0.689655172413793,
32.5,
14.625
]
|
%---------------------------------------------------------------------------% % vim: ts=4 sw=4 et ft=mercury %---------------------------------------------------------------------------% :- module binary_search. :- interface. :- import_module bool. :- import_module int. :- import_module io. :- pred main(io::di, io::uo) is det. :- pred silly_even(int::in, bool::out) is det. :- implementation. :- import_module binary_search_1. :- import_module list. main(!IO) :- a(A), b(B), add1s([1, 2, 3, 4, 5, 6, 7, 8, 9, 10], L), write(A, !IO), write(B, !IO), write(L, !IO), nl(!IO). :- pred a(bool::out) is det. a(X) :- binary_search.silly_even(1001, X). :- pred b(bool::out) is det. b(X) :- binary_search.silly_even(1003, X). silly_even(N, R) :- ( N > 0 -> ( (N =< 600 , N >= 405 ; N mod 3 = 0) -> binary_search_1.sillier_even(N, R) ; ( N = 619 -> binary_search.silly_even(N-1, R) ; binary_search.silly_even(N-2, R) ) ) ; ( N = 0 -> R = yes ; R = no ) ). :- pred add1s(list(int)::in, list(int)::out) is det. add1s([], []). add1s([H0 | T0], [H0+1 | T]) :- add1s(T0, T). | Mid | [
0.568027210884353,
41.75,
31.75
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806 F.Supp.2d 1078 (2009) CRITERION 508 SOLUTIONS, INC., Plaintiff, v. LOCKHEED MARTIN SERVICES, INC., Defendant. No. 4:07-cv-00444-JAJ-CFB. United States District Court, S.D. Iowa, Central Division. September 29, 2009. *1082 Gordon R. Fischer, Bradshaw Fowler Proctor & Fairgrove, Des Moines, IA, for Plaintiff. David A. Tank, Megan C. Dempsey, William J. Miller, Dorsey & Whitney LLP, Des Moines, IA, for Defendant. ORDER JOHN A. JARVEY, District Judge. This matter comes before the court pursuant to Defendant Lockheed Martin Services, Inc.'s ("Lockheed") February 16, 2009, Motion for Summary Judgment (Dkt. No. 78). On August 30, 2007, Plaintiff *1083 Criterion 508 Solutions, Inc. ("Criterion") filed a petition in Polk County Iowa District Court, which Lockheed removed to federal court on September 28, 2007 (Dkt. No. 1). Criterion filed a Brief in Resistance to Defendant's Motion for Summary Judgment on April 14, 2009 (Dkt. No. 95-2), as well as a Statement of Undisputed Facts (Dkt. No. 95-3) and a Response to Lockheed's Facts (Dkt. No. 95-4). On May 11, 2009, Lockheed filed a Response to Criterion's Facts (Dkt. No. 106) and a Reply Brief (Dkt. No. 112). Criterion responded with a Sur Reply on June 22, 2009 (Dkt. No. 121) and an Addendum to the Sur Reply on June 25, 2009 (Dkt. No. 123). For the reasons set forth below, the court grants summary judgment on Counts I, III, and VIII, and grants in part and denies in part summary judgment on Counts II and V. I. STATEMENT OF MATERIAL FACTS[1] Criterion is an Iowa company specializing in technological "accessibility solutions" in compliance with Section 508 of the Rehabilitation Act. Section 508 requires federal agencies to make all electronic and information technology accessible to persons with disabilities. Specifically, Criterion specializes in "independent third-party validation of Web sites, Web applications, software, PDF documents, and/or fillable forms." (Pl. Facts, dkt. 95-3 at 1.) Criterion also offers on-site training and e-learning courses. (Pl. Facts, dkt. 95-3 at 2.) Angy Brooks created an S-corporation called Brooks Web Services ("BWS") in November 2000. BWS began working for Criterion in 2001 and performed Section 508 compliance work, including but not limited to, technical development, template creation, documentation, and technical training development. (Def. Appx. at 129.) BWS signed a Subcontractor's Services Agreement with Criterion on May 23, 2004. (Def. Appx. at 147-50.) The Agreement included a confidentiality provision, a "right to title" for all work product, and a restrictive covenant preventing direct or indirect competition for two years following termination. (Def. Appx. at 148-49.) Criterion gave BWS 60-days' notice of termination in May 2005. (Def. Appx. at 129.) On June 30, 2006, BWS filed suit against Criterion for allegedly unpaid invoices in Polk County District County. (Pl.'s Br. in Resistance, dkt. 95-2 at 9.) Criterion responded with counterclaims and the court ultimately granted judgment for Criterion. (Pl.'s Br. in Resistance, dkt. 95-2 at 18.) When BWS failed to pay the judgment, Criterion successfully pierced BWS's corporate veil and Brooks was held personally liable for the judgment against BWS on June 27, 2008. (Pl.'s Response to Def.'s Statement of Undisputed Facts, dkt. 95 at 2; Pl.'s Br. in Resistance, dkt. 95-2 at 22.) During the 60-day notice period of termination and before Brooks' end date of July 2005, Brooks began looking for new employment. In May, almost immediately after Criterion gave her notice of termination, Brooks responded to a job advertisement that Global Commerce & Information ("GCI") had posted. GCI partners with Lockheed Martin Services[2] ("Lockheed") "to locate and hire people who will provide services to Lockheed Martin." (Def. Facts, dkt. 78-2 at 2; see also Def. Appx. at 160-207.) GCI sent Brooks' resume to Kathy Plourd, a Lockheed employee, *1084 on May 13, 2005. (Pl. Appx. at 9). Plourd interviewed Brooks[3] (Pl.'s St. of Undisputed Facts, dkt. 95-3 at 10) and on May 23, 2005, BWS entered into a Subcontractor Agreement with GCI. (Def. Appx. at 151.) From that point on, Brooks performed various subcontractor assignments associated with Section 508 compliance for the Social Security Administration ("SSA"). (Pl.'s St. of Undisputed Facts, dkt. 95-3 at 12-14.) The SSA paid Lockheed a total of $345,723 for Brooks' work. (Pl.'s St. of Undisputed Facts, dkt. 95-3 at 14.) During Brooks' employment with Lockheed, Brooks was at all times bound by the terms of a two-year restrictive covenant. (Pl.'s St. of Undisputed Facts, dkt. 95-3 at 14.) Thus, Criterion contends that Brooks' Section 508 work product for SSA/Lockheed was a direct result of the trade secrets and proprietary information Brooks learned while working for Criterion. (Pl.'s St. of Undisputed Facts, dkt. 95-3 at 14.) A. Material Facts Relating to the Nature of Brooks' Employment with Lockheed The parties dispute whether Brooks was a full-time employee or an independent contractor for Lockheed. Lockheed argues that Brooks was not a Lockheed employee and therefore it is not vicariously liable for the tortious acts of independent contractors. Criterion disputes Lockheed's characterization of Brooks' employment and maintains that Lockheed is responsible for Brooks' actions because she was an employee. Lockheed asserts that Brooks was an independent contractor because of the Subcontractor's Services Agreement she signed with GCI on May 23, 2004. The Agreement states that she is not an employee to GCI or to any of its clients, nor will she receive any employee benefits.[4] Criterion admits that Brooks signed the agreement, but denies that it "implies Brooks was a contractor or subcontractor." (Pl. Resp. to Def.'s Facts, dkt. 95-4 at 5.) Lockheed also asserts that Brooks received wages from GCI and GCI withheld employment taxes. (See Def. Appx. at 139.) In her deposition, Brooks confirmed that GCI paid her for Lockheed-related work. (Def. Appx. at 212.) Additionally, Brooks stated that she used the SSA computers and worked at SSA offices, not at Lockheed offices. (Def. Appx. at 214.) However, Criterion asserts that Brooks was, at all times, a full-time employee of Lockheed. Although GCI referred Brooks to Lockheed (Pl. Appx. at 9), Criterion states that Brooks' job interview was with Kathy Plourd, an employee for Lockheed, and not GCI. (Def. Appx. at 143.) Additionally, Brooks received work assignments from Lockheed and submitted her work for review by Plourd. Lockheed agrees that Plourd "acted as a supervisor and/or administrator to Brooks and ensured that Brooks' project for the SSA was fulfilled." (Def. Facts, dkt. 78-2 at 4.) *1085 However, Lockheed states that while Plourd was a supervisor, she did not "tell [Brooks] how to do the work," nor did she "dictate to [Brooks] the means or methods [Brooks] [was] to follow to accomplish the goals set forth in the project." (Def. Appx. at 214A, 215.) Criterion objects and points to emails from Plourd to bolster its argument that Brooks was actually an employee of Lockheed. In an email from Brooks to Plourd, Brooks stated, "[S]ince I will be held responsible for the deliverables of the word order, I want to capture them in writing so that we're all in agreement as to what is expected from me...." (Pl. Mat. Facts, dkt. 95-3 at 10.) In another email from Brooks to Plourd, Brooks stated, "I WELCOME and ENCOURAGE your criticism and comments." (Pl. Mat. Facts, dkt. 95-3 at 11) (emphasis in original.) Lastly, Brooks also sought Plourd's "input and feedback." (Pl. Mat. Facts, dkt. 95-3 at 11.) Other factors also indicate Lockheed's involvement in financial matters. For example, Criterion contends that Brooks sought Lockheed's permission to attend a conference and to receive reimbursement from Lockheed for certain expenses. (Pl. Mat. Facts, dkt. 95-3 at 11.) Brooks' email signature line also included Lockheed's name and Brooks recorded her hours using the Lockheed timecard system. (Pl. Mat. Facts, dkt. 95-3 at 11.) B. Material Facts Relating to Lockheed's Knowledge of Brooks' Criterion Work Whether or not Lockheed knew about Brooks' restrictive covenant with Criterion remains in dispute. Lockheed claims that it did not intentionally interfere with Brooks' restrictive covenant because it did not know that Brooks had any contractual limitations from previous employment. Criterion asserts that Lockheed intentionally interfered with Brooks' restrictive covenant and that it hired Brooks to gain proprietary Criterion information. Criterion contends that Lockheed had ulterior motives in hiring Brooks because Lockheed knew it could gain the functional equivalent of Criterion's products by hiring Brooks to design new Section 508 products for clients. Lockheed states that Brooks never "inform[ed] [GCI] that she had a restrictive covenant, noncompete agreement, or confidentiality agreement as part of her prior relationship and/or contract with Criterion." (Def. Facts, dkt. 78-2 at 3; see also Def. Appx. at 212-13.) Brooks signed an Employee Consent Agreement which stated, "Contractor Employee acknowledges... that he/she is not restricted by any employment or other agreement from providing services to Client, and understands that any misstatements or lack of candor by Contractor Employee of his/her qualifications or availability may be grounds for immediate termination by the Client." (Def. Appx. at 157.) Lockheed also states that it never had a copy of Brooks' subcontractor services agreement with Criterion. (Def.'s Resp. to Pl.'s Statement of Disputed Facts, dkt. 106 at 21.) Criterion denies everything related to Lockheed's claim that it was unaware of Brooks' employment agreement with Criterion. Criterion suggests an email from Brooks to Plourd provides evidence that Lockheed was aware of the restrictive covenant. In this email, Brooks stated, "If you recall, I worked for Criterion Solutions prior to coming to work as a contractor for [Lockheed]. I told you at that time that this was not a violation of the contract I had with Criterion, since [Lockheed] wasn't a client of Criterion's, nor was the SSA. This was, and still is, true." (Pl. Resp. to Def.'s Facts, dkt. 95-4 at 9; see also Pl.'s Appx. 1-2.) Criterion challenges Brooks' credibility, urging the court to *1086 take judicial notice of her dishonesty and unethical conduct. While performing services for Lockheed/GCI, Brooks' projects included work for the SSA. Her tasks included the creation of handbooks to explain to its employees: "(i) the process of how to make/convert a Word document to a PDF file and (ii) how to make a PDF file accessible to people with disabilities." (Def. Facts, dkt. 78-2 at 4; see also Def. Appx. 216.) The record is conflicting regarding the extent of overlapping knowledge between Brooks' knowledge-base derived from Criterion and her subsequent work at Lockheed. Criterion asserts that Brooks worked on "at least 10 Section 508/accessibility projects for [Lockheed]." (Pl. Resp., dkt. 95-4 at 18.) Lockheed argues that there were only four assignments and Criterion is artificially inflating the number by including revisions. (Def.'s Resp. to Pl.'s Statement of Disputed Facts, dkt. 106 at 25.) C. Criterion and BWS Prior State Court Law Suit Additionally, the Polk County state court suit between Criterion and BWS/ Brooks presents a controversy as to whether the state suit operates to preclude Criterion's suit against Lockheed. Lockheed claims that Criterion is barred by claim preclusion from pursuing matters already resolved in state court, such as unjust enrichment, misappropriation of trade secrets, and copyright infringement. Criterion contends that Lockheed cannot satisfy the elements of claim preclusion. In essence, Criterion asserts that it can still adjudicate certain claims against Lockheed, despite Lockheed's allegations that several of the current claims are substantially similar to claims made in the state court suit with Brooks. On June 30, 2006, BWS sued Criterion in Iowa District Court in and for Polk County. BWS alleged breach of contract, an open account, and quantum merit. BWS, through Brooks, claimed that Criterion failed to pay BWS for approximately $63,000 of work. (Def. Appx. at 1-3.) On July 12, 2006, Criterion counterclaimed, claiming breach of fiduciary duty, unjust enrichment, breach of written contract, breach of restrictive covenant, negligence, and conversion. (Def. Appx. at 6-11.) The case went to a jury trial held June 4-6, 2007. At the close of Brooks' evidence, the court granted Criterion's motion for directed verdict on all three counts of Brooks' petition and dismissed the counterclaims related to breach of fiduciary duty, and portions of the negligence and breach of confidentiality claims. (Def. Appx. at 17-18.) Regarding the unjust enrichment claim, the court[5] found, Criterion 508 failed to prove that Plaintiff received funds that she unjustly deserved. Plaintiff performed services while working as a subcontractor for Criterion 508, and was partially paid for those services. Those funds were rightfully due and owing to Plaintiff. Plaintiff in fact performed many services for Defendant which were not paid for by the Defendant because she submitted the bills too late. (Def. Appx. at 19.) The court found for Criterion on the breach of contract, breach of restrictive covenant, negligence, and conversion claims. As to the breach of contract claim, the court found that Brooks violated the confidentiality provision of her contract in several waysshe had revealed information to a non-party, Georgia Spurgeon; posted an article online detailing Criterion's "PDF testing and repair technique;" and had posted Criterion's "business *1087 methods on the internet, available for anyone, for free access." (Def. Appx. at 20-22.) The court also found that the covenant not to compete was valid and enforceable, and that Brooks had violated it in several ways. The court found that the non-compete covenant applied to Brooks from the date of her termination, July 17, 2005, to on or about July 17, 2007. (Def. Appx. at 27.) She violated the covenant by posting an advertisement for web and PDF design for 508 compliancy, as the court stated, "[A] logical inference is made that [Brooks] was intending for people who were interested in PDF accessibility to click on this link." (Def. Appx. at 28.) Additionally, Brooks' actions of creating and posting on the SSA's website a desk guide for creating accessible documents used "business methods and services which Criterion 508 Solutions specialized and developed." (Def. Appx. at 29.) An additional online posting on the internet "included more of Criterion 508 Solutions' business methodologies, revealed without Criterion 508 Solutions' permission." (Def. Appx. at 29.) The court found that Brooks had learned all of this confidential information while being employed by Criterion. However, Criterion failed in proving damages (both liquidated and otherwise) for either the breach of contract or restrictive covenant claims because it failed to present evidence supporting more than a speculative loss of income. (Def. Appx. at 22, 30, 32.) The court also rejected Criterion's claim that Brooks had violated the restrictive covenant while she worked for Lockheed[6] because Brooks never worked for Lockheed while still employed as a subcontractor for Criterion. (Def. Appx. at 30.) Lastly, the court held that Brooks had been negligent in failing to complete a project and then retaining materials needed for completion. The court awarded Criterion $11,200 that it had been forced to pay for completion bonuses. (Def. Appx. at 34.) Likewise, Brooks' acts of retaining documents and registering Criterion508.net for her own company were found to be intentional acts of conversion. (Def. Appx. at 36.) Criterion again failed to establish lost income by a preponderance of the evidence and its claim for damages was denied. (Def. Appx. at 36.) II. SUMMARY OF THE ARGUMENTS Lockheed asks the court to consider summary judgment on the five remaining Criterion counts: Intentional Interference with a Contract (Count I), Unjust Enrichment (Count II), Misappropriation of Trade Secrets (Count III), Copyright Infringement (Count V), and Civil Conspiracy to Breach Fiduciary Duties (Count VIII). Lockheed bases its motion for summary judgment on several theories: the prior state court judgment precludes the vicarious liability claims (Counts II, III, and V), the vicarious liability claims are barred because Brooks was an independent contractor for Lockheed (Counts II, III, and V), there is insufficient evidence to establish a prima facie case (Counts I, II, and VIII), the copyright claims are barred because the copyrights were not registered (Count V), and the state law claims are preempted by the copyright statute (Counts I and II). Criterion presents several arguments as to why summary judgment is inappropriate. *1088 Criterion argues that Brooks was a Lockheed employee and not an independent contractor, the vicarious liability claims are not precluded by the prior state court judgment, Criterion has set forth sufficient facts to establish prima facie cases, copyrights do not have to be registered to be protected, and the copyright statute does not preempt state law. The court will address each claim and basis for summary judgment in turn. III. CONCLUSIONS OF LAW A. Summary Judgment Standard A motion for summary judgment may be granted only if, after examining all of the evidence in the light most favorable to the nonmoving party, the court finds that no genuine issues of material fact exist and that the moving party is entitled to judgment as a matter of law. HDC Medical Inc. v. Minntech Corp., 474 F.3d 543, 546 (8th Cir.2007) (citation omitted); see also Kountze ex rel. Hitchcock Foundation v. Gaines, 536 F.3d 813, 817 (8th Cir.2008) ("[S]ummary judgment is appropriate where the pleadings, discovery materials, and any affidavits show that there is no genuine issue as to any material fact and that the movant is entitled to summary judgment as a matter of law."). Summary judgment is appropriate when the evidence is so one-sided that "there exists only one conclusion." Webb v. St. Louis Post-Dispatch, 51 F.3d 147, 148 (8th Cir.1995) (citation omitted). Once the movant has properly supported its motion, the nonmovant "may not rest upon the mere allegations or denials of [its] pleading, but ... must set forth specific facts showing that there is a genuine issue for trial." Fed.R.Civ.P. 56(e). A genuine issue of material fact exists "if the evidence is sufficient to allow a reasonable jury verdict for the nonmoving party." Great Plains Real Estate Dev., L.L.C. v. Union Central Life Ins. et al., 536 F.3d 939, 944 (8th Cir.2008) (citation omitted). A genuine issue of fact will be material if it "might affect the outcome of the suit under the governing law." Saffels v. Rice, 40 F.3d 1546, 1550 (8th Cir.1994) (citation omitted). The nonmovant is then "entitled to all reasonable inferences that can be drawn from the evidence without resort to speculation." Sprenger v. Fed. Home Loan Bank of Des Moines, 253 F.3d 1106, 1110 (8th Cir.2001) (citation omitted). Although the non-movant is not required to submit "direct proof that genuine issues of fact exist for trial, the facts and circumstances that she [or he] relies upon must attain the dignity of substantial evidence and not be such as merely to create a suspicion." Taylor v. White, 321 F.3d 710, 715 (8th Cir.2003) (internal quotation omitted). A "scintilla" of evidence supporting the movant's position is alone insufficient because "there must be evidence on which the jury could reasonably find for the plaintiff." Sprenger, 253 F.3d at 1110. "To survive summary judgment, a plaintiff must substantiate his allegations with enough probative evidence to support a finding in his [or her] favor." Roeben v. BG Excelsior, Ltd. P'ship, 545 F.3d 639, 643 (8th Cir.2008) (citing Haas v. Kelly Services, Inc., 409 F.3d 1030, 1034 (8th Cir.2005)). B. Vicarious Liability Lockheed argues that summary judgment is appropriate on Criterion's Unjust Enrichment (Count II), Misappropriation of Trade Secrets (Count III), and Copyright Infringement (Count V) claims, because Brooks was not a Lockheed employee and therefore it is not vicariously liable under the doctrine of respondeat superior. Criterion argues that Brooks was an employee of Lockheed and that whether an employee/employer relationship exists is a question of fact reserved for the jury. *1089 According to Iowa law, a corporation is liable for tortious conduct committed during the scope of an employee's employment. Pippert v. Gundersen Clinic, Ltd., 300 F.Supp.2d 870, 877 (N.D.Iowa 2004). It is a "well established rule ... that under the doctrine of respondeat superior, an employer is liable for the negligence of an employee committed while the employee is acting within the scope of his or her employment." Lyons v. Midwest Glazing, L.L.C., 235 F.Supp.2d 1030, 1044 (N.D.Iowa 2002). However, "ordinarily the employer ... of an independent contractor... is not liable for injuries arising out of the latter's negligence." Clausen v. R.W. Gilbert Constr. Co., 309 N.W.2d 462, 466 (Iowa 1981). Thus, to succeed on a claim of vicarious liability under the doctrine of respondeat superior, there must be "proof of an employer/employee relationship (or employment as an independent contractor), and proof that the injury occurred within the scope of that relationship." Zimmer v. Travelers Ins. Co., 521 F.Supp.2d 910, 936 (S.D.Iowa 2007) (quoting Walderbach v. Archdiocese of Dubuque, Inc., 730 N.W.2d 198, 201 (Iowa 2007) (failure to establish an employer/employee relationship due to multiple statements that priest was an independent contractor, church was a separate legal entity, and priest's salary paid by church, not Archdiocese)). To determine whether a person is an employee or an independent contractor, the court must look at the totality of circumstances surrounding the employment. Relevant factors include: "(1) who had the right to control the physical conduct of the work, (2) whether the purported employee was on the employer's payroll, and (3) who provided the equipment to accomplish the work." Iowa Mut. Ins. Co. v. McCarthy, 572 N.W.2d 537, 543 (Iowa 1997). The Iowa Supreme Court also considers: "(1) the existence of a contract for the performance by a person of a certain piece or kind of work at a fixed price; (2) independent nature of [her] business or of [her] distinct calling; (3) [her] employment of assistants, with the right to supervise their activities; (4) [her] obligation to furnish necessary tools, supplies, and materials; (5) [her] right to control the progress of the work, except as to final results; (6) the time for which the work[woman] is employed; (7) the method of payment, whether by time or by job; [and] (8) whether the work is part of the regular business of the employer." Id. at 543 (quoting Nelson v. Cities Serv. Oil, 259 Iowa 1209, 1214-15, 146 N.W.2d 261 (Iowa 1966)). See also Walderbach v. Archdiocese of Dubuque, Inc., 730 N.W.2d 198, 200 (Iowa 2007) (relevant factors include: "the right of selection or employment at will, the responsibility to pay wages, the right to terminate the relationship, the right to control the work, the benefit received by the alleged employer, and the intent of the parties." (citing Iowa Mut. Ins. Co. v. McCarthy, 572 N.W.2d 537, 541-42 (Iowa 1997))). Despite the numerous factors the court must weigh, the important distinction "is the degree of retention by [the] principal of the right to control the details of the work as well as the results." McDonald v. Dodge, 231 Iowa 325, 1 N.W.2d 280, 282 (1941). Even if there is no "actual control," then it is still the "right to control which is determinative of whether [an] employer-employee relationship exists," as some types of work need little or reduced supervision. Air Terminal Cab, Inc. v. United States, 478 F.2d 575, 580 (8th Cir.1973). An employer of an independent contractor may "properly retain control necessary to see the result is obtained according to plan." Schlotter v. Leudt, 255 Iowa 640, 123 N.W.2d 434, 437 *1090 (1963). However, signing an agreement "stating that [a] worker is [a] self-employed contractor and designating [that] person [as an] independent contractor" does not automatically establish one as an independent contractor. Louismet v. Bielema, 457 N.W.2d 10, 13 (Iowa Ct.App. 1990). Whether a person is an independent contractor or an employee is a question that is typically reserved for the jury unless the evidence is insufficient and can be decided as a matter of law. See Pippert v. Gundersen Clinic, Ltd., 300 F.Supp.2d 870, 877 (N.D.Iowa 2004) (stating this rule in the context of whether an employer/employee relationship exists). Furthermore, a court may also properly decide a "question of relationship created by written contract...." Rouse v. State, 369 N.W.2d 811, 813 (Iowa 1985). Where all evidence points to one side and "there is no rational basis for reasonable minds to differ as to [the] status of [the] servant the issue is one of law for the court to resolve." Watland v. Walton, 410 F.2d 1, 3-4 (8th Cir.1969). Applying the factors discussed above to the facts of this case, the court finds that there are no genuine issues of material fact and that Brooks was an independent contractor of Lockheed. Control Over Work. First, regarding the "primary focus"whether Lockheed had control over Brooks' workthe parties point to countervailing evidence. Criterion notes that in two emails, Brooks asked Lockheed employee, Kathy Plourd, for feedback, comments, and direction. Plourd supervised and directed Brooks' work assignments. (Def. Appx. at 214A.) Brooks also went to Plourd for permission to attend a conference and to be "paid for [her] hours spent in attendance" for that conference, as Brooks stated that this conference was "directly related to [the SSA] work order." (Pl. Appx. at 61.) Brooks stated in her deposition that Plourd did not "tell [her] how to do the work," or "dictate ... the means or methods [Brooks was] to follow to accomplish the goals set forth in the project." (Def. Appx. at 114A-15.) Additionally, Brooks noted that Lockheed's role was "[a]dministrative, ensuring that the project was fulfilled." (Def. Appx. at 214A.) Once Plourd assigned Brooks a project, any input Brooks needed for project completion came directly from the SSA. (Def. Appx. at 215.) Lockheed did not have creative control over the content of Brooks' work product. In Brooks' deposition, she stated, A: I received an outline from the SSA that was the Adobe PDF accessibility handbook's outline. And they asked me to write something similar along that outline that was easier to read and understand. Q: All right, soand that direction was from SSA? A: That's correct. Q: When you had questions about what the project involved or what you were to do, who would you ask? A: I had bi-weekly meetingsevery other week meetingswith Robert somebody that was the SSA guy.... And I didn't necessarily have questions because I knew how to do my job, but their requirements changed based on my work. Thus, the record is clear that Lockheed had administrative control over Brooks' work product, but that the SSA gave her the feedback and directions she needed to meet its expectations. Physical Control of Work Product. Brooks turned her completed work into Plourd and from that point on, Lockheed was in control of Brooks' physical work product. (Def. Appx. at 220B.) *1091 Payroll. GCI, and not Lockheed, paid Brooks because the Lockheed/GCI contract stipulated Lockheed would pay contractors GCI had referred to Lockheed after "submission of properly certified time sheets." (Def. Appx. at 162-64.) The Subcontractor Agreement between Brooks and GCI stated that GCI would not provide Brooks with "... disability insurance, paid vacations, sick leave or other leave, retirement plans, health plans, premium 'overtime' pay, and the like." (Def. Appx. at 153.) Brooks was also responsible for withholding employment taxes as Lockheed (Def. Appx. at 165) and GCI expressly disavowed this responsibility: It is understood and agreed that since the Contractor is an independent contractor, [GCI] will make no deductions from fees paid to Contractor for any federal or state taxes or FICA, and [GCI] and [Lockheed] have no obligation to provide Worker's Compensation coverage for Contractor or to make any premium `overtime' payments at any rate other than the normal rate agreed to in the Purchase Order. (Def. Appx. at 153.) The initial Purchase Order from Lockheed to Brooks allocated a maximum of $9600 or 200 hours for Brooks' assignment. (Def. Appx. at 155.) To track these hours, Brooks used the Lockheed timecard system because her compensation from GCI was based on approved and completed billable hours. (Def. Appx. at 207.) Type of Contract. Brooks signed a "subcontractor agreement" with GCI. (Def. Appx. at 151-59.) The agreement states, The parties to this Agreement agree that the relationship created by this Agreement is that of broker-independent contractor. Contractor agrees and has advised its personnel that Contractor and its personnel are not employee(s) of Global Commerce & Information, Inc. or the Client and are not entitled to (and also hereby waive) any benefits provided or rights guaranteed by Global Commerce & Information, Inc. or the Client, or by operation of law, to their respective employees.... (Def. Appx. at 153.) Lockheed also notes that Brooks' contract was for a discrete amount of time (Def. Appx. at 155) and for a discrete purposeto create two handbooks and two "desk guides" for the SSA. There is some disagreement over the number of total projects in which Brooks was involved; Lockheed suggests a total of four, whereas Criterion asserts there were ten projects. Brooks stated in her deposition that she worked on four projects: I produced a handbook on how to make PDFs accessible and a handbook on how to make Microsoft Word documents accessible and then export them to PDF and then two desk guides that basically took the most important things in each of those two documents and condensed it into a single page. (Def. Appx. at 216.) The court finds it irrelevant that multiple versions or drafts could have increased the total number of projects to ten. Other Factors. Criterion argues that Brooks held herself out as a Lockheed employee by using the Lockheed information on her email signature.[7] However, Brooks' email address was associated with the SSA project[8] and she clearly stated in her signature that she was a contractor for Lockheed. (Pl. Appx. at 61.) *1092 GCI initially referred Brooks to Lockheed and Plourd conducted Brooks' interview for the position. Brooks testified in her deposition that she never used Lockheed computers and only worked at SSA offices. (Def. Appx. at 214.) Lockheed may have printed the final work product in-house, but Brooks did not use Lockheed's physical facilities or its computers in the creation of the work product. Here, Criterion's claim that Brooks was an employee of Lockheed must fail. Criterion has failed to generate a genuine issue of material fact as to whether Brooks was an employee. The overall nature of Brooks' projects, the minimal oversight and direction from Lockheed, the pay structure, and the location of Brooks' work establish that Brooks was an independent contractor for Lockheed. The court finds summary judgment is appropriate on the issue of whether Lockheed is vicariously liable because Brooks was not a Lockheed employee. For that reason, the court grants summary judgment to Lockheed on the vicarious liability issue as to the Unjust Enrichment (Count II), Misappropriation of Trade Secrets (Count III), and Copyright Infringement (Count V) claims. C. Claim Preclusion Lockheed next asserts that summary judgment is proper on Criterion's Unjust Enrichment (Count II), Misappropriation of Trade Secrets (Count III), and Copyright Infringement (Count V) claims because they are precluded by the Polk County court's previous ruling. Lockheed contends that Criterion's claims would hold Lockheed vicariously liable for Brooks' actions, and argues that under Iowa law, where claims have resulted in a judgment against an individual, the same plaintiff cannot then bring a claim against another individual or company that is vicariously liable. Criterion responds that (1) claim preclusion only applies to the same parties, (2) the issues were not fully litigated during the first case, (3) its claims against Lockheed involve different facts and are thus independent to the prior suit, and alternatively, (4) there is a change in circumstances present to warrant not applying claim preclusion. Claim preclusion centers around the principle that a "party may not split or try his claim piecemeal, but must put in issue and try his entire claim or put forth his entire defense in the case on trial." Iowa Coal Min. Co., Inc. v. Monroe Cty., 555 N.W.2d 418, 441 (Iowa 1996) (internal citations omitted). Iowa law states that a party asserting claim preclusion, or res judicata, must establish the following: "(1) the parties in the first and second action were the same; (2) the claim in the second suit could have been fully and fairly adjudicated in the prior case; and (3) there was a final judgment on the merits in the first action." George v. D.W. Zinser Co., 762 N.W.2d 865, 868 (Iowa 2009) (internal citations omitted). See Spiker v. Spiker, 708 N.W.2d 347, 353 (Iowa 2006). A party may not return to court "simply by alleging a new ground of recovery for the same wrong." Westway Trading Corp. v. River Terminal Corp., 314 N.W.2d 398, 401 (Iowa 1982). Likewise, an additional claim will likely be barred when the alleged acts, recovery demanded, or the "same evidence will support both actions." Id. (internal citations omitted). Accord Whalen v. Connelly, 621 N.W.2d 681, 685 (Iowa 2000). Under the rule of claim preclusion, "a valid and final judgment on a claim precludes a second action on that claim or any part of it." Arnevik v. Univ. of Minn., 642 N.W.2d 315, 319 (Iowa 2002). However, claim preclusion also requires distinguishing between the "same" and "related" causes of action. Iowa Coal Min. Co., Inc. v. Monroe County, 555 N.W.2d 418, 441 (Iowa 1996) (citing *1093 Westway, 314 N.W.2d at 401). The factors for causes of action that are the "same" for claim preclusion purposes include: "(1) the same principles of substantive and procedural law are applicable to both actions; (2) the same right is alleged to be infringed by the same wrong in both actions; (3) the judgment sought in the second action would infringe rights established in the first; (4) the same evidence would support both actions; or (5) the operative facts are the same in both actions." Id. at 443 (internal citation omitted). If a "distinct claim" was not joined, but there was a right to join a related claim, then claim preclusion will not apply to that distinct claim. Leuchtenmacher v. Farm Bureau Mut. Ins. Co., 460 N.W.2d 858, 860 (Iowa 1990). 1. Vicarious Liability In the traditional context, claim preclusive effects of a judgment were limited to parties who would have been bound by a judgment, otherwise known as the "rule of mutuality." 18A CHARLES ALAN WRIGHT ET AL., FED. PRAC. & PROC. JURIS.2D § 4463, at 677. There is increasing authority, however, in favor of extending claim preclusion to derivative liability relationships because the party asserting preclusion should have been joined in the original litigation. Id. § 4464.1.[9] Courts have embraced a litmus test for extending claim preclusion to non-original parties depending largely on the degree of privity between the affected parties; where there is insufficient privity between parties, courts have rejected extending claim preclusion.[10] The Supreme Court has held on multiple occasions that parties could invoke claim preclusion if "their liability was ... `altogether dependent upon the culpability' of the [prior] defendants.'" Lawlor v. Nat'l Screen Service Corp., 349 U.S. 322, 330, 75 S.Ct. 865, 99 L.Ed. 1122 (1955) (quoting Bigelow v. Old Dominion Copper Mining & Smelting Co., 225 U.S. 111, 32 S.Ct. 641, 56 L.Ed. 1009 (1912)). See also Saudi Arabia v. Nelson, 507 U.S. 349, 375-76, 113 S.Ct. 1471, 123 L.Ed.2d 47 (1993) (related lawsuit *1094 against a foreign sovereign "may be entitled to preclusive effect with respect to the [plaintiff's] similar claims"); Montana v. United States, 440 U.S. 147, 153, 99 S.Ct. 970, 59 L.Ed.2d 210 (1979) ("a final judgment on the merits bars further claims by parties or their privies based on the same cause of action"). Additional guidance for applying claim preclusion to vicarious liability claims comes in the form of RESTATEMENT (SECOND) OF JUDGMENTS § 51.[11] Section 51 operates to protect vicariously liable parties from litigation when an injured person has already lost an earlier suit. Despite different parties, there is only one claim, if "[t]he same loss is involved, usually the same measure of damages, and the same or nearly identical issues of fact and law." RESTATEMENT (SECOND) OF JUDGMENTS § 51, cmt. b. In Kimmel v. Iowa Realty Co., 339 N.W.2d 374, 377 (Iowa 1983), the Iowa Supreme Court adopted § 51, which states, If two persons have a relationship such that one of them is vicariously responsible for the conduct of the other, and an action is brought by the injured person against one of them, the judgment in the action has the following preclusive effects against the injured person in a subsequent action against the other. (1) A judgment against the injured person that bars him from reasserting his claim against the defendant in the first action extinguishes any claim he has against the other person responsible for the conduct unless: (a) The claim asserted in the second action is based upon grounds that could not have been asserted against the defendant in the first action; or (b) The judgment in the first action was based on a defense that was personal to the defendant in the first action. RESTATEMENT (SECOND) OF JUDGMENTS § 51. In Kimmel, the Kimmel plaintiffs sued Iowa Realty for vicarious liability based on its former employee's fraud, negligence, and breach of fiduciary duty in a real estate transaction. In the Kimmels' earlier suit, an Iowa Realty employee had sued the Kimmels for an unpaid balance. The Kimmels then filed a counterclaim seeking reformation of the contract based on allegations of mutual mistake and fraud. Kimmel, 339 N.W.2d at 378. The lower court issued a final decree ordering reformation. Id. Plaintiffs later initiated a new suit against Iowa Realty alleging vicarious liability on the same claims for its employee's tortious conduct. Id. The court agreed with the defendant, Iowa Realty, that claim preclusion applied for any claims derived from the plaintiffs' prior counterclaim for reformation against Iowa Realty's former real estate agent. Id. at 378-79. However, the court made clear that claim preclusion would not apply if "different rules govern the measure of *1095 damages in the two actions." Id. at 379 (quoting RESTATEMENT (SECOND) OF JUDGMENTS § 51(2)(b)).[12] As long as there is sufficient privity between the parties, Iowa courts have applied Section 51 on several occasions. The court has held that negligence and breach of fiduciary duty claims that were advanced against an estate's trustees in prior litigation, were barred under the doctrine of claim preclusion when the subsequent defendants were found to be in privity. Shivvers v. Hertz Farm Mgmt., Inc., 595 N.W.2d 476, 481(Iowa 1999). In Peppmeier v. Murphy, 708 N.W.2d 57, 64 (Iowa 2005), the court found that a judgment in favor of the defendant doctor barred suit against the clinic for which he worked where the plaintiff asserted liability based on a theory of vicarious liability. The Eighth Circuit also tests for privity before allowing claim preclusion in a vicarious liability claim. See Yankton Sioux Tribe v. United States Dep't of Health and Human Serv., 533 F.3d 634, 641 (8th Cir.2008) (individual's inclusion in a "Tribe [that] understood itself to be acting in a representative capacity for the benefit of its individual members [was] sufficient to establish constructive notice...."); Friez v. First Am. Bank & Trust of Minot, 324 F.3d 580, 583 (8th Cir.2003) ("It is true that the mere relationship of employer and employee sometimes gives rise to a preclusive effect being given to a prior judgment in favor of one or the other."); Black Clawson Comp., Inc. v. Kroenert Corp., 245 F.3d 759, 764 (8th Cir.2001) (with "divergent interests" between the parties asserting claim preclusion, there was "little practical incentive ... [to] provide [other] with virtual representation...."). In the facts before the court, Criterion is asserting vicarious liability against Lockheed based on Brooks' tortious acts related to the claims of Unjust Enrichment (Count II), Misappropriation of Trade Secrets (Count III) and Copyright Infringement (Count V). Lockheed defends based on claim preclusion. The court has already found as a matter of law that Brooks was an independent contractor working for Lockheed. See Section III.B. Because Brooks was not a Lockheed employee, Lockheed cannot be vicariously liable for any tortious acts Brooks committed against Criterion. However, Section 51 applies not only in vicarious liability situations, but also when there is sufficient privity between the parties to merit extending claim preclusion to a non-original suit party. This is especially true in instances where the losses and damages are similar, and "the same or nearly identical issues of fact and law" are present. RESTATEMENT (SECOND) OF JUDGMENTS § 51, cmt. b. Here, the facts demonstrate that there is sufficient similarity between the claims Criterion is alleging against Lockheed and Brooks, similar damages, and only superficial differences between issues of fact and law. Additionally, Lockheed and Brooks are in privity because Criterion's claims against Lockheed are based on tortious acts Brooks committed while working as an independent contractor for Lockheed. All of the facts indicate that Criterion is suing Lockheed as the functional equivalent of Brooks and Criterion "cannot show any good reasons to justify a second chance." 18A CHARLES ALAN WRIGHT ET AL., FED. PRAC. & PROC. JURIS.2D § 4464.1, at 724. Thus, this court grants Lockheed's motion and applies claim preclusion to Counts II, III, and V. *1096 2. Criterion Arguments Against Summary Judgment Although the court finds that there are not genuine issues of material fact based upon privity between Lockheed and Brooks, it is expedient to also address Criterion's counter-arguments against summary judgment on the issue of claim preclusion. For, as discussed above, the court finds that there is sufficient privity between Lockheed and Brooks to merit applying claim preclusion to Counts II, III, and V. Thus, Criterion responds with three arguments as to why claim preclusion would be improper for the remaining elements of claim preclusion. a. Prior Suit not Fully and Fairly Litigated Criterion argues that the issue of Lockheed's liability was not fully litigated during the Polk County case because Criterion was not fully aware of the relationship between Brooks and Lockheed. Claim preclusion operates to prevent additional litigation where "the party against whom preclusion is asserted had a full and fair opportunity to litigate the claim or issue in the first action." Arnevik, 642 N.W.2d at 319 (internal citations omitted). In some cases, "ignorance may temper a strict application of issue or claim preclusion in subsequent litigation." Kimmel, 339 N.W.2d at 379 (citing City of Chariton v. J.C. Blunk Const. Co., 253 Iowa 805, 112 N.W.2d 829, 834 (1962) (city's reliance on insufficient engineer certification did not support defendant's contention that city lacked due diligence and should be barred from counterclaim suit; court made an exception to claim preclusion)). The court thus examines the facts to determine whether Criterion had the opportunity to fully and fairly litigate its claim against Lockheed in the prior suit. Criterion admits that prior to its suit against Brooks, it "knew that Brooks had posted information on SSA's website" but that it did not connect the SSA work to Brooks' "involvement with Lockheed." (Pl.'s Br., dkt. 95-2 at 42.) Criterion claims that it had "no idea about the true nature" of Brooks' involvement with the SSA and Lockheed until her trial testimony. (Pl.'s Br., dkt. 95-2 at 42.) Criterion offers its requests for damages in the original suit to underscore its patent unawareness of Lockheed and Brooks' true relationship. (Pl.'s Br., dkt. 95-2 at 42-44.) Lockheed counters Criterion's asserted ignorance of the Brooks-Lockheed relationship by referring to trial briefs, testimony, and the court's findings.[13] (Def.'s Reply Br., dkt. 112 at 18-20.) Lockheed gleans awareness from Criterion's own statements, such as Brooks' response during discovery that she currently worked for Lockheed (Pl.'s St. of Undisputed Facts, dkt. 95-3 at 4) and the trial transcript in which Brooks discussed her accessibility work with Lockheed and SSA (Pl.'s St. of Undisputed Facts, dkt. 95-3 at 9). Lockheed also cobbles together Criterion's awareness of Brooks' relationship with Lockheed by asserting that Criterion should have connected the abrupt contract terminations with SSA and Lockheed to Brooks: "It's the only two instances where negotiations stopped with real no [sic] explanation. That just doesn't happen." (Def. Appx. at 0044.) Lockheed thus asserts that Criterion had enough indicators *1097 from Brooks that Criterion should have investigated the relationship more fully, either through depositions or other discovery requests. Criterion undisputedly knew that Brooks was working for the SSA; the onus was on Criterion to use litigation tools to discover the extent of Brooks' other projects and employment. The court, while recognizing that ignorance or unawareness may temper some applications of claim preclusion, agrees with Lockheed in the present instance that Criterion did have the opportunity to fully and fairly litigate in the prior suit. b. Claims in Present Suit are Independent to Lockheed Alternatively Criterion asserts that the claims in the present suit are not precluded because the claims are independent to Lockheed. Criterion maintains that the claims against Brooks in the first lawsuit were based on her own wrongful conduct in breaching the restrictive covenants in her Subcontractor's Services Agreement with Criterion, and the damages sought against her were based on her own misconduct. By contrast, the claims against Lockheed are based on its decision to hire Brooks, while still bound by her Criterion restrictive covenant, for the purpose of obtaining Criterion trade secrets and proprietary information. Additionally, Criterion alleges that the claims and damages in the present case derive from Lockheed's sale of Criterion's secrets to SSA, with the subsequent publishing of this sensitive information on the web. Criterion maintains that although there are many similar and common facts between the two cases, the claims against Lockheed are independent to those against Brooks. (Pl.'s Br. in Resistance, dkt. 95-2 at 44.) Lockheed objects to this characterizing of the independent claims, "as each of those claims is based solely on the bad acts of Brooks, with [Lockheed]'s liability alleged to be `vicarious.'" (Def.'s Br., dkt. 81 at 32.) As discussed previously, claim preclusion only operates in the context of the "same" cause of action. Iowa Coal, 555 N.W.2d at 441 (Iowa 1996). Iowa courts use a balancing multi-factor test for determining whether claims are the same for claim preclusion purposes, including whether: (1) the substantive and procedural law is the same; (2) the same right is alleged to be infringed; (3) a judgment in the second action would infringe rights from the first; (4) the same evidence is used in both; or (5) the facts are the same in both actions. Id. at 443. In applying this independent claim test to the present case, the facts indicate that Criterion is not asserting independent claims. The substantive law in both the former and current suit is based on Brooks' breach of her restrictive covenant, thus leading to unjust enrichment, misappropriation of trade secrets, and copyright infringement. It follows that the outcome of Brooks breaching her restrictive covenant led to the same alleged infringed right; namely, Criterion's ability to sell and profit on its product without proprietary information leaks. The parties dispute to the extent Brooks shared Criterion's proprietary information with SSA and Lockheed, although the parties agree that if Brooks did share proprietary information, that she was in breach of her restrictive covenant. Although there may be a reasonable inference that Lockheed's motive in hiring Brooks was to gain Criterion proprietary information indirectlywithout paying Criterion the licensing fees Criterion has failed to bolster this allegation with any evidence that Lockheed's motive was improper. Criterion also fails to demonstrate that a judgment in its favor against Lockheed would not infringe Brooks' rights in the former suit. For *1098 example, the court has already found that Lockheed and Brooks have party privity. If Lockheed were to be held liable in the present suit, it could seek indemnification from Brooks as the active tortfeasorwho was already adeemed not liable. Lastly, much of the same evidence and facts are used in the present suit as in the former suit. Criterion had been aware that Brooks had subverted confidential information and made some information publicly available. Through discovery in the present case, Criterion has uncovered Brooks' assigned project work, additional evidence relating to her employment contract and communication with Lockheed and GCI, as well as control over work product. However, the additional facts Criterion has presented do not establish the existence of an "independent claim." Although the facts do perhaps signal intent on behalf of Lockheed to use Brooks as a cheap source for proprietary Section 508 information, Criterion has not supported this allegation with sufficient evidence. Additionally, Criterion has not managed to factually demonstrate with any certainty, as to how the new alleged damages based on Lockheed's conduct differ materially from the original damages sought.[14] Criterion asserts that Lockheed vicariously benefitted from its use of Brooks and this interference resulted in Criterion's lost contracts with Lockheed and the SSA. Criterion calculates these damages range up to $ 100,000,000 based on the four courses and Lockheed's cost per course for its 60,000 employees. (Def. Appx. at 00223-26.) These are the same damages Criterion asserted against Brooks, with the exception of converting the claim for Brooks' breach of fiduciary duty to a civil conspiracy to breach fiduciary duty (Count VII). Considering that the suit against Brooks called for damages resulting from lost contracts with Lockheed and the SSA, Criterion does not allege any separate bases for damages against Lockheed. Criterion has thus presented no evidence to suggest that Lockheed intentionally accepted proprietary information and trade secrets with its decision to hire Brooks or its use of Brooks on the SSA project. Additionally, the damages, evidence, and facts do not differ materially between the cases. The court therefore agrees with Lockheed that Criterion's claims are not independent from the claims asserted in the prior suit. c. Change of Circumstances Last, Criterion argues that there has been a change of circumstances in the case, requiring that this case should be treated differently than the earlier litigation between Brooks and Criterion. Criterion cites Kimmel and section 24 of the RESTATEMENT (SECOND) OF JUDGMENTS, comment f, for the proposition that "changed circumstances afford a basis for concluding that the second action constitutes a different claim from the first." Kimmel, 339 N.W.2d at 379. The changed circumstances in this case, according to Criterion, include: new information about the relationship among Brooks, Lockheed, and the SSA; Brooks' creation of 10 documents for Lockheed; and the SSA publishing the Section 508 information "to all section 508 coordinators across the country." (Pl.'s Br. in Resistance, dkt. 95-2 at 45.) Lockheed *1099 opposes the characterization of this information as "changed circumstances," because "it is undisputed that Criterion discovered, or at a minimum, should have discovered, during state court litigation all of the circumstances that form of [sic] the basis of its claims in the current suit." (Def.'s Reply Br., dkt. 112 at 18.) As discussed previously, Criterion admits that it was aware that Brooks did work for the SSA and that Brooks may have been the influencing factor behind the abrupt termination of the contract talks with SSA and Lockheed. Criterion knew that Brooks breached her restrictive covenant; there was a corresponding duty to investigate the extent of her contractual violations. For example, Criterion could have subpoenaed Lockheed and SSA in the prior suit if Criterion found Brooks' answers lacked detail. Criterion's counter-claim to Brooks' petition was in July 2006 (Def. Appx. at 0012), the state suit final order was issued in July 2007 (Def. Appx. at 0038), and Criterion did not initiate its suit against Lockheed until September 2007 (Def. Appx. at 0091). Criterion's abrupt suit against Lockheed following its small damage recovery in the Brooks suit does not suggest changed circumstances, but does indicate Criterion sought additional recovery based on vicarious liability. The court finds that there is not a substantial change in circumstances present between the two cases to overcome claim preclusion. 3. Claim Preclusion Conclusion Lockheed contends that Criterion's claims would hold Lockheed vicariously liable for Brooks' actions, and argues that under Iowa law, where claims have resulted in a judgment against an individual, the same plaintiff cannot then bring a claim against another individual or company that is in privity or vicariously liable. Criterion responds that (1) claim preclusion only applies to the same parties, (2) the issues were not fully litigated during the first case, (3) its claims against Lockheed involve different facts and are thus independent to the prior suit, and alternatively, (4) there is a change in circumstances present to warrant not applying claim preclusion. The court rejects Criterion's counter-arguments to the extent that the issues were not fully litigated during the first case, the claims against Lockheed are independent to that of Brooks, and that a change in circumstances could overcome claim preclusion. Criterion has not presented sufficient evidence to support these counter-arguments. Furthermore, the court finds that there are no genuine issues of material fact as to whether Brooks' employment (or privity) with Lockheed would result in vicarious liability for Lockheed. Lockheed can assert party privity and claim preclusion as a shield against Criterion's claims. The court therefore grants summary judgment to Lockheed on Counts II, III, and V based solely upon Lockheed's assertion that the claims are precluded by the prior Polk County suit. D. Failure to Establish a Prima Facie Case on Counts I, II, and VIII Lockheed asserts that the court should grant summary judgment on Criterion's Intentional Interference with a Contract (Count I), Unjust Enrichment (Count II), and Civil Conspiracy to Breach Fiduciary Duties (Count VIII) claims because Criterion has failed to establish prima facie claims. The non-movant may not rest upon mere allegations in its pleading, but must set forth specific facts "showing the existence of a genuine issue for trial." Cemen Tech, Inc. v. Three D Indus., L.L.C., 753 N.W.2d 1, 5 (Iowa 2008). *1100 1. Intentional Interference with a Contract Criterion asserts that Lockheed intentionally interfered with the restrictive covenant agreement between Criterion and Brooks by accepting proprietary information belonging to Criterion. Lockheed disagrees because it was unaware of any contractual provisions that would prevent Brooks from performing the work in question. Under Iowa law, the elements to establish intentional interference with a contract are: (1) the existence of a valid contractual relationship, (2) knowledge of the relationship on the part of the interfering party, (3) intentional and improper interference that induced or caused a breach or termination of the contract, and (4) damages. Revere Transducers, Inc. v. Deere & Co., 595 N.W.2d 751, 763 (Iowa 1999) (internal citations omitted); Kern v. Palmer College of Chiropractic, 757 N.W.2d 651, 657-68 (Iowa 2008). A valid claim for tortious interference with a contract only arises with a valid contract. Bump v. Stewart, Wimer, & Bump, P.C., 336 N.W.2d 731, 737 (Iowa 1983). However, a claim may also be based on a "prospective business relationship that has not yet been reduced to contract." Economy Roofing & Insulating Co. v. Zumaris, 538 N.W.2d 641, 651 (Iowa 1995). Iowa Model Civil Jury Instruction 1200.7 defines a prospective business relationship as a "reasonably likely contract of financial benefit to the plaintiff" or "a reasonably likely business relationship of financial benefit to the plaintiff." Id. (written agreement existed between Economy and Alcoa, such that combination of agreement with other improper actions of interferor resulted in a "scheme to financially harm or destroy Economy's business."). See also RESTATEMENT (SECOND) OF TORTS § 766B cmt. c. The second prong establishes that the interfering party's knowledge does not need to be actual, as "it is sufficient that the defendant had knowledge of facts which, if followed by reasonable inquiry, would have led to the disclosure of the contractual relationship between plaintiff and third parties." Revere Transducers, Inc., 595 N.W.2d at 764. See Iowa Civil Jury Instruction 1200.4 (2004); ACT. Inc. v. Sylvan Learning Systems, Inc., 296 F.3d 657 (8th Cir.2002). The third prong requires conduct that was unfair and unreasonable under the circumstances. Nesler v. Fisher & Comp., Inc., 452 N.W.2d 191, 197 (Iowa 1990). Courts consider a multitude of factors, including: the nature of the conduct, defendant's motive, interests of the party with which the conduct interferes, defendant's interests sought to be advanced, social interests to protect freedom of action and contractual interests of the parties, degree of nearness of defendant's conduct to the interference, and the relations between the parties. Id. See also Rail Intermodal Specialists, Inc. v. Gen. Elec. Capital Corp., 103 F.3d 627 (8th Cir. 1996); Sawheny v. Pioneer Hi-Bred Int'l, Inc., 93 F.3d 1401 (8th Cir.1996). Interfering actions are not wrongful if they are undertaken to advance the defendant's own business interests, Fin. Marketing Serv., Inc. v. Hawkeye Bank & Trust of Des Moines, 588 N.W.2d 450 (Iowa 1999), or when conduct is merely a consequence resulting from "actions taken for a purpose other than to interfere with a contract." Green v. Racing Ass'n of C. Iowa, 713 N.W.2d 234, 244 (Iowa 2006) (citing Berger v. Cas' Feed Store, Inc., 543 N.W.2d 597, 599 (Iowa 1996)). Interference is intentional if done "on purpose or [the defendant] knows the conduct is substantially certain to interfere." Iowa Model Civil Jury Instructions 1200.6 (2004); see also RESTATEMENT (SECOND) OF TORTS *1101 § 766 cmt. j. The plaintiff has a higher burden to prove interference with a prospective business advantage, as the plaintiff must prove "that defendant acted with the purpose of injuring or destroying plaintiff's business; if a business acts for more than one purpose, the improper purpose must predominate to establish liability." EFCO Corp. v. Symons Corp., 219 F.3d 734, 744 (8th Cir.2000); see also Iowa Model Civil Jury Instructions 1200.8 (2004). There is no tortious interference if the alleged tortfeasor's conduct does not cause the contract to be breached. Reihmann v. Foerstner, 375 N.W.2d 677 (Iowa 1985). Lastly, courts will not grant relief unless damages result from the tortious interference. Bump, 336 N.W.2d at 737. Criterion alleges that sufficient facts exist to satisfy the elements for intentional interference with a contract. Criterion points to the Subcontractor's Services Agreement it had with Brooks, which restricted Brooks' ability to work in the Section 508 industry and provided Criterion "rights of title" to all Section 508-related material Brooks produced. (Def. Appx. at 147-50.) Criterion gave Brooks sixty days' notice of termination on May 17, 2005, and alleges that Brooks was aware of the SSA/Lockheed/Criterion negotiations for contracts to produce Section 508 material. (Pl.'s Br. in Resistance, dkt. 95-2 at 56.) Before the termination of the Agreement with Criterion, Brooks entered into a Subcontractor Agreement with GCI on May 23, 2005 (Def. Appx. at 151-59), whereupon she was then retained by Lockheed to perform Section 508 work for the SSA. Criterion relies upon one email from Brooks to Plourd that evidences Brooks' disclosure to Lockheed of her past employment: If you recall, I worked for Criterion 508 Solutions prior to coming to work as a contractor for Lockheed Martin. I told you at that time that this was not a violation of the contract I had with Criterion, since Lockheed wasn't a client of Criterion's, nor was the SSA. This was, and still is, true. (Pl. Appx. at 1.) Lockheed refutes any intentional interference with Brooks' restrictive covenant with Criterion, and states that "the only thing that that emails [sic] evidences is Criterion's assertion that LMS knew, at one time, that Brooks had a contract with Criterion." (Def.'s Reply Br., dkt. 112 at 26) (emphasis in original). In addition, Lockheed asserts that Brooks' misconduct occurred prior to joining Lockheed, it had "no knowledge of any restrictive covenant agreement," GCI had a duty to conduct a background check on Brooks, Brooks had her employment contract with GCI, and that Brooks learned some information about PDF technology through public web sites. (Def. Appx. at 0139.) In sum, Lockheed states that it is "undisputed that LMS had no knowledge of any restrictive covenant agreement or other agreement between Criterion and Brooks that prevented Brooks from working with LMS or the SSA." (Def.'s Reply Br., dkt. 112 at 26.) The court finds that while Lockheed may have had notice from Brooks that Criterion was a former employer, the facts do not support Criterion's contention that Lockheed had knowledge of the contract or intended to interfere with the terms of the restrictive covenant. A party has a duty to make reasonable inquiry, such that an interfering party may have constructive notice of a contract. But in this case, Brooks contracted directly with GCI, GCI referred Brooks to Lockheed, and Criterion has not presented any evidence to demonstrate that Lockheed would have learned of the contractual limitation through a reasonable inquiry or that Lockheed had actual knowledge of the Brooks' *1102 restrictive covenant. Lockheed hired Brooks through GCI; GCI had the duty to investigate Brooks' employment history and any potential conflict of interest limitations. Criterion also fails to establish a prima facie case because there are insufficient facts to support its contention that Lockheed intentionally intended to interfere with Brooks' restrictive covenant. Since there is no proof in the record that Lockheed hired Brooks for an "improper purpose" or intended to induce or cause Brooks to breach her restrictive covenant, the court finds that Criterion fails to establish a prima facie case for Intentional Interference with a Contract. Accordingly, summary judgment is granted for Lockheed on Intentional Interference with a Contract (Count I). 2. Unjust Enrichment Criterion alleges that Lockheed, through Brooks' employment, was unjustly enriched by accepting proprietary information and trade secrets belonging to Criterion. Lockheed disputes Criterion's claim for unjust enrichment and asserts that there is insufficient evidence to establish a prima facie claim. The doctrine of unjust enrichment flows from the principle that, at the expense of another, a party should not be unjustly enriched, receive property, or receive benefits without paying just compensation. Credit Bureau Enters., Inc. v. Pelo, 608 N.W.2d 20, 25 (Iowa 2000). "A third-party claim based on unjust enrichment only requires that a legally cognizable claim exists, not the actual assertion of that claim." State, Dept. of Human Serv. ex rel. Palmer v. Unisys Corp., 637 N.W.2d 142, 152 (Iowa 2001). Unjust enrichment provides restitution for the injured party, based upon the following recovery elements: "(1) defendant was enriched by the receipt of a benefit; (2) the enrichment was at the expense of the plaintiff; and (3) it is unjust to allow the defendant to retain the benefit under the circumstances." Id. at 154-55; see also Iowa Waste Systems, Inc. v. Buchanan County, 617 N.W.2d 23, 29 (Iowa Ct.App.2000). Unjust enrichment is a broad doctrine and includes the conferral of indirect benefits, including "benefits conferred by third parties." Id. at 155. The critical inquiry is that the benefit received be at the expense of the plaintiff. Id. (citing Guldberg v. Greenfield, 259 Iowa 873, 146 N.W.2d 298, 301 (1966)); see also Slade v. M.L.E. Inv. Co., 566 N.W.2d 503, 506 (Iowa 1997) ("A plaintiff seeking recovery under this doctrine must prove the defendant received a benefit that in equity belongs to the plaintiff"). Lockheed avers that it never "appreciated, accepted, and retained the benefit under inequitable circumstances," that GCI technically hired Brooks, and the work product Brooks made was for the SSA, not Lockheed. (Def.'s Br., dkt. 81 at 54.) Criterion argues that Lockheed's "factual and legal analysis [regarding unjust enrichment] ... was unanswered and unanswerable."[15] (Pl.'s Sur Reply, dkt. 121 at 30.) Additionally, Criterion rejects Lockheed's assertion that Brooks did not confer a benefit on Lockheed because the projects were for the SSA. (Pl.'s Br. in Resistance, dkt. 95-2 at 59-60.) Neither side disputes that Brooks' work for the SSA resulted in more than $300,000 in revenue; but Criterion insists that "[t]he *1103 work product contained Criterion's trade secrets and proprietary information such that Lockheed's sale of the information for a profit came at Criterion's expense." (Pl.'s Br. in Resistance, dkt. 95-2 at 60.) On balance, the court rejects Lockheed's argument that if Brooks made work product for the SSA's benefit, then Lockheed was not unjustly enriched. This argument ignores the more than $300,000 the SSA paid Lockheed for Brooks' work product. If this argument were to prevail, then the simple tactic of hiring independent contractors could bar plaintiffs from justifiably seeking restitution for unjust enrichment. Additionally, case law is clear that the broad doctrine of unjust enrichment captures indirect benefits from third parties. Furthermore, the prior state suit established that the majority of Brooks' knowledge of Section 508 and PDF conversion did come from Criterion's proprietary information. There are sufficient genuine issues of material fact present regarding the extent of unjust enrichment, such that it is a matter better suited for a jury. Accordingly, the court denies summary judgment to Lockheed on Unjust Enrichment (Count II). 3. Civil Conspiracy to Breach Fiduciary Duties Criterion advances that Lockheed knew Brooks owed fiduciary duties to Criterion and acted in concert with Brooks in her breaching of duties, the purpose of which was to establish Lockheed's ability to compete directly with Criterion. Lockheed denies that there was ever any agreement or conspiracy between Brooks and itself to encourage Brooks to breach her fiduciary duties to Criterion. To establish a civil conspiracy under Iowa law, two or more persons must act together "to accomplish an unlawful purpose, or to accomplish by unlawful means some purpose not in itself unlawful." Wright v. Brooke Group, Ltd., 652 N.W.2d 159, 171 (Iowa 2002) (quoting Basic Chems., Inc. v. Benson, 251 N.W.2d 220, 232 (Iowa 1977)); accord Brown v. Kerkhoff, 504 F.Supp.2d 464, 525 (S.D.Iowa 2007). An agreement "must exist between the two persons to commit a wrong against another." Ezzone v. Riccardi, 525 N.W.2d 388, 398 (Iowa 1994). Agreement is defined by the Iowa Model Civil Jury Instructions as: ... The agreement can be oral or written, informal or formal, and need not be detailed. The agreement need not be expressed in words and may be implied and understood to exist from the conduct itself. It may be proved by direct or circumstantial evidence. Merely because two or more persons associate with each other, or meet to discuss common interests or goals does not, by itself, establish a conspiracy. Iowa Model Civil Jury Instructions 3500.2 (2004). Correspondingly, a conspiracy only arises when there is voluntary and knowing participation in a "common scheme." Wright, 652 N.W.2d at 174. By contrast, mere "[s]peculation, relationship, or association and companionship do not establish a conspiracy." Ezzone, 525 N.W.2d at 398. For example, the Eighth Circuit held in PFS Distrib. Co. v. Raduechel, that defendants "did not possess the requisite knowledge to enter into a conspiracy." 574 F.3d 580, 593 (8th Cir.2009). In PFS, PFS Distrib. Co. alleged that a bank and bank's vice president participated in a civil conspiracy scheme with Defendants Raduechel and Spain to breach fiduciary duties and misappropriate trade secrets. Id. In PFS, a bank extended loans to employees of PFS to fund the operation of a new competing business, with the employees subsequently breaching their fiduciary duties to PFS and misappropriating trade secrets. Id. Based on *1104 expert testimony stating that the "loan application would not trigger concern over the confidentiality of the information," the court held that the bank's vice president was not aware of any employment contracts, did not knowingly conspire with Raduechel and Spain, and the court thus denied a conspiracy claim against the bank and its vice president. Id. The conspiracy itself does not give rise to the claim; rather, it is the underlying wrongful acts. Basic Chems., 251 N.W.2d at 233. Civil conspiracy is merely a method to impose vicarious liability on a party for the wrongful conduct of another with whom the party has acted in concert. Wright, 652 N.W.2d at 172. Iowa law extends the wrongful conduct beyond intentional torts and requires that the conduct taken by a co-conspirator must only be actionable in the absence of a conspiracy. Id. at 174 (in a negligence suit, "plaintiff may base a claim of civil conspiracy on wrongful conduct that does not constitute an intentional tort."). If the plaintiff does not present sufficient evidence generating genuine issues of material fact for the underlying wrongful conduct, then the civil conspiracy claim also fails. Doe v. Baxter Healthcare Corp., 380 F.3d 399, 410 (8th Cir.2004); accord Jensen v. Barlas, 438 F.Supp.2d 988, 1004-05 (N.D.Iowa 2006). In terms of the underlying claim, Criterion claims that Brooks breached her fiduciary duties when she shared proprietary information with Lockheed. According to Iowa law, a fiduciary duty is when, "[a] fiduciary relationship exists between two persons when one of them is under a duty to act for or to give advice for the benefit of another upon matters within the scope of the relationship." Kurth v. Van Horn, 380 N.W.2d 693, 695 (Iowa 1986) (citing RESTATEMENT (SECOND) OF TORTS § 874 cmt. a (1979)). According to Kurth, A fiduciary relationship imparts a position of peculiar confidence placed by one individual in another. A fiduciary is a person with a duty to act primarily for the benefit of another. A fiduciary is in a position to have and exercise, and does have and exercise influence over another. A fiduciary relationship implies a condition of superiority of one of the parties over the other. Generally, in a fiduciary relationship, the property, interest or authority of the other is placed in the charge of the fiduciary. 380 N.W.2d at 698 (internal citations omitted) (emphasis in original). A fiduciary relationship may also arise "whenever confidence is reposed on one side, and domination and influence result on the other... Such [a] relationship exists when there is a reposing of faith, confidence and trust, and the placing of reliance by one upon the judgment and advice of the other." Economy Roofing & Insulating Co. v. Zumaris, 538 N.W.2d 641, 647-48 (Iowa 1995). Additionally, there may be some instances where a lack of inequality suggests "no compelling evidence" of a fiduciary relationship. Employers Mut. Casualty Co. v. Collins & Aikman Floorcoverings, Inc., 422 F.3d 776, 782 (8th Cir.2005) ("two large, sophisticated business entities" indicated a lack of influence or domination between them). Additionally, even if there is a fiduciary relationship, to prevail on a breach of fiduciary duty claim, the plaintiff must prove duty, breach, causation, and damages. Lyons v. Midwest Glazing, 265 F.Supp.2d 1061, 1076 (N.D.Iowa 2003) (citing RESTATEMENT (SECOND) OF TORTS § 874). Lockheed asserts that the Civil Conspiracy to Breach Fiduciary Duties claim must fail because there was never an agreement or intent to enter into a conspiracy. "There is absolutely no evidence of any agreement between LMS and Brooks to breach Brooks' fiduciary duties." *1105 (Def.'s Br., dkt. 81 at 55.) Furthermore, Brooks testified in her deposition that Lockheed never asked her to "commit a wrongful act," "to breach a noncompete agreement," "to use trade secret information," "to use any copyrighted information," or "to improperly claim rights of authorship in materials so that [she] could defraud the SSA." (Def.'s Br., dkt. 81 at 55-56.) Criterion disputes Lockheed's claim that it lacked knowledge of the restrictive covenant because of the email between Brooks and Plourd, and that "[r]easonable inquiry into the contents of the contract would have revealed the restrictive covenant." (Pl.'s Sur Reply, dkt. 121 at 31.) According to Criterion, other circumstantial evidence suggesting an "agreement" or conspiracy between Brooks and Lockheed includes: Brooks' prior experience with Criterion, Lockheed's sale of Criterion's Section 508 proprietary information to the SSA, and the SSA's subsequent publishing of Brooks' work. (Pl.'s Sur Reply, dkt. 121 at 32.) Criterion thus asserts that the underlying claim of breach of fiduciary duty is met because Brooks violated her fiduciary duty when she "produced at least 10 Section 5081[sic] accessibility projects for Lockheed." (Pl.'s St. of Undisputed Mat. Facts, dkt. 95-3 at 12.) Furthermore, Criterion alleges Lockheed conspired with Brooks to breach her fiduciary duties when it hired Brooks, "for the purpose of obtaining Criterion's trade secrets and proprietary information without having to pay Criterion for it." (Pl.'s St. of Undisputed Mat. Facts, dkt. 95-3 at 13.) Viewed in the light most favorable to Criterion, the court finds that there is insufficient factual support to establish a civil conspiracy to breach fiduciary duties. It is undisputed that Brooks violated her restrictive covenant with her Lockheed and SSA work, but there is insufficient evidence to support Criterion's contention that Lockheed conspired with Brooks to gain Criterion's proprietary information. The court finds that there is insufficient evidence of an agreement, voluntary participation, or intent to enter into a civil conspiracy. Lockheed hired Brooks through GCI, and Criterion itself points out that GCI contracted to conduct a "Standard Background Investigation" and "represents and warrants that the information in all credentials relating to Contract Labor Employees that are furnished to Lockheed Martin ... have been verified as complete and accurate...." (Pl.'s St. of Undisputed Mat. Facts, dkt. 95-3 at 12.) Thus, Lockheed would have lacked the requisite knowledge or intent to enter into a conspiracy if GCI "vetted" all the candidates before referring them onto Lockheed. Criterion cannot rely on "[s]peculation, relationship, or association and companionship [to] establish a conspiracy." Ezzone, 525 N.W.2d at 398. Accordingly, the court grants summary judgment to Lockheed on the Civil Conspiracy to Breach Fiduciary Duties (Count VIII) claim. E. Copyright Infringement Claim Lockheed also argues that Criterion's Copyright Infringement (Count V) claim cannot be maintained because the copyrights have not been registered and the Intentional Interference with a Contract (Count I) and Unjust Enrichment (Count II) claims cannot succeed because federal copyright law preempts any state contract claims related to copyrights. Criterion concedes that although it has not met the requirements for copyright registration, non-statutory damages are available as a remedy. Criterion also claims that the Copyright Act only preempts state law rights that abridge or infringe an exclusive right provided by the federal act. *1106 1. Copyright Registration Lockheed avers that Criterion "cannot maintain a civil action for money damages for copyright infringement when it has not registered for copyright protection." (Def.'s Br., dkt. 81 at 44.) The Copyright Act provides that no civil action for copyright infringement can be maintained until registration of the copyright claim has been made: (a) Except for an action brought for a violation of the rights of the author under section 106A(a), and subject to the provisions of subsection (b), no civil action for infringement of the copyright in any United States work shall be instituted until preregistration or registration of the copyright claim has been made in accordance with this title. 17 U.S.C. § 411 (emphasis added). Congress alone has the task and burden of defining the "scope of the limited monopoly that should be granted to authors...." Sony Corp. v. Universal City Studios, Inc., 464 U.S. 417, 429, 104 S.Ct. 774, 78 L.Ed.2d 574 (1984). "The case law is clear that copyright registration is a jurisdictional prerequisite to an infringement action under section 411." TMT Mfg., Inc. v. Illowa Resource Develop., Inc., 2008 WL 4911850 (S.D.Iowa 2008). See Action Tapes, Inc. v. Mattson, 462 F.3d 1010, 1013-14 (8th Cir.1006) ("[T]he copyright owner may not sue for infringement under the federal Copyright Act until the owner has delivered the deposit, application, and fee required for registration to the United States Copyright Office ...") (internal citations omitted); Sun Media Systems, Inc. v. KDSM, L.L.C., 564 F.Supp.2d 946, 975 (S.D.Iowa 2008) (registration of a copyright is a jurisdictional prerequisite to an infringement action). While registration is a prerequisite for bringing a copyright infringement suit, in some instances, "registration of a copyright is permissive" and whether or not a party can sue for infringement of unregistered materials depends on the type of damages sought. Walker Mfg., Inc. v. Hoffmann, Inc., 220 F.Supp.2d 1024, 1039 (N.D.Iowa 2002) (citing Olan Mills, Inc. v. Linn Photo Co., 23 F.3d 1345 (8th Cir.1994)). In all instances, if a party is seeking statutory damages, then registration is required. Id. However, a party seeking injunctive relief or actual damages is not required to register a copyright before filing suit for copyright infringement. 220 F.Supp.2d at 1039-41 (citing Olan Mills, 23 F.3d at 1349). Injunctive relief and actual damages remain available to the infringed party, even without copyright registration. Id. at 1041. Despite its failure to register the copyrights, Criterion asserts that it should recover actual damages from Lockheed based on copyright infringement. (Pl.'s Amended Complaint, dkt. 17 at 5.) Lockheed's argument against Criterion's ability to recover actual damages is that the law does not support recovery of actual damages. (Def.'s Br., dkt. 81 at 44.) Much of the facts the court has already discussed suggest there are genuine disputed issues between the parties as to Brooks' creative process and alleged use of Criterion's proprietary information. Without direct evidence of copying, to establish a claim of infringement, the plaintiff must prove that: (1) defendants had access to the copyrighted material; and (2) that there is a substantial similarity between the works. Hartman v. Hallmark Cards, Inc., 833 F.2d 117, 120 (8th Cir.1987). The parties dispute the number of projects Brooks made for the SSA, Brooks' basis of knowledge, and how similar the projects Brooks created for the SSA were to her work at Criterion. The court thus finds a genuine issue of material fact exists as to whether, and to what extent, Criterion has sustained *1107 actual damages from Lockheed's alleged infringement of the Section 508 materials. Accordingly, the court denies Lockheed's motion for summary judgment on the Copyright Infringement (Count V) claim. 2. Intentional Interference with a Contract Claim Preempted by Copyright Statute Lockheed contends that Criterion's claims for Intentional Interference with Contract (Count I) and Unjust Enrichment (Count II) are preempted by the Copyright Act. Federal law preempts state law claims that fall within the subject matter of and are based upon rights protected under the Copyright Act. 17 U.S.C. § 301(a). Section 301(a) provides: (a) On and after January 1, 1978, all legal or equitable rights that are equivalent to any of the exclusive rights within the general scope of copyright as specified by section 106 in works of authorship that are fixed in a tangible medium of expression and come within the subject matter of copyright as specified by sections 102 and 103, whether created before or after that date and whether published or unpublished, are governed exclusively by this title. Thereafter, no person is entitled to any such right or equivalent right in any work under the common law or statutes of any State. 17 U.S.C. § 301(a) (2008). The Eighth Circuit's interpretation of copyright preemption is that "[a] state cause of action is preempted if: (1) the work at issue is within the subject matter of copyright as defined in §§ 102 and 103 of the Copyright Act, and (2) the state law created right is equivalent to any of the exclusive rights within the general scope of copyright as specified in § 106." Nat'l Car Rental Sys., Inc. v. Computer Assocs. Int'l, Inc., 991 F.2d 426, 428 (8th Cir.1993), cert. denied, 510 U.S. 861, 114 S.Ct. 176, 126 L.Ed.2d 136 (1993) (internal citations omitted). Exclusive rights under Section 106 include the right to: (1) reproduce a copyrighted work; (2) prepare derivative works; and (3) distribute copies of the copyrighted work to the public. The Copyright Act only preempts state law rights that "may be abridged by [a state law] which, in and of itself, would infringe one of the exclusive rights provided by federal copyright law." Nat'l Car Rental, 991 F.2d at 431. See Cipollone v. Liggett Group, Inc., 505 U.S. 504, 524 n. 22, 112 S.Ct. 2608, 120 L.Ed.2d 407 (1992) (Congress has the ability to preempt "particular common-law claims, while saving others."). For example, the Copyright Act has expressly preempted common law misappropriation. Hallmark Cards, Inc., 833 F.2d at 121. Thus, the Copyright Act does not preempt state law claims if the state law protects rights that are "different in kind" from those protected under federal law. BVS Performance Systems, Inc. v. Mercantile Bancorp., Inc., 2000 WL 34031502, at *1 (N.D.Iowa 2000). To determine if the state law rights are "different in kind," the Eighth Circuit has developed the "extra element" test. According to the extra element test, "if an extra element is required, instead of or in addition to the acts of reproduction, performance, distribution or display, in order to constitute a state-created cause of action, then the right does not lie within the general scope of copyright and there is no preemption." Nat'l Car Rental, 991 F.2d at 431 (internal quotations omitted). In BVS Performance Systems, the court held that a failure to pay for duplicated copyrighted material was sufficient as an "extra element" and "shelter[ed] the state law claim from preemption." 2000 WL 34031502, at *3. The court disagreed with the infringer that remuneration was a necessary element to copyright infringement; instead, the failure to pay under the contract *1108 was "qualitatively different from [the] copyright infringement claim." Id. at *4. Furthermore, the National Car Rental System court held that an unjust enrichment claim can survive if it is an "allegation of damage as a further explanation of the damages [the plaintiff] intends to prove arising from the breach of contract." 991 F.2d at 434-35. Because the court has already found Criterion has failed to establish a genuine issue of material fact for Count I, the court need not address Lockheed's argument that Count I is preempted by the Copyright Act. Applying the "extra element" test to the facts in the Unjust Enrichment (Count II) claim leads to a different result. Although Lockheed points to other jurisdictions and persuasive authority supporting the preemption of an unjust enrichment claim (Def.'s Br., dkt. 81 at 48-49), this jurisdiction has held otherwise. National Car Rental System, 991 F.2d at 434-35. Criterion attempts to meet the extra element test by asserting that the unjust enrichment claim falls outside the Section 106 preemptions of reproduction, distribution, or display. The extra element consists of Lockheed's hiring of Brooks, "as opposed to contracting with Criterion for its trade secret information." (Pl.'s Br. in Resistance, dkt. 95-2 at 56.) Criterion's posturing of the unjust enrichment claim mirrors National Car Rental System, at least in terms of explaining the damages; especially because the claim is not merely about improper Section 106 activities, but is based on unjust enrichment through Lockheed's contractual relationship with Brooks. The question as to whether and to how much Lockheed was unjustly enriched by Brooks' copyright infringement is a genuine issue of material fact. The court finds that Criterion's claim for Unjust Enrichment (Count II) does satisfy the extra element test. Accordingly, the court denies Lockheed's motion for summary judgment on the Unjust Enrichment (Count II) claim. Upon the foregoing, IT IS ORDERED Defendant Lockheed's Motion for Summary Judgment (Dkt. No. 78) on Counts One, Three, and Eight is GRANTED. Defendant Lockheed's Motion for Summary Judgment (Dkt. No. 78) on Counts Two and Five is GRANTED IN PART and DENIED IN PART. NOTES [1] These facts are either undisputed or if disputed in good faith, taken in the light most favorable to Criterion. [2] Lockheed Martin Services is a Lockheed Martin Company. (Def. Appx. at 00160.) [3] The facts are not clear as to the order of Brooks' hiring process; namely, whether Brooks was interviewed by Plourd before or after she signed the Subcontractor Agreement with GCI. [4] The Agreement states: The parties to this Agreement agree that the relationship created by this Agreement is that of broker-independent contractor. Contractor agrees and has advised its personnel that Contractor and its personnel are not employee(s) of Global Commerce & Information, Inc. or the Client and are not entitled to (and also hereby waive) any benefits provided or rights guaranteed by Global Commerce & Information, Inc. or the Client, or by operation of law, to their respective employees.... (Def. Appx. at 153.) [5] The Honorable Artis J. Reis, District Judge, Fifth Judicial District of Iowa. [6] "According to [Criterion], Lockheed Martin became a client of Criterion 508 Solutions on or about July 25, 2006, when Lockheed Martin purchased one eLearning course. Angy Brooks did not perform services for Lockheed Martin which had been provided to Lockheed Martin by her as a subcontractor while working for Criterion 508 Services." (Def. Appx. at 30.) [7] The Court notes that Kathy Plourd's email address, a Lockheed employee, was kathleen. [email protected]. (Pl. Appx. at 9.) [8] Brooks' email address was angy.brooks@ ssa.gov. (Pl.Appx. at 61.) [9] Nonmutual claim preclusion is most attractive in cases that seem to reflect no more than a last desperate effort by a plaintiff who is pursuing a thin claim against defendants who were omitted from the first action because they were less directly involved than the original defendants.... [Parties should apply] claim preclusion only if the new party can show good reasons why he should have been joined in the first action and the old party cannot show any good reasons to justify a second chance. 18A CHARLES ALAN WRIGHT ET AL., FED. PRAC. & PROC. JURIS.2D § 4464.1, at 724. Many circuits have actively applied and extended claim preclusion in the context of vicarious liability or parties in privity. See Russell v. SunAmerica Securities, Inc., 962 F.2d 1169, 1172-76 (5th Cir.1992) (close relationship between successive corporations established privity to apply claim preclusion); Lubrizol Corp. v. Exxon Corp., 929 F.2d 960, 966 (3d Cir.1991) ("We note that a lesser degree of privity is required for a new defendant to benefit from claim preclusion than for a plaintiff to bind a new defendant in a later action."); Platsis v. E.F. Hutton & Co., 946 F.2d 38, 42-43 (6th Cir. 1991) (claim preclusion when plaintiff first sued employer, lost, then sued employee); Citibank, N.A. v. Data Lease Fin. Corp., 904 F.2d 1498, 1502-03 (11th Cir.1990) (plaintiff's settlement precluded claim against person vicariously responsible). [10] Gulf Island-IV, Inc. v. Blue Streak-Gulf Is Ops., 24 F.3d 743, 746-47 (5th Cir.1994), cert. denied, 513 U.S. 1155, 115 S.Ct. 1112, 130 L.Ed.2d 1076 (1995) (defendant could not assert claim preclusion because he was not a party in the earlier action and lacked privity); Shaw v. Cal. Dept. of Alcoholic Beverage Control, 788 F.2d 600, 606 (9th Cir.1986) (California law did not allow parties who were not in privity to assert claim preclusion); Harrington v. Vandalia-Butler Bd. of Educ., 649 F.2d 434, 437 (6th Cir.1981) (defendant parties not in original litigation could assert claim preclusion only if they were in privity with the defendant). [11] relationships between persons result in one of them being vicariously liable for the conduct of another, the primary obligor. Among these relationships are that of master and servant, wherein the master is liable for certain wrongs committed by the servant in the course of his employment; ... principal contractor and sub-contractor to the extent the former is responsible for the conduct of the latter; co-obligors.... RESTATEMENT (SECOND) OF JUDGMENTS § 51 cmt. a. Section 51 prevents inapposite outcomes, such as a vicariously liable party seeking indemnity from the primary obligor, who was already deemed not liable for conduct. Without the § 51 claim preclusion effects, "the primary obligor would have to pay indirectly an obligation from which he had been directly exonerated." Id. at cmt. b. [12] For example, P may be precluded from seeking punitive damages from A, but not from B. In this case, P Section 51(2)(b) would apply and P could seek punitive damages only as against B. RESTATEMENT (SECOND) OF JUDGMENTS § 51(2)(b) cmt. d. [13] In his findings, Judge Artis Reis also noted that, "Plaintiff would have opportunity to help Lockheed Martin, and others, pirate Criterion 508 Solutions' ideas, products, customers, and good will." (Def. Appx. at 8.) Also, "[t]he documents posted on SSA's website explained Criterion 508 Solutions' specialized, technical, and unique process for making documents ... [Brooks] breached the contract when she chose to post this confidential and proprietary information on the internet." (Def. Appx. at 5-6.) [14] For example, in Criterion's prior suit against Brooks, the court held that, "There was unrebutted testimony the average contract engaged by Criterion was $25,000. However, any loss of contracts due to these violations is speculation and not supported by the evidence." (Def. Appx. at 0022.) Additionally, "[w]ithout proving actual damages, the defendant cannot enforce the liquidated damages clause of the covenant not to compete." (Def. Appx. at 0033.) [15] Criterion is correct in its assertion (Pl.'s Sur Reply, dkt. 121 at 30) that Lockheed did not address Count II in its Reply Brief. (Def.'s Reply Br., dkt. 112.) However, Lockheed did dispute the adequacy of Criterion's unjust enrichment claim in its Summary Judgment Brief. (Def.'s Br., dkt. 81 at 53.) | Low | [
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Callahan, a native/resident of Franklin, Mass., watched the draft while attending the wedding of one of his cousins in Lake Placid, N.Y. His hope of being drafted by Arizona became reality when the Coyotes snatched the young defenseman with the 142nd overall pick. GLENDALE -- Michael Callahan felt a good vibe as he left his interview with the Coyotes at the NHL Scouting Combine in Buffalo a few weeks before the NHL Draft. "I was really excited," Callahan said. "I interviewed with Arizona at the Combine and I thought it went really, really well. I felt the Coyotes were one of the teams that liked me a lot as a person, so when I heard they were the ones who chose me I was overjoyed." Arizona scouts noticed Callahan playing for the Youngstown Phantoms of the USHL while also scouting goalie Ivan Prosvetov, whom the Coyotes selected 28 picks before Callahan. The two draftees not only were teammates in Youngstown, but lived together with the same billet family, and both played key roles during Youngstown's playoff run that ended in the Clark Cup Finals. "It's been a dream of mine for a long time to be where I'm at now," said Callahan, who notched three goals and 15 assists in 59 USHL games last season and was named to the USHL's All-Rookie Team. "It's been an awesome journey so far." The Coyotes like Callahan's hockey IQ and his skating ability. They also like the way he plays defense first. "He's a steady, smart defenseman," said Coyotes Director of Amateur Scouting Tim Bernhardt. "There's nothing flashy about this guy; he's not running up the ice all the time. He's just a 6-foot-2, steady defenseman that moves pucks and jumps in at the opportune times. The more you watched him, you kept walking away going 'You know, this guy's a real solid contributor.'" Callahan comes from an athletic family and credits being a multi-sport athlete for helping him become an NHL draft pick. He played football while in middle school. He also played baseball and lacrosse until committing to hockey full-time as a junior in high school. He's set to continue his hockey career at Providence College, which has reached the NCAA playoffs five years in a row. The Friars won the national title in 2015. "I obviously need to work on everything," Callahan said. "Getting to play in the NHL, I'm not at that point yet. Even though my skating is one of my strengths, I've got to get faster. And even though I'm definitely a physical player now, I know I need to become even harder to play against." Callahan recently attended the Coyotes Prospect Development Camp along with his pal Prosvetov, and the other seven players the team drafted in Dallas last month. It was his first visit to Arizona. "The camp is an awesome experience," Callahan said. "I didn't know what to expect going into it, but it was incredible being able to get on the ice with the coaches and also getting into the weight room with the strength and conditioning staff. I also liked going out into the community. It was all a great way to get a feel for what the Arizona Coyotes are all about." | Mid | [
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Complete Guide to Mail Merge Personalization in Gmail [UPDATED 2018] GMass offers a number of ways to personalize the Subject and Message of your mail merge campaigns sent with Gmail. From basic mail-merge style personalization to fallback values and automatic-first-name detection, this guide takes you through all of the options. Simple Personalization At the most basic level, you can use {FirstName} and {LastName} to personalize emails if you’re sending to email addresses that are your existing Gmail Contacts, meaning people with whom you’ve had prior email conversations. Your Gmail Contacts contain names along with email addresses. If you’re connecting to a Google Sheets spreadsheet, then you can use any column from the spreadsheet to personalize, like {Company}, {LastPurchase}, or {DateOfBirth} for example, assuming that your spreadsheet contains the columns Company, LastPurchase, and DateOfBirth. You can use these simple personalization variables in the Subject and Message. GMass gives you one-click buttons in the Settings panel to insert personalization variables.Note that the buttons will only insert the personalization variables into the Message, but you can copy/paste them into the Subject too. Fallback Values If you know that your personalization variables will have a value for some email addresses but won’t for others, you can set a fallback value to be used when the personalization value is blank. For example, you could use {FirstName|Friend} in your message. If a “FirstName” is available, it will be substituted; otherwise “Friend” will be substituted. You can use the fallback value syntax, a pipe symbol, followed by the fallback value, with any personalization variable. Google Sheets vs No Google Sheets If you’re connecting to a Google Sheets spreadsheet, then you’ll get separate personalization buttons in the GMass Settings Box, one button corresponding to each column in your spreadsheet. If you are not connecting to a spreadsheet, then you’ll just get the standard FirstName, LastName, EmailAddress personalization buttons, where the values correspond to the email addresses and names of your Gmail Contacts. Multi-word Names Sometimes the names associated with your Gmail Contacts have not just two words, but three or four words. This is especially common in East Asian cultures. Therefore, in addition to FirstName and LastName, which will use the first word of the name and the last word of the name, you can instead use the syntax {Name1}, {Name2}, {Name3}, and {Name4}. Name1 corresponds to the first word in the name, Name2 to the second word, and so on. For example, if you are sending to a Gmail Contact that looks like: <[email protected]> “Loh Kin Poh” Asian convention dictates that you address someone by all three words of the name, so in this case you would use: Combining techniques You can use personalization values along with auto first name detection and fallback values. For example, let’s say you’re using a spreadsheet with these columns: FirstNameLastNameEmail Some of the FirstName values are blank. So for those, you want GMass to auto detect the first name. And in cases where GMass cannot auto detect the first name, you want to use “old friend”. In that case, the syntax would look like: Hi {FirstName|auto-first|old friend}: The personalization tokens are tried in order they are placed inside the curly brackets. Fallback values should be separated by the pipe symbol ( | ). Advanced Personalization Techniques Testing Personalization It’s easy to make sure your personalization is working before you send your email to all of your recipients. You can use the Send Test Email button to send a test email to yourself or anyone else. Then just check your Inbox, or your Sent Mail Folder, to make sure the test email looked the way you expect. You can also choose to create Drafts first instead of sending the mass email. That allows you to spot check all of Drafts, one for each recipient, and then if the personalization in the Drafts looks the way you expect, you can click a link to send all the Drafts. First you have to bang on Messenger on the left hand edge of the computer display and add the individual you desire to drive a note to as a contact. Then that individual obtains a notification that you supplemented them as a ally, and can reply to the invitation.click here I have been using G mail for years now and been emailing the same 60 buddies almost daily during these years. Now as of yesterday all my outgoing emails are bouncing back blocked with this message: Message rejected. See https://support.google.com/mail/answer/69585 for more information. After reading all I could about this problem I found myself here. Is this GMASS program what I need to go to? Unfortunately, no. You would need to add the entire sentence in the country column instead. You can do a “Concatenate” formula in Google sheets to combine the sentence and the country then use the results (sentence with the country) as the merge field. | Mid | [
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He designed and built a short-range missile during Iraq's four-year hiatus from United Nations arms inspections. Inspectors who returned in late 2002, enforcing Security Council limits, ruled that the al-Samoud missile's range was not short enough. The UN team crushed the missiles, bulldozed them into a pit and entombed the wreckage in concrete. "It was as if they were killing my sons," Tamimi said. But Tamimi, 47, had other brainchildren, and these stayed secret. Concealed away from his Karama Co. factory in Baghdad were concept drawings and computations for a family of much more capable missiles, designed to share parts and features with the declared al-Samoud. The largest was meant to fly six times farther. "This was hidden during the UNMOVIC visits," Tamimi said, referring to inspectors from the UN Monitoring, Verification and Inspection Commission. "It was forbidden for us to reveal this information." Tamimi's covert work, which he recounted publicly for the first time in five hours of interviews last month, offers fresh perspective on the question that led the United States, Britain and Australia to war. Iraq flouted a legal duty to report the designs. The weapons they depicted, however, did not exist. After years of development - against significant obstacles - they might have taken form as nine-tonne missiles. In March they fitted in Tamimi's pocket, on two digital compact discs. The nine-month record of arms investigators since the fall of Baghdad includes discoveries of other concealed arms research, mostly less advanced. Iraq's former government engaged in abundant deception about its ambitions and, in some cases, early steps towards development or production. Interviews with Iraqi weaponeers and US and British investigators turned up unreported records, facilities and materials that could have been used in unlawful weapons. But investigators have found no support for the two main fears expressed in Washington and London before the war: that Iraq had a hidden arsenal of old weapons and had built advanced programs for new ones. In public statements and unauthorised interviews, investigators said they had discovered no work on old germ war agents such as anthrax and no work on a new pathogen - combining pox virus and snake venom - that led US scientists on a highly classified hunt for several months. The investigators assess that Iraq did not, as claimed in Washington and London, resume production of its most lethal nerve agent, VX, or learn to make it last longer in storage. And they have found the former nuclear weapons program - described as a "grave and gathering danger" by President George Bush and a "mortal threat" by Vice-President Dick Cheney - in much the same shattered state as UN inspectors left it in the 1990s. A review of evidence, including some not known to coalition investigators and some not made public, portrays a nonconventional arms establishment less capable than US analysts judged before the war. Leading figures in Iraqi science and industry, supported by observations on the ground, described factories and institutes thoroughly beaten down by 12 years of conflict, arms embargo and economic sanctions. The remnants of Iraq's biological, chemical and missile infrastructures were riven by internal strife, bled by schemes for personal gain and handicapped by deceit along lines of command. The broad picture emerging from the investigation to date suggests that, whatever its desire, Iraq did not possess the wherewithal to build a forbidden armoury on anything like the scale it had before the 1991 Gulf War. David Kay, who directs the weapons hunt on behalf of the Bush Administration, reported no discoveries last year of finished weapons, bulk agents or ready-to-start production lines. Members of his Iraq Survey Group, in unauthorised interviews, said the group held out little prospect of such a find. Some researchers at Baghdad University's College of Science - such as immunologist Alice Krikor Melconian, the chairwoman of the biotechnology department - and other elite institutions remain under scrutiny in part because investigators deem them capable of doing dangerous biological research. Investigators said they were casting a wide net at Iraq's "centres of scientific excellence". Kay's Iraq Survey Group, which has numbered up to 1400 personnel from the Defence Department, US laboratories and intelligence agencies, is looking for biological weapons far more dangerous than those of Iraq's former arsenal. A US National Intelligence Estimate, published October 2002, said "chances are even" that Iraqi weaponeers were working with smallpox, one of history's mass killers. A scientific assessment panel known as Team Pox returned home in July without finding reason to believe Iraq possessed the variola virus, which causes smallpox. Even so, interviews with Iraqi scientists led to a redoubled search for work on animal poxes, harmless to humans but potentially useful as substitutes for smallpox in weapons research. According to an informed account of the debriefing of Rihab Taha, a British-educated biologist known in the west as Dr Germ, she acknowledged receiving an order in 1990 to develop a biological weapon based on a virus. That same year, virologist Hazem Ali began research on camelpox. There is no corresponding record, however, that Iraq had the capability or made the effort to carry out such an intent. Taha, according to the same debriefing account, said Iraq had no access to smallpox. Ali's research halted after 45 days, with the August 1990 outbreak of war in Kuwait, and did not resume. And Taha, like all those in custody, continues to assert that biowar programs ceased entirely the following year. Late last month, fresh evidence emerged on an old question about Iraq's illegal arms: Did the Baghdad government, as it said, rid itself of all the biological arms it produced before 1991? The new evidence appears to be an Iraqi government record of a pivotal moment in Baghdad's long struggle to shield arms programs from outside scrutiny. Written just after the defection of Saddam Hussein's son-in-law in 1995, the document anticipates the collapse of cover stories for undisclosed weapons. The defection of Hussein Kamel, who controlled Baghdad's Military Industrial Commission, was a turning point in the UN-imposed disarmament of Iraq in the 1990s. He told his Western debriefers about major programs in biological and nuclear weaponry that had gone undetected or unconfirmed. Iraq was forced to acknowledge what he exposed. A handwritten Iraqi damage report, written by Hossam Amin, the head of Iraq's National Monitoring Directorate who liaised with inspectors, made an unambiguous report that Iraq destroyed its entire inventory of biological weapons. Amin reminded Saddam's son Qusay of the government's claim that it possessed no such arms after 1990, then wrote that in truth "destruction of the biological weapons agents took place in the summer of 1991". It was those weapons to which Secretary of State Colin Powell referred in the Security Council last February when he said, for example, that Iraq still had an estimated 8500 to 25,000 litres of anthrax. A prewar US intelligence report that said Iraq had weapons of mass destruction was based on 15 years of information, and the hunt should continue, a senior US intelligence official has said. Stuart Cohen, vice-chairman of the National Intelligence Council, which produced the October 2002 National Intelligence Estimate report on banned weapons, said he was not surprised stockpiles of weapons had not been found. "I believe that our work was well-grounded. We know he (Saddam) had it, he used it, you don't unlearn that." | Low | [
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Polymorphism in the 5'-leader cistron of the beta2-adrenergic receptor gene associated with obesity and type 2 diabetes. We screened the 5'-untranslated region of the beta2-adrenergic receptor gene from 40 obese subjects by the PCR-direct sequencing technique. Two polymorphic sites were identified; a T-->C substitution at -47 and a T-->C substitution at -20. We further analyzed the association of the polymorphisms with obesity in 574 subjects by PCR and restriction digestion. The substitution at -47 was in tight linkage disequilibrium with that at -20. The polymorphisms were also in linkage disequilibrium with codon 16 and codon 27 polymorphisms. Subjects carrying the -47C/-20C allele had greater body mass index (25.5+/-4.5 vs. 24.4+/-4.1 kg/m2, p=0.007) and higher serum triglyceride levels (166+/-160 vs. 139+/-95 mg/dl, p=0.015) than -47T/-20T homozygotes. The variant allele frequency was significantly higher in obese subjects than in non-obese subjects (0.18 vs. 0.11, p=0.0026). Furthermore, an increased frequency of the variant allele was shown in diabetic patients compared with non-diabetic subjects (0.19 vs. 0.11, p=0.0005). The association may be attributable to the greater proportion of diabetic patients in the obese group. The exchange at -47 may alter the expression level of the beta2-adrenergic receptor gene, because the nucleotide substitution at -47 results in a Cys-->Arg exchange at the C terminal of the leader peptide. The -47C/-20C allele may be associated with genetic predisposition to obesity and obesity-related metabolic disorders. | High | [
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Ringer 2011 Ringer: Bridget is six months sober and starting to get her life back on track when she becomes the sole witness to a professional hit. She flees to New York, telling no one. In New York, Bridget reunites with her estranged twin, Siobhan. Wealthy, pampered and seemingly happily married, Siobhan lives what appears to be a fairy tale life. The identical twin sisters seem to be mending their frayed relationship, until Siobhan disappears overboard during a boat trip the two take together, and Bridget makes the split decision to take on her sisters identity. She discovers shocking secrets, not only about her sister and her marriage, but other secrets as well. Bridget soon realizes she is no safer as Siobhan than she is as herself. | Low | [
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On the relation between seizures and brain lesions after intracerebroventricular kainic acid. To analyze the relation between kainic acid-induced limbic seizures and the associated brain lesions, various doses of kainic acid (117-940 pmol) were administered intracerebroventricularly to unanesthetized rats. Rats which experienced status epilepticus developed lesions in several limbic, neocortical and thalamic regions. However, rats which experienced only temporally discrete seizures (less than 30 min each) suffered neuronal degeneration exclusively in the CA3-CA4 area ipsilateral to the kainic acid infusion, even when other regions exhibited the same total electrographic seizure duration. These results can best be explained by postulating that, in addition to evoking seizures, kainic acid also enhances the toxic effects of seizures on CA3-CA4 neurons. | High | [
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Do alternate bacterial indicators and pathogens increase after centrifuge dewatering of anaerobically digested biosolids? The objectives of this research were to evaluate the potential for sudden increase and/or regrowth of alternative bacteria as either indicators or pathogens after dewatering of thermophilic and mesophilically digested biosolids. The results showed that, in general, for thermophilic processes, even when a statistically significant (p < 0.05) sudden increase and regrowth occurred for fecal coliforms, Escherichia coli, and Enterococci, it did not occur for Salmonella or Aeromonas. For the mesophilic process evaluated, sudden increase did not occur, but regrowth occurred for fecal coliforms, E. coli, Enterococci, and Salmonella. The results have implications for Class A and B biosolids regulations, as both fecal coliform and Salmonella are part of the regulatory limits. The results also suggest that the public health risks are minimal, as a result of the potential sudden increase and regrowth that may occur. | Mid | [
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A core knowledge architecture of visual working memory. Visual working memory (VWM) is widely thought to contain specialized buffers for retaining spatial and object information: a 'spatial-object architecture.' However, studies of adults, infants, and nonhuman animals show that visual cognition builds on core knowledge systems that retain more specialized representations: (1) spatiotemporal representations for object tracking, (2) object identity representations for object recognition, and (3) view-dependent snapshots for place recognition. In principle, these core knowledge systems may retain information separately from one another. Consistent with this hypothesis, this study provides evidence that these three types of information are subject to independent working memory storage limits. These results, combined with those from previous studies, indicate that VWM contains three specialized buffers for retaining spatiotemporal information, object identity information, and snapshot information. Thus, VWM buffers parallel core knowledge systems. This 'core knowledge architecture' links the study of visual working memory to the study of the biological foundations of visual cognition. | High | [
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Intracellular phospholipase A2 expression and location in human macrophages: influence of synthetic material surface chemistry. Phospholipase A(2) (PLA(2)) enzymes participate in a potent inflammatory pathway through the liberation of arachidonic acid upon hydrolysis of membrane glycerophospholipids. The presence of implanted polycarbonate-urethane (PCNU) materials, used in several medical applications, has the ability to influence inflammatory responses of human macrophages that are recruited to a tissue-material interface; however, the specific inflammatory pathways that are activated upon macrophage attachment to PCNU are largely unknown. Previous studies suggested the participation of PLA(2) pathways in material degradation with the use of chemical inhibitors, such as aristolochic acid (ARIST), however not accurately defining the specific PLA(2) enzymes involved. The current study aimed to establish specific groups of PLA(2) involved in the macrophage foreign body response to PCNU. ARIST was assessed for specific effects on secretory PLA(2) (sPLA(2)) protein expression and non-specific effects on key proteins, beta-actin and monocyte-specific esterase, implicated in the macrophage attack on PCNU materials. Macrophage attachment to PCNU materials induced increased intracellular expression of cytosolic PLA(2) (cPLA(2)), but not sPLA(2), relative to tissue culture polystyrene (TCPS) as detected by immunoblot analysis, demonstrating an early and delayed stimulation during the time course of increased cPLA(2) protein expression. Laser scanning confocal microscopy images indicated a change in location of cPLA(2) in macrophages adherent to PCNU surfaces compared to TCPS. This study has illustrated changes in macrophage cPLA(2) expression in response to cell-attachment to PCNU surfaces, demonstrating that the macrophage foreign body response to biomaterials induces a potent inflammatory pathway, which may lead to tissue damage near the site of material implantation. | High | [
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Killer Manhattan nanny Yoselyn Ortega was sentenced to the maximum prison sentence of life without parole Monday for fatally stabbing two of her little charges, Lulu and Leo Krim — after devastating statements from the children’s parents. Kevin and Marina Krim brought many in the packed courtroom to tears as they talked about their horrific ordeal and how they survived it. Meanwhile, Ortega remained stone-faced. Marina first talked about the couple's only surviving daughter, Nessie, who was 3 when her siblings were killed. JURY CONVICTS NEW YORK CITY NANNY OF KILLING TWO KIDS IN 2012 "Each time she makes a wish, it's always for Lulu and Leo to come back to us. Nessie knows that wish will never come true," the mom said, struggling to fight back tears. The couple’s two sons, "Felix and Linus, born after the murders, never got the chance to meet Lulu and Leo. But I see Lulu and Leo living within all three of the kids every day." She ripped Ortega and her family, who were blamed for setting them up with the deeply troubled women, lying to get her the job. "My family and I, we create and built. The defendant and her family, they destroy and ruin," Marina said. "The defendant set out to destroy what Kevin and I had created and built — and inspired, happy, thriving family. But she failed. "The defendant’s son, Jesus Frias, sat in front of a traumatized jury, winking and grinning at the jury members as if it were some kind of reality TV show he wants to win," the mom said. "What is wrong with them?" Her husband’s statement included what he read at a November 2012 memorial service for their dead children. "I'm not really giving a eulogy today. Because I want to talk about all our kids. We called them Team Krim," Kevin said. He said they called Lulu "Our Little Buddha." "We were madly in love" with Leo, too, the dad added. "We miss them so, so much. "We miss picking Leo up out of his crib, with a happy 'Mama' or 'Dada' from him and always a big hug. "We miss holding their hands as we walked down the sidewalk. "We miss attempting to argue them out of a Mr. Softee cone, and losing most of the time. "We miss hearing them call out my name and run to hug me when I got home from work." Calling Ortega "an evil and utterly dangerous narcissist and a complete failure," Kevin addressed Judge Gregory Carro. "I trust that you do not need this request from Lulu and Leo's dad after all you've heard and seen, but I will make it anyway: in your sentencing decision, please follow the law as you always have … by ensuring that the defendant can never leave prison alive," the dad said. "The defendant knows nothing of responsibility or remorse. She should also know nothing of hope." Click for more from the New York Post. | Mid | [
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National Team After a long absence, the Malta National Hockey team is back! The players have taken advantage of this situation and are now gearing up to participate in their first European challenge with the national side. Following the appointment of Pieter Bregman as National Team Coach, a preliminary squad was put together, after which the coach, along with his staff, selected the final 18 to travel to Lithuania in July. | Mid | [
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Mailbox You can scarcely say that Germany's treatment after the war was self-righteous. Ask the Israelis about that. After suffering at German hands in two world wars, I doubt many others in Europe would agree with you either. Large German corporations that had used slave labor during the war were let off very lightly. If the price the Germans paid for their aggression was being "demoralized by endless reproaches," that's tough. No one is interested in de-Germanizing Germany, and Germans today would be insulted by your statement that they are somehow "less German." Nor do they "eagerly disown their own rich cultural traditions." Have you ever been there? Germans are very proud of their culture. Even rebellious kids study the piano and play Beethoven. European classical music is part of the fabric of life there, unlike here. As for Japan, I think few Japanese, outside of the right-wing nationalist wackos, would find much to agree with in your analysis. Japan before 1945 was run by militarists. It was not a democracy. The Americans dismantled the government and inserted the antiwar clause in the constitution because it was considered too dangerous not to do so. Do you have any idea how Japan's neighbors in Asia, most of whom have been occupied by the Japanese army for shorter or longer periods, feel about the Japanese? Just ask any Asian. It is the one issue they all agree on. Complaining that the antiwar clause was humiliating is like saying that murderers should not be jailed because that would be humiliating. As for Hirohito, he could have easily been prosecuted as a war criminal. He got off scot-free. Making him renounce his divinity was part of bringing Japan into the 20th century. You will not find any rational Japanese who will say that was not a positive and necessary step. Joe Rodrigue, New Haven Get Off the Love Train MUGGER: Enjoyed your 8/11 column in NYPress, save for the portion wherein you tried to agree with The New York Times' castigation of the BSA. Being homosexual (which is voluntary) cannot be compared with being black, Asian or Polish (which is predetermined). Rather, a homosexual's rights are similar to a smoker's rights. If you choose to smoke, you may be prohibited from doing so in certain places, facilities or work situations. You know that in advance, and can decide to smoke (and give up going into those places) or not to smoke (with corresponding access). So it should be with homosexuality. The Boy Scouts, the Army, your private club?whatever?should be able to announce that no people who choose to be homosexual are allowed; an individual makes the decision to be in the Army or not. Any group should be allowed to establish its membership requirements provided they don't discriminate against naturally predetermined subgroups. But when the applicant's voluntary choices don't conform with the group's standards or stated requirements, he or she has no "right" to be admitted. You can modify your choices and conform, thereby earning admission. No group should be forced to accept homosexuals (voluntary) or criminals (again, voluntary), etc., if its membership criteria exclude such?but it should be required to accept women or blacks, or any other biologically controlled subgroup. Confusing the "rights" of people and groups who elect to do things with those of people who have no choice in what they are, is the big con of the gay community. It seems very reasonable to not discriminate against minorities?until you realize that in this instance, the minority has chosen to be a minority. You were right to feel uncomfortable agreeing with the Times. David Messner, Marina Del Rey, CA Bull Penn MUGGER: In your 8/18 column, you discuss Gov. George W. Bush's win in the Ames straw poll and the "tut-tutting" that followed. On the opposing side, in the upcoming primary, I have to wonder what Bill Bradley's chances will be if Sen. Joe Biden and others are right about the Gore campaign. Biden and others have stated, publicly, that people from the Gore campaign are holding Democrats hostage in their endorsements for the Democratic presidential run. It has also been alleged that Sen. Daniel Patrick Moynihan has been informed that his plans for New York City's Penn Station will not go through if he endorses Bill Bradley. If this is true, it's obscene that our senior statesman can't use his final months to see through this wonderful plan for Penn Station. I also would not be surprised if Moynihan was deceived into believing that if he supported Hillary Clinton, and invited her to his virginal farm upstate, his plan for the station would go through. Flora L. Ramonowski, Manhattan Nostril-Burning Bush MUGGER: I always enjoy your articles, but I particularly appreciate your approach to Gov. Bush's presidential campaign. You seem to be the only journalist who consistently recognizes the Governor's personal and political skills. I'm stunned that there isn't wider acknowledgment of his achievements in Texas. I personally think he's the best governor we've had since John Connally. Anyone who questions his views only has to look at his existing record. He's never attempted to hide his feelings on important matters. However, while other candidates (from all the parties) often come across as narrowminded zealots, Bush possibly realizes that a president is more important for his leadership than for his opinions. I think we're all a little tired of politicians standing on a stump and either telling us what we should believe or telling us what they think we want to hear. I wish someone would take note of Al Gore's audacity in declaring that Bush doesn't have enough experience in foreign affairs. How much experience did Clinton have when he ran for the nation's top office? (Of course, he managed to bungle all of his international forays. Despite the claims of success for the recent disaster in Bosnia, the only military victory this administration can claim occurred in Waco, TX, during the first term.) Ernie Kirkham, College Station, TX Learning From Loss I'm sorry to see Amy Sohn go, but I knew that someday she'd hit the big time and leave us. Perhaps it's for the best. Anyway, she seems to have finally gotten herself into a functional relationship, which can only hurt the column. But we love Amy, so what's good for her is what's good for us. Congrats! C. Lizzner, Hoboken Girl Eighty-Six When someone told me the whiny bitch who writes for NYPress was leaving, I immediately assumed it was Russ Smith. Too bad it's actually Amy Sohn. Whose menstrual flow will I read about now? Whose fart-lighting antics will I follow? This is the saddest day in New York journalism since Pete Hamill gave up the sauce. Alan Roberts, Manhattan The Portly Gentlemen Of 333 You fat bastards! How could you let her go? How? Goddammit! What the fuck do I read now? Jonathan Ames has had Mangina on the brain for the past year. Jim Knipfel has about 11 days left before he spontaneously combusts and transmogrifies into a hot, blue gas. What do I have left? Sanchez's ass-fetish? MUGGER's "Diary of a Peckish Tribecan"? No! I need awkward metaphors for lubricated vaginal canals! Give me awkward metaphors for lubricated vaginal canals! I don't care how much money she got. Top it! Chain her to the floor with some gynocentric porn and a laptop that dispenses a pellet of food every hundred words typed! Or... ...every third awkward metaphor for lubricated vaginal canals! What am I supposed to do, buy Run Catch Kiss? I accidentally bought Go Dog Go! and by the time I realized my mistake I was engrossed. Was it the hate mail? Can someone please tell her that hate mail is like a Nielsen rating? For every irate letter you receive, your column is read by 1000 other people who don't have the free time to write shit like this. Whatever. I either get one awkward metaphor for lubricated vaginal canals per week, or I take my free show listings elsewhere. I thank you in advance. Bob Powers, Brooklyn Iron Filing I am an ardent supporter of a free press, but if someone placed a gun to my head and forced me to choose, the one thing I would ban is the use of the word "capitalism" by film critics. Armond White's favorite children's movie did poorly in theaters, so he asserts that capitalism has created a nation of "robotic consumers" incapable of appreciating a beautiful film ("Film," 8/18). How tiresome. Surely some of his other recent favorites have been hits; would that invalidate his argument? What if Iron Giant does well on video? Did Mr. White consider the possibility that Iron Giant was poorly promoted? I'm as faithful an absorber of Hollywood's "corporate hard-sell" as the next moron. Last week I saw about two commercials for Iron Giant and about two hundred commercials for The Thomas Crown Affair. Sure, I was nauseated when the Thomas Crown Affair ad, quoting some critic, bragged, "the most sizzling performances of the decade!" Perhaps I'm not as passive as the robot I'm supposed to be. That same sickening feeling returned reading Mr. White's opening line: "The kids are not all right." Because they didn't see a movie? The use of the word "corporate" as a pejorative adjective modifier to "hard-sell" also triggers the absurdity reflex. How is this different from the sole proprietorship hard-sell or the limited partnership hard-sell? What about the nonprofit hard-sell? Ever watch PBS during pledge week? The difference is that Mr. White knows that keywords like "capitalism" and "corporate" in his text are analogous to cinematic fireballs and fruit carts for his robotic audience?those who don't stop to think about the great films we couldn't see if not for capitalism. Like Dr. Pavlov, Armond White rings his paranoid-leftist bell and expects us all to salivate. Save your spit, and rent Iron Giant for the kids. David Nadle, Manhattan | Low | [
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This brown Stereum or Peniophora-looking crust on Pine (found by Sally at Longshaw) took me some weeks to identify. I followed the instructions provided by Corticiacaea of Northern Europe (CNE) – the 7 volume most authoritative guide: “ First place a drop of KOH or your staining reagent on the slide”. I used KOH as my dried specimen was very hard and quite thick. After softening I added ammoniacal Congo Red. I was able to make a reasonable squash preparation, and could identify hyphae (dimitic – thin-walled generative and thick-walled straighter skeletal hyphae). Basidia were extremely hard to find, but basidioles with clamps were seen. The most striking feature were the smooth cystidia/hyphal ends protruding from the surface. Spores were not easy to find on the dried specimen, but as usual I had obtained a spore print before drying – the spores were Stereum-like ( hyaline, oblong-oval, approx 6-7 x 3, and amyloid). From Fungi of Switzerland and CNE I got tentatively to Stereum, but as my specimen didn’t bleed red, and it didn’t look like any non-bleeding Stereum, and it also had clamps, I was at a loss. I’ve been finding that sticking dried crust fungi straight into KOH , although helping to soften the material to be able to disperse the elements, can also destroy the cystidia. It can dissolve the beautiful crystalline covering of lamprocystidia and skeletocystidia which are crucial for some IDs. I therefore made another section of the herbarium specimen in plain water – which showed the striking skeletocystidia of Amylostereum chailletii. This specimen fits both the descriptions in CNE and FOS. (It is recorded on Pine in the UK as well as Spruce). At least it does for me. If I'm right then it's another first for Longshaw, and possibly for Derbyshire. Steve Field photo Stereo microscope image Cystidia after treatment with KOH and ammoniacal Congo Red - they are denuded of crystals | High | [
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Taking the pseudo out of pseudogenes. Pseudogenes are defined as fragments of once-functional genes that have been silenced by one or more nonsense, frameshift or missense mutations. Despite continuing increases in the speed of sequencing and annotating bacterial genomes, the identification and categorisation of pseudogenes remains problematic. Even when identified, pseudogenes are considered to be rare and tend to be ignored. On the contrary, pseudogenes are surprisingly prevalent and can persist for long evolutionary time periods, representing a record of once-functional genetic characteristics. Most importantly, pseudogenes provide an insight into prokaryotic evolutionary history as a record of phenotypic traits that have been lost. Focusing on the intracellular and symbiotic bacteria in which pseudogenes predominate, this review discusses the importance of identifying pseudogenes to fully understand the abilities of bacteria, and to understand prokaryotes within their evolutionary context. | Mid | [
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From Barilla Pasta: Feed the Hungry and Get a Free Cookbook! I was recently contacted by the pasta brand Barilla regarding their “Share the Table” program, which was created to help families come together more often over shared meals. Between now and October 15th, visit www.ShareTheTable.com and click on the icon that says you “believe in meaningful meals.” When you do, Barilla will donate $1 to Meals On Wheels Association of America, for a total donation of up to $150,000. Then, after doing that good deed, you can download the free 32-page cookbook which contains pasta recipes from Mario Batali, Julianne Moore, Meryl Streep and other celebrities. Both the book and the website also contain lots of useful tips about sharing family meals — everything from menu planning, eliminating distractions, ideas for dinner conversation and more. I was also particularly interested to read the results of a survey conducted by Barilla about U.S. families’ eating habits. Amazingly, three out of four families don’t sit down to family meal regularly. You can read the entire article summarizing the survey findings here. | Mid | [
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Tweet There are a little more than 4 million children in Canada aged 0 to 12 years.[1] They need care and education. I don’t think anyone really disputes this–youth 13 and older obviously also have needs for care and education but they’re not the focus of this post. In most cases, decisions about that care and education are made by parents or legal guardians who will have the bests interests of their children at heart. I don’t think anyone disputes this either. Those children and the families making decisions for them are really, really diverse. So why do we keep trying to produce national public policies on child-care that are one-size solutions? Sometimes one-size fits all means everyone gets the same kind of choices for childcare. Supply-side solutions look for ways to increase the number of spaces for children in quality childcare programs. For example, Quebec’s provincial childcare system provides all families with a regulated space in a childcare centre or in licensed homecare and regulates the out-of-pocket costs to parents. In a long-overdue move the province has started to tie that fee to household income. The 2005 federal-provincial agreement on childcare was similarly intended to increase the supply of regulated spaces in the rest of the country. All provinces in the country provide some financial support (from some combination of federal transfers and their own tax revenues) for the early learning and care services in their jurisdiction. In 2006-07, there was also a short-lived federal effort to look for recommendations to encourage employers to create more childcare spaces for their employees. That last effort ended quietly. It’s not totally clear we have a supply-side problem when it comes to learning and care for kids. Our indicators on the supply of childcare in Canada are a bit problematic in that they exclude other options used by families like after-school recreational programs and homecare with too few clients to require a license.[2] What we do know is that there were 585,274 licensed spaces (in centres or licensed homecare) across Canada (outside Quebec), which makes it sound like as many as 85% of kids are going without childcare from infancy to middle school. In reality, we have to adjust that ratio to account for other factors like access to parental leave, private care arrangements and programs that may be high quality and developmental but fall outside provincial regulation. Furthermore, depending on the age of the child, between 40 and 60%[3] of families say they don’t use any daycare services (note the switch here to “daycare”) at all. How do they manage? Well, probably through some combination of private arrangements, adjusting their work hours and relying on things like full-day kindergarten (where they can) and after-school recreational programs. When parents are asked what matters most to them when they choose their childcare, parents report that location, trust in the provider and affordability are, in descending order, their 3 primary criteria with location by far the most frequently-cited factor.[4] So, getting the supply-side right has to mean attention to a really wide range of types of care, the market price of that care and even the minutiae of where that care is physically located. That’s a tall order if you want to rely on just one policy instrument, no matter what that one instrument is. Sometimes, one-size fits all means giving everyone the same financial support, regardless of need or ability to pay. This is when really strange things can happen. Demand-side solutions look for ways to reduce the need for childcare or to subsidize the market price of that care. For example, all provinces outside of Quebec offer income-tested subsidies for licensed childcare services. Quebec did away with subsidies when it introduced its universal daycare plan which has led to an interesting puzzle: Among households who say they use childcare, Quebec households are more likely to say they pay $10 a day or less, but modest income households (making under $40,000/year) are significantly more likely to say they pay $0 out-of-pocket for that care if they live outside Quebec than inside Quebec.[5] In short, swapping subsidies for flat fees seems to mean that costs for childcare are lower on average across all households but are actually higher for lower income households. Federally, there are two key instruments intended to help families with the costs of childcare. The Child Care Expenses Deduction (CCED) lets parents deduct eligible out of pocket childcare costs, within certain limits. It was recently increased to $8,000 for each child under age 7 starting in the 2015 tax year. When the 2005 federal-provincial supply-side agreement on childcare was cancelled, the money was used to create a new flat cash transfer of $100 per month for each child under 6 years–the Universal Child Care Benefit (UCCB). Financing the UCCB also meant diverting money out of the income-tested Canada Child Tax Benefit system.[6] The UCCB was recently expanded so each child under 6 creates a flat entitlement to $160 per month and each child aged 6 to 18 years generates flat entitlement to $60. The CCED and the UCCB are both responsive to parental income in some weird ways. The CCED has to be claimed by a working (or student) parent with the lower income and the UCCB is taxable in the hands of the lower income parent (regardless of their labour force activity). Let’s take a simple case, where two parents in a household have equal incomes, or at least incomes in the same federal tax bracket. Figure 1 (below) shows the maximum federal benefit they could receive out of the CCED and UCCB for one child under 7 years of age in the 2015 tax year. The net effect is that direct federal demand-side support generally rises with household income. The UCCB purposefully pays the same amount, before taxes, no matter a household’s actual expenditure on learning and care. The CCED lets families claim some tax relief only after they’ve spent the money on eligible forms of daycare–an approach that works far better if a family can afford the cashflow pressures in the interim and has enough tax liability get some real benefit out of a deduction. Policy proposals that promise the same amount of money to all families, whether they are supply-side or demand-side solutions, are politically attractive. They make for nice pithy bumper-sticker commitments that are easy to communicate. But they come with real problems because neither is able to adjust to the needs and means of Canada’s diverse families. In either case, some strange things seem to happen. Maybe the primary problem in the current childcare policy debate is that it has pitted families who use daycare against families who don’t. Families who use daycare are reduced to supporting a one-sized supply-side approach. Families who don’t are reduced to supporting equally one-sized demand-side option instead. In neither case does the debate acknowledge or respond to a more realistic range of preferences, needs and ability to pay. What if instead, our starting point was that: Childcare is what all families provide for their kids. All of those kids need learning and care. Many, but not all families meet their kids’ needs for learning and care through daycare. Different families will have different demands for early learning and care in their community. Different families will have different abilities to pay and out of pocket costs. There are lots of different levers that could be used on the family policy front and it’s time they started to be used in more nuanced, integrated ways. This route doesn’t lead to simple policy solutions of $X per day or $X per month. Maybe we’ll just have to start making some bigger bumper-stickers. Tweet Jennifer Robson is an Assistant Professor at Carleton’s School of Political Management. Contact her at jennifer.robson[at]carleton.ca | Low | [
0.5228758169934641,
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1. Field of the Invention The present invention is related to an electrical connector, and more particularly to an electrical connector having a spacer for positioning tails of a plurality of terminals thereof. 2. Description of Related Art To increase the transmission speed of input/output messages between electrical connectors in electrical apparatus like computer systems, high density electrical connectors, which have a plurality of contacts in a high density arrangement, are proposed. However, the high density arrangement of the contacts results in a very small pitch between adjacent contacts. Therefore, high density electrical connectors are usually equipped with a spacer to orient contacts thereof and to prevent the contacts from coming too close to each other. Some conventional high density electrical connectors each comprises a plurality of contacts, each of which comprises a horizontal portion extending horizontally to mate with a complementary element of a complementary connector and a vertical portion extending vertically and downwardly through a spacer assembled to the housing. The vertical portions are often too long to be exactly inserted into corresponding apertures of the printed circuit board, which results in the buckling of the contacts. To solve the buckling problem of the contacts, U.S. Pat. Nos. 5,879,171 and 6,183,270 each discloses a two-stage locking means formed on a housing and a pair of latching portions formed on a spacer. By means of gradual cooperation between the two-stage locking means and the latching portions, the contacts are gradually oriented and guided in two stages through holes of the spacer. Contacts of U.S. Pat. Nos. 5,879,171 and 6,183,270 have both horizontal and vertical portions and make the connectors using the same have a relatively large width and occupy relatively more space on a printed circuit board. Sometimes electrical connectors occupying less space are desired, which, however, often have a relatively stringent height limitation. Two-stage locking means formed on the housing increases the height of the connector. Hence, it is requisite to provide an improved electrical connector to overcome the above-mentioned disadvantages. Accordingly, an object of the present invention is to provide an electrical connector with a spacer without buckling contacts thereof. Accordingly, another object of the present invention is to provide an electrical connector with a spacer for reducing both a width and a height of the electrical connector. In order to achieve the object set forth, an electrical connector in accordance with the present invention comprises an insulative housing defining a plurality of passageways, a plurality of conductive terminals, a metal shell assembled onto the insulative housing and a spacer. The housing has a pair of blocks formed on opposite ends thereof. Each block has an engaging portion projecting sidewardly. Each terminal has a mating portion received in the passageway and a tail portion extending downwardly beyond the housing. The spacer includes a pair of hooks extending upwardly from opposite ends thereof and a plurality of positioning holes for retaining the tail portions of the terminals in position. Each hook has a first retention portion and a second retention portion positioned above the first retention portion. When the spacer is in a first position where the spacer is initially retained to the housing, the first retention portions of the spacer engage with the engaging portions of the housing. When the spacer is in a second position where the spacer is finally retained to the housing, the engaging portions of the housing engage with the second retention portions of the spacer. Other objects, advantages and novel features of the invention will become more apparent from the following detailed description of the present embodiment when taken in conjunction with the accompanying drawings. | Mid | [
0.5491803278688521,
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NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism. Aminoacylase 1 deficiency is a novel inborn error of metabolism. The clinical significance of the deficiency is under discussion, as well as the possible consequences of the defect for brain metabolism and function. This study includes the five originally published cases as well as three novel ones. NMR spectroscopy of urine, serum and cerebrospinal fluid has been used to study these patients. A typical profile with 11 accumulating N-acetylated amino acids was observed in urine from the patients. The concentration of most of the accumulating metabolites is typically 100-500 micromol/mmol creatinine. Two additional minor N-acetylated metabolites remain unidentified. The concentrations of the accumulating metabolites are <20 micromol/L in serum from the patients. Interestingly we found no evidence of an increased concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient. Our data define aminoacylase 1 deficiency at the metabolite level providing a specific urinary profile of accumulating N-acetylated amino acids. | High | [
0.6868686868686861,
29.75,
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