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COVID-19 Health Alert – U.S. Embassy Kuala Lumpur (May 19, 2020)
Health Alert – U.S. Embassy Kuala Lumpur, Malaysia
Event: COVID-19
Please share this information with other U.S. citizens who may not be registered for these alerts.
International commercial flight options currently exist in Malaysia. U.S. citizens who wish to return to the United States should make commercial arrangements as soon as possible unless they are prepared to remain abroad for an indefinite period. The U.S. government does not anticipate arranging repatriation flights in Malaysia at this time.
On May 10, 2020, the Prime Minister announced that the Movement Control Order (MCO) has been extended until June 9, 2020.
On May 16, the Ministry of Tourism, Arts and Culture Malaysia, which manages the Malaysia My Second Home (MM2H) program, announced that MM2H visa holders outside of Malyasia may return from May 17, 2020 subject to medical screening and a 14-day quarantine upon arrival. While this has been publicly announced, we are currently seeking additional clarity on the requirements for MM2H holders to return to Malaysia. We strongly advise all MM2H holders to postpone return travel to Malaysia until further notice.
Please note that all routine Consular Services at the U.S. Embassy Kuala Lumpur remain suspended. Routine American Citizen Services, including passports, Consular Reports of Birth Abroad, and notarial services, are suspended until further notice. Immigrant and nonimmigrant visa services are also suspended worldwide. We will resume routine consular services as soon as possible but are unable to provide a specific date at this time.
Although consular services remain suspended, we are assessing demand for services, including applications for U.S. passports, Consular Reports of Birth Abroad (CRBA), and notarial services. Please complete the form at: https://bit.ly/2SPVSFf to request a future emergency appointment when consular services are re-established or to request pickup of an already issued passport or Consular Report of Birth Abroad. Again, please note that the U.S. Embassy is not providing routine services at this time.
If you are a U.S. citizen with a life or death emergency (e.g. victim of a violent crime, arrest, reporting a death of a U.S. citizen) you may reach us at +60-3-2168-5000 or via email at: KLACS@state.gov.
We will announce the resumption of services via alerts to registered U.S. citizens in the Smart Traveler Enrollment Program (STEP) and on our Embassy's website.
Malaysian Immigration Services
On May 10, the Prime Minister announced the Movement Control Order (MCO) will continue through June 9. During the MCO, the Government of Malaysia will open limited immigration services.
If you are a U.S. Citizen with immigration questions regarding your current status or permission to stay in Malaysia, please refer to the Malaysian Department of Immigration directly regarding your particular situation. U.S. Citizens with specific questions or concerns may also contact the Malaysian Government call center (MyCGG) at 03-8000-8000.
During the MCO, Malaysian Immigration services will resume by appointment only – no walk-ins are permitted. Immigration has informed the U.S. Embassy that their online appointment system cannot be used by those seeking to extend 90-day social visit (tourist) passes, and Malaysian Immigration strongly encourages all social visit pass holders whose passes have expired to depart Malaysia as soon as possible.
U.S. citizens whose passes expired after January 1, 2020 seeking to depart Malaysia may do so within 14 working days after the MCO period ends on June 9, 2020 without undergoing any Immigration processing or penalties. There should be no expectation that 90-day social visit (tourist) passes will be extended due to the global pandemic.
Per Immigration guidance, U.S. citizens seeking renewal or extension of passes that have expired after February 1, 2020 must apply within 30 working days after the MCO period ends (June 9, 2020) at immigration offices nationwide. However, please note that if your renewal or extension is denied, and you have remained in Malaysia more than 14 days after the end of the MCO, you may be subject to Immigration fines or other enforcement action.
We understand that Malaysian Immigration is experiencing a high call volume and U.S. citizens have reported difficulty accessing scheduling websites and that many appointment slots are full. Please be patient as Malaysian Immigration is experiencing a high demand for its services and is implementing procedures to promote social distancing. The U.S. Embassy cannot make appointments with the Malaysian Department of Immigration on your behalf.
On May 12, Malaysian Immigration published an updated FAQ at their website that includes the below information. U.S. citizens who wish to "present themselves" at Malaysian Immigration must make an appointment in advance.
"For foreigners holding Long Term Pass and their passes expired before or during MCO, they are requested to present themselves at nearest Immigration Offices for validation and facilitation of passes according to the Immigration rules within the stipulated 30 working days period.
For foreigners holding Social Visit Pass (visitors) and their passes expired before or during MCO, who are stranded to leave Malaysia after 14 days of MCO are required to present themselves at nearest Immigration Offices within the stipulated 30 working days period for facilitation subject to supporting letter from the respective embassy."
While the U.S. Embassy in Kuala Lumpur cannot intervene on your behalf when you apply for a Malaysian visa, we are issuing letters that ask Malaysian Immigration to consider the COVID-19 pandemic and our advice to avoid all international travel. The U.S. Embassy CANNOT certify or validate your specific or personal justification for remaining in Malaysia and reminds U.S. citizens that permission to enter and remain in Malaysia is at the decision and discretion of the Malaysian Immigration Department.
If you require such a letter, you may request one from the U.S. Embassy by completing this form: https://bit.ly/2Wd64te
The U.S. Embassy in Kuala Lumpur encourages all citizens with visas that have expired during the MCO to depart Malaysia as soon as possible to be in compliance with Immigration requirements.
Travel Letter from the U.S. Embassy
IMPORTANT NOTICE: U.S. citizens and Foreign Nationals traveling to the United States who wish to depart Malaysia during the Movement Control Order MUST have a letter from the U.S. Embassy to present to the Royal Malaysia Police while traveling to the airport during the MCO and CMCO. For additional information and instructions on how to request this letter, please visit our website and complete this form: https://bit.ly/2Wd64te
Movement Control Order and Mandatory Quarantine
The Malaysian government extended the MCO through June 9, 2020, though this end date may be extended again at the discretion of the Malaysian government. All foreign nationals are restricted from entry to Malaysia during this time. Any travelers permitted to enter Malaysia during the MCO will be subject to COVID-19 testing and a mandatory fourteen-day quarantine. Travelers will be transported directly from the airport to a quarantine facility by Malaysian authorities. Foreign nationals, including Malaysian permanent residents, will be required to cover the costs of this quarantine, which will be a minimum of RM150/day. For additional information on quarantine requirements and costs, please contact the Malaysian National Disaster Management Agency (NADMA).
Foreign nationals may transit through the international terminals of Malaysian airports but may not pass through Immigration. The MCO prohibits all individuals – Malaysian citizens and foreign nationals – from movement and mass assembly within Malaysia. U.S. citizens may be subject to temperature screening at workplaces, grocery stores, or at police checkpoints. U.S. citizens should avoid crowded areas, practice social distancing, and wash hands frequently. U.S. citizens should carry a copy of their passport and visa with them at all times. U.S. citizens are subject to local laws and regulations while visiting or living in Malaysia.
Malaysia COVID-19 Information
Malaysia has confirmed cases of COVID-19 throughout the country. For more information regarding COVID-statistics in Malaysia, please review the Malaysian Ministry of Health's COVID-19 Portal and visit our Embassy webpage on COVID-19.
Commercial Flight Availability and Travel Restrictions
The Department of State advises U.S. citizens to avoid all international travel due to the global impact of COVID-19.
Very limited commercial flights remain an option for U.S. citizens wishing to depart Malaysia. Many airlines have cancelled international flights and several transit countries have set up new quarantine restrictions or have barred international transit altogether. Please note that flight schedules are likely to change with little advance notice. Limited domestic flights continue to operate in Malaysia, including Sabah and Sarawak.
The U.S. Embassy is unable to book airline tickets on your behalf. Please continue to reach out to airlines and utilize commercial websites to book or change your tickets. We encourage you to look at all flight options flying into the United States, regardless of whether the flight is going to your final destination; it may be necessary to book a second ticket onward. We will post any alerts and updates on the COVID-19 situation in Malaysia on our Embassy's webpage on COVID-19.
The Centers for Disease Control and Prevention (CDC) has issued a Level 3 – Avoid Non-Essential Travel– Notice for Malaysia. The State Department has issued a Global Level 4 Health Advisory – Do Not Travel.
Countries around the world are experiencing COVID-19 outbreaks and implementing travel restrictions and mandatory quarantines, closing borders, and prohibiting non-citizens from entry with little advance notice. Any U.S. citizen returning home should be prepared for additional travel restrictions to be put into effect with little or no advance notice. Travelers should closely monitor the situation in Malaysia and other transit countries before travel.
Actions to Take:
Consider returning to your country of residence immediately using whatever commercial means are available.
Have a travel plan that does not rely on the U.S. Government for assistance.
Review and follow the CDC's guidelines for the prevention of coronavirus.
Check with your airline or travel operator regarding any updated information about your travel plans and/or restrictions.
Visit travel.state.gov to view individual Travel Advisories for the most urgent threats to safety and security. Review what the State Department can and cannot do for you during an international crisis.
Visit our Embassy webpages on COVID-19 for information on conditions in each country or jurisdiction.
Visit the Department of Homeland Security's website on the latest travel restrictions to the United States
Visit keeping workplaces, homes, schools, or commercial establishments safe.
U.S. Embassy Kuala Lumpur, Malaysia
376 Jalan Tun Razak
KLACS@state.gov
https://my.usembassy.gov/
State Department – Consular Affairs: 888-407-4747 or 202-501-4444
Malaysia Country Information
Enroll in Smart Traveler Enrollment Program (STEP) to receive Alerts.
Alerts, News, U.S. Citizen Services


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U.S. Army Corps of Engineers South Pacific Division gets New Commander
SAN FRANCISCO – Colonel (Promotable) Mark Toy will take command of the South Pacific Division of the U.S. Army Corps of Engineers during a change of command ceremony at the Bay Model visitor center in Sausalito Friday, June 30, 2014.
COL. (P) Toy becomes the 56th commander the South Pacific Division. He assumes command from Brig. Gen. C. David Turner, who took command in 2013 and will serve as Commander of the South Atlantic Division.
COL. (P) Toy brings with him knowledge gained from over 27 years of Army service. Prior to commanding the South Pacific Division, COL. (P) Toy served as the Chief of Staff for the U.S. Army Corps of Engineers, an organization consisting of over 37,000 military personnel and civilian employees.
Established in 1888, South Pacific Division is one of nine Corps regions. Four operating Districts, headquartered in Los Angeles, Sacramento, San Francisco, and Albuquerque, provide federal and military engineering support in California, Arizona, Nevada, Utah, New Mexico and in parts of Colorado, Oregon, Idaho, Wyoming and Texas.
The civil works program is oriented around major watersheds in the region and leverages federal resources for navigation, flood damage reduction and ecosystem restoration. Major river basins include the Sacramento, San Joaquin, Santa Ana, Colorado and Rio Grande, which are governed by complex water rights.
The Change of Command Ceremony symbolically transfers authority and responsibility from one commander to the next, ensuring a continuous, unbroken chain of command from the lowest military unit to the Commander in-Chief of the Armed Forces, the President of the United States.
Media interested in covering the event, please contact the Public Affairs office at 415-503-6514.
Torrie McAllister
victoria.mcallister@usace.army.mil
Randy Gon
randy.gon@usace.army.mil
Release no. 14-004

redpajama_set_name: RedPajamaCommonCrawl


Many people are apprehensive about getting an industrial Joint Pain Hack Review piercing because they are concerned over the amount of pain involved. Here is information about the procedure and how much it will hurt.
Industrial piercing refers to a piercing procedure where two pierced holes are connected with a straight piece of jewelry. Industrial piercing is also referred to as scaffold piercing or even construction piercing.
This type of piercing is generally done on the upper ear cartilages. The first piercing is done at the top of the ear and the second piercing is further down the ear diagonal and opposite the first spot.
How Much Does it Hurt The amount of pain involved in getting an industrial piercing depends on each person's threshold for pain. But in general it is quick and considered only slightly more painful that a traditional piercing in an ear lobe. The big difference is that it is done twice-upper piercing and lower piercing.


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Arrangements in the area Ships in the area
The Heineken Experience is created for all the Heineken fans. This former brewery, where the popular Heineken beer was brewed during a century, has now been transformed into a museum where you can experience an interactive journey through the world of Heineken. Step inside and take a look at the history of this beloved beer brand.
Populair ships from Amsterdam
Excellent service before the trip and friendly and relaxed team from NAUPAR on board.
Sights in Amsterdam
Amsterdam Begijnhof
The New Church Amsterdam
Amsterdam Cheese Museum
The history of the Heineken Experience
The building in which the Heineken Experience is now located, was built in 1867 and it was known as the first brewery of Heineken. The building has operated as a brewery for over 100 years. In 1991 a part of the complex was demolished and in the part that was left, the Heineken reception and information center was opened. In 2001 it was named "Heineken Experience".
Experience it yourself
The Heineken Experience brings its visitors through all the facets of the popular beer brand. Learn how the typical Heineken flavor is developed, take a look at the old brewery and create your own Heineken video. There's plenty to do!


No one would ever accuse Bernie Sanders of thinking small. The senator from Vermont and Democratic presidential candidate wants to transform one of the world's most boisterous free-market economies into an exemplar ofScandinavian-style "democratic socialism." He wants to jail Wall Street executives and double the minimum wage. And he wants to spend taxpayer money, lots of it.
According to an estimate by The Wall Street Journal, Sanders' spending plans would cost $18 trillion over 10 years, increasing the federal government's size by roughly a third. He would create a single-payer health plan, make public universities free, expand Social Security, spend big on infrastructure, create universal child-care and pre-K programs, provide federal jobs for young people and bail out struggling pension plans, among other things.
To be sure, fully $15 trillion of the $18 trillion would come from Sanders' health plan, which seems unlikely to cost that much. Bringing all Americans under the umbrella of a single-payer system would create enormous power to hold down prices.
Even so, there's no doubt that Sanders, who's running a surprisingly strong second to Hillary Clinton in the latest polls, is talking serious money.
Yes, no one would ever accuse Bernie Sanders of thinking small. And no one should ever accuse the USA Today editorial page staff of explaining why increasing the federal government's size by roughly a third is per se a bad idea. I mean other than just saying we can't afford it.
I give the writer of this editorial credit for saying upfront and explicitly that $15 trillion of the $18 trillion would come from Sanders' health plan. That's more than Washington Post editorial writer Stephen Stromberg did the day after that WSJ report last month.* And it's more than the WSJ reporter did in the article itself, if I remember right.
But why exactly is it per se bad to expand the federal government significantly? That is what Medicare and Social Security did, and the National Labor Relations Act and the Securities Exchange Act and the EPA, etc. If you think these pieces of legislation should not have been enacted, fine. But most people would disagree with you.
Sanders wants to replace private-industry healthcare insurance with federal, nonprofit, single-payer insurance. Like Denmark! And like Medicare. I would love to see Sanders have an economist like Uwe Reinhardt or Joseph Stiglitz compute what the cost to individuals receiving Medicare would be now if there were no Medicare. Especially since most of them are retired, so there would not be the possibility of employer-based private insurance.
What drives me crazy about this mindless but politically potent canard is that these folks don't attempt to explain why it would be worse to expand the federal government by a third in this respect than it is to have private, for-profit health insurance companies playing this role instead. How much more income tax revenue would the federal government receive if the money that employers now pay in insurance premiums went instead to wages and salaries? And how much better would the economy be if that happened, and if individuals weren't saddled with premiums and large out-of-pocket healthcare costs?
Josh Barro has an outstanding column in today's New York Times, the theme of which is that Sanders unnecessarily complicates his candidacy and causes confusion—providing an opening to his opponents like the one Clinton took at the debate last week to imply that Sanders wants to nationalize businesses, large and small; he cited Clinton's comment—by calling himself something he is not: a democratic socialist. He's a social democrat, Barro and others he quotes, say, accurately.
The idea behind the Affordable Care Act, and behind Mrs. Clinton's approach to tinkering with Obamacare, is that quality health insurance should be affordable to everyone, and that people who can't afford it should be given subsidies to buy it. For a democratic socialist, that's not good enough; instead, health care should simply be provided to everyone without charge, removing the profit motive from health care. But even this is a matter of degrees. Mr. Sanders favors Medicare for all: a singlepayer health care system, with the federal government as the sole insurer. This would remove the profit motive from health insurance but not from health care, which could continue to be provided by private doctors and hospitals, often working on a forprofit basis. Mr. Sanders is not proposing to go further, like Britain, and have doctors work directly for the government. Nor does he appear inclined to decommodify broad swathes of the economy; in other countries, even conservatives often endorse special, less-marketized rules for health care than for other sectors.
This distinction is real, but it's not clear to me that it merits Mr. Sanders his own ideological label.
That—the idea that some goods and services are so important that they ought to be removed from the market economy altogether—is why it is absolutely incumbent upon the USA editorial writer, Stephen Stromberg, Hillary Clinton, and anyone else who takes the position that a single-payer, Medicare-for-all healthcare insurance system is per se bad because it would be run by the federal government, to actually state why this is so.


How often do we consider the significance of inanimate objects? Do they have consciousness, a soul, or some depth of existence we cannot begin to realise? Living where I do in the rugged tablelands of the Blue Mountains I am often confronted with the awe-inspiring beauty of the landscape and I have cause to reflect on the nature or essence of the landscape: its timelessness, scale and the provoking thoughts of consciousness involved with the landscape.
Rocks and formations are attributed names so we can personalise them and have them more easily recognisable. With this in mind I have named some of the objects Brutti Ma Buoni- (iced Italian biscuits). The phrase quirkily translates as 'Ugly But Good'.


Aptly referred to as the 'Queen of the Hills', Mussoorie is a stunning hill station with scenic views of snow capped mountains, dense forests and pristine lakes. The town is enveloped in dense clouds for most of the year, rendering it a surreal and mystical aura. From nature walks to trekking and exploring the colonial buildings, Mussoorie offers a plethora of activities and sightseeing spots. The popular tourist attractions in Mussoorie Being one of the most visited holiday destinations in the country, there is no dearth of hotels in Mussoorie – from budget to luxurious 5 star hotels and everything in between. Most of the hotels in Mussoorie hotels come under the four star category and popular one is The Claridges Nabha Residency. The top rated Mussoorie hotels are Hotel Emerald Heights, Hotel Dwaper, Hotel Ashoka Continental, Honeymoon Inn, Shiva Continental and H. Grand. Travellers seeking a hotel with the perfect balance of comfort, luxury and value can check out the following hotels.
A quaint hotel that is often rated as one of the best value for money hotels in Mussoorie, Honeymoon Inn offers clean, cozy and comfortable rooms with friendly service. Though the resort is popular with couples, there are almost equal if not more number of families who choose the hotel for their accommodation. The hotel is centrally located with the mall road at a walking distance. There is ample space for guests arriving on their vehicles. The in house restaurant serves freshly prepared and hygienic local fares. Try booking the rooms on the higher floor for stunning views of the valleys.
A centrally located 3 star hotel that is popular amongst families and couples. The rooms are spacious and clean and centrally heated. The Deluxe Rooms are nice but if you are put off by small spaces go for the Valley Rooms with balconies. This hotel in Mussoorie is located on Kempty Fall road and which about 10 minute walk to the Mall road. The quality and variety of the food leaves a bit to be desired but guests willing to forgo that will find this budget hotel more than good.
An excellent budget hotel in Mussoorie located on Happy Valley Road. This is one of the last few Mussoorie hotels with a rustic charm. The entire hotel is dotted with memorabilia that induces a warm nostalgia about a bygone era. The atmosphere is serene and the hospitality is one of the best in town. Try to to book the two front rooms which provide stunning views of the Himalayan range. The in house restaurant is one of the best in Mussoorie and offers a range of specialties like honey roast chicken, spinach baked in cheese and fish orly and kakori kebabs.
Located on Oasis Convent Road, this is a quaint property that might stretch stretch your budget a wee bit more than makes up for it in terms of amenities and hospitality. From the front desk to the house keeping to the manager, everyone at this Mussoorie goes above and beyond to deliver a comfortable stay to the guests. The rooms are fitted with modern amenities and the private balcony offers stunning views of the valley. The hotel is located close to the Mall road yet is well secluded from the noise and rush.


MESQUITE, NV / ACCESSWIRE / September 12, 2018 / Cannabis Sativa, Inc. (CBDS) is pleased to announce that Debby Goldsberry, a member of the Cannabis Sativa Inc. Board of Directors, tops the High Times list of their first ever 'Women in Weed" themed issue. Women owners, executives and innovators were listed for their contributions, influence and accomplishments in cannabis. Debby Goldsberry was lauded as an advocate and owner operator of Magnolia Oakland Dispensary.
Previous StoryWill the New Congress End Cannabis Prohibition in Early 2019?


PayPal offers a subscription-based payment service, which is used to send or receive regularly recurring payments. These are often used for subscriptions to magazines, newspapers or websites, or... "How do I cancel a Paypal monthly subscription payment?" Unfortunately Paypal does not make this easy to find and there is no big "cancel subscription button" anywhere on the website.
"How do I cancel a Paypal monthly subscription payment?" Unfortunately Paypal does not make this easy to find and there is no big "cancel subscription button" anywhere on the website.
PayPal is a digital wallet system. As one of the largest eCommerce websites in the world, PayPal users create accounts and send/receive money electronically for goods and services.


Vacuum Bagging Materials By National Aerospace Supply Co.
National Aerospace Supply Company was established in 1986 by Joyce Lentz and is woman owned small business.
The materials handled by National Aerospace Supply Company meet the required specifications of McDonnell Douglas - Boeing, Lockheed Martin, Northrop Grumman, Triumph Aerostructures - Vought Aircrfaft and General Atomics. We are an approved supplier of these companies and many other subcontractors.
National Aerospace Supply Company is a sponsor for the Orange County and San Diego chapters of the Society for the Advancement of Material and Process Engineering (SAMPE) and sponsors Cerritos College Composite Classes.
National Aerospace Supply Company has also been instrumental in projects at Cal State Pomona, Long Beach State, UC Davis and Cal State Fullerton.
Our commitment is to supply our customers the best quality materials and to be cost effective.


For details see the following reference. This Table however does not appear in the paper.
Kochhar R 2012 Early natural history: contributions from the Americas and India. J Biosciences 37 937-947.
1570-1577 Francisco Hernandez (1515-1587) Royal Spanish Mission to America; influential manuscript, not published in entirety.
1578-1580 Bernardino de Sahagun (1499-1590) Influential manuscript Florentine Codex on Aztec natural history etc.
1582 Clusius (1526-1609) Prepares composite natural history combining d'Orta, Monardes and C. Acosta.
1651 Federico Cesi (1585-1634) Cesi and others complete the encyclopedic work Rerum, with Hernandez as the nucleus.


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CHAI WU ARRIVES AT HARRODS
Posted on 26th February 2015 Tagged Knightsbridge
Chefs Ian Pengelley and Jason See Meng Hwa reveal what's in store for new Harrods contemporary Chinese restaurant Chai Wu, starting with their Beijing duck
Could this be the finest Beijing Duck in London served in the most luxurious setting? The ratio of crackling to fat is perfectly balanced as it is carved in front of me. It comes with freshly made fluffy Mantou buns as well as pancakes and a vast array of homemade sauces and moreish pickles. I am seated at a sophisticated chocolate leather banquette in the newly created fifth floor restaurant Chai Wu at Harrods and Group Executive Chef Ian Pengelley, one of the UK's leading experts in Asian cuisine and Malaysian/Chinese Chef Jason See Meng Hwa have my rapt attention as they explain the intricacies of what makes this such a special dish.
The interior was created by Harrison to reflect the five elements of Chinese philosophy
Appropriately Chai in Chinese means wealth, and no expense has been spared in creating the discreet restaurant. Wu means the number five, referring to Chai Wu's 5th floor location. In addition, the five elements of Chinese philosophy: wood, metal, water, earth and fire have been incorporated by Harrison designers into the look of the restaurant. Fire is explicitly represented with the restaurant's lava rock charcoal grill.
Chai also refers back to the Pan Chai restaurant that is already well established in Harrods Food Hall, also serving Pan Asian dishes created by Ian Pengelley. Chai Wiu is a restaurant for lingering in more private surroundings with the emphasis on very refined presentation. I learn that David Beckham and family often pop in downstairs and are fully expected to be among the fans of the new restaurant, besides a growing number of Chinese visitors to Harrods (now making up 30% of their visitors).
Chef Ian Pengelley's name is likely to be familiar to London restaurant scene watchers. Having trained all over Asia including Thailand, Malaysia and China, Ian was the launch chef of E&O Notting Hill and started his own massively successful Pan Asian restaurant, Gilgamesh back in 2011.
Chef Ian Pengelley
Chef Jason See Meng Hwa
A busy man, he is also executive chef of Thai Mango Tree in Belgravia and a regular on Masterchef. Ian reveals that his passion for Asian food goes back even further. He spent his early childhood in Hong Kong as his father was in the army. He recalls that one day when he was only seven, he ran away from his mother in the middle of the market and found himself in a Chinese restaurant. 'Even then I was blown away by the assault on my senses. It was incredible, steamy and noisy. I was sat in a chair in the kitchen watching the chefs prepare Hainanese chicken. My mother burst in looking terrified.'
Jason has been Ian's right-hand man in the kitchen for more than 10 years and they work intuitively together. 'My background combines Malaysian and Chinese influences, so I was born cooking Pan Asian food. For example, our red snapper dish has a sauce that represents the different areas of Asia with sweet, sharp and spicy notes,' explains Jason. Ian is more explicit. 'Quite simply, I am setting out to sex up Pan Asian cuisine, using authentic techniques yet making dishes that are rather different and very refined and pleasing to behold. Dishes such as our Chilean seabass in champagne.'
Besides flavour, there's lots of colour to dishes, such as their take on sweet and sour chicken balls served tumbling out of a dragon fruit. 'Diners really do want to eat with their eyes too,' observes Ian.
Alaskan king crab with baby asparagus
'The greatest compliment diners have given about Chai Wu so far is that it is impossible to tell that it was once a retail space,' reveals designer Andrew Kirk of Harrison. 'We were working with a very limited space and needed to make it streamlined, yet really warm and inviting. It had to exude simple luxury as well as a touch of theatre.' Most importantly, the lighting is immensely flattering, 'we deliberately chose copper mirrors. They make everyone look better,' he says.
Both Ian and Jason travel extensively for international openings and to gain new insights for their menus. The chefs agree that right now Shanghai and Hong Kong are probably the most exciting places to visit. 'Both these cities are especially vibrant, blend East and West, and are attracting lots of investment and change. They tend to be ahead of the trends,' says Ian.
And now, you might just be able to sample them for yourself by travelling to the heights of Harrods 5th floor.
Words by Sudi Pigott
Harrods 5th Floor, 87-135 Brompton Road, Knightsbridge SW1X 7XL; 020 3819 8888, chaiwu.co.uk
21st Century Grocery Store Opens in Clapham


History What Happened When Shackleton Was Stranded In The Antarctic For Years?
Few exploits of the 20th century could match the courage and perseverance of the Shackleton expedition. Ernest Shackleton became the ultimate model for crisis management when his ill-fated 1914 Antarctic expedition met with disaster. His ship, the Endurance, was stranded amidst the expanding ice floes of the South Atlantic. Initially forced to abandon the vessel (which would eventually sink as a result of the hull being crushed by pack ice), Shackleton established a series of temporary camps on the ice, in the hopes that his party would eventually drift closer to civilization. When this failed, Shackleton was forced to abandon most of his group on remote Elephant Island and attempt a 700-nautical mile journey to the populated outpost of South Georgia Island. The plan, a long shot at best, called for him to then return to Elephant Island with a ship to rescue the remainder of the expedition.
Shackleton and five other men successfully navigated a 20-foot lifeboat across open ocean for 15 days and reached South Georgia Island. Having landed on the remote southern side of the island, Shackleton and two others then traversed a rugged 20-mile route to the tiny port of Stromness. The three other men were quickly rescued from the south side of the island, but it would take almost five months before Shackleton would successfully rescue all 22 men that he had left behind on Elephant Island.
Shackleton died of a heart attack in 1922 and slipped into obscurity until the sheer magnitude of his inspirational journey returned him to his current status as a popular culture icon of bravery and leadership. Some facts about his incredible mission illuminate why his return to prominence was so well-deserved.
Because both Roald Amundsen and Robert Scott had already reached the South Pole, in 1914, Ernest Shackleton proposed to make the first continental crossing of Antarctica, an unprecedented mission. So lengthy was this trek that Shackleton assembled one team he would lead from South America and a second team that would leave from Tasmania and land on the opposite side of the continent along the Ross Sea. Shackleton would not be able to carry enough supplies to make it completely across Antarctica; the Ross Sea party would have to trek almost a third of the way across the continent in order to set up the necessary supply depots. This whole plan was rendered impossible by Shackleton's failure to reach Antarctica before his ship became trapped in the ice, preventing him from landing at an appropriate site.
Shackleton's 1914 Imperial Trans-Antarctic Expedition was beset with problems before he even reached his intended landfall at Vahsel Bay. In January of 1915, unusually cold temperatures precipitated an increase in the pack ice around the ship, the suitably named Endurance, and less than 100 miles from land, the ship became completely immobilized in solid ice. Two days were spent attempting to chop a passage through this barrier to no avail. Even worse, the ship was also moving away from its goal, as the Endurance was at the mercy of the drifting ice floe.
With temperatures routinely hitting -20 degrees centigrade, (-4 F) Shackleton would not be able to reach land until the ice melted, which would potentially take months.
Shackleton's dilemma was not unprecedented. A 1911 German Antarctic exploration commanded by Wilhelm Filchner had also been trapped for six months before enough ice melted to allow his ship, the Deutschland, to escape and return to South Georgia Island. However, Shackleton also had to prepare for the possibility that the ice might begin to exert pressure on the sides of the ship.
He removed weight from the sides of the ship, hoping this would allow the Endurance to rise in the event that the ice began to push together, keeping the vessel intact as opposed to being crushed. Beneath the frozen ice, sea currents exerted tremendous force that pulled the ice floes and Shackleton's ship for many miles. Frequent blizzards and freezing wind also impacted the ice. Shackleton and his crew could only wait.
"The ice is rafting up to a height of 10 or 15 ft. in places, the opposing floes are moving against one another at the rate of about 200 yds. per hour. The noise resembles the roar of heavy, distant surf. Standing on the stirring ice one can imagine it is disturbed by the breathing and tossing of a mighty giant below."
By the end of the month, the ship began to sustain serious damage to its stern. Within a matter of days, it was clear that the Endurance was not going to make it. On October 27, Shackleton gave the order to abandon ship.


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OVERVIEW: A COMMITMENT TO EXCELLENCE
TWAS was founded in 1983 by a distinguished group of scientists from the developing world, under the leadership of Abdus Salam, the Pakistani physicist and Nobel laureate. There were 42 Founding Fellows.
As of the start of 2023 the Academy had 1,384 elected Fellows representing 110 countries, 12 of them Nobel laureates; 231 women comprise 16.7% of the total. Currently 121 scientists from the developing world are serving five- or six-year terms as Young Affiliates, with 66 women accounting for 55% of the total. Another 290 scientists are Alumni of the Young Affiliate programme.
FellowsYoung Affiliates
TWAS: a snapshot
Highcharts.chart('chart_container_fg', { chart: { type: 'area' }, colors: [ '#257db1', '#c6333b', '#e58a44', '#eddf6f', '#8db6e0', '#68b5b7', '#478c6d', '#2d6f99', '#7660a5', '#71695c', ], title: { text: '' }, xAxis: { categories: ["1983","1984","1985","1986","1987","1988","1989","1990","1991","1992","1993","1994","1995","1996","1997","1998","1999","2000","2001","2002","2003","2004","2005","2006","2007","2008","2009","2010","2011","2012","2013","2014","2015","2016","* 2017","2018","2019","2020","2021","2022","2023"], tickmarkPlacement: 'on', title: { enabled: false } }, yAxis: { title: { text: 'Fellows' } }, tooltip: { split: true, valueSuffix: ' Fellows' }, plotOptions: { area: { stacking: 'normal', lineColor: '#666666', lineWidth: 1, marker: { lineWidth: 1, lineColor: '#666666' } } }, series: [{name: 'Male', data : [41,53,88,111,133,193,227,257,294,306,332,352,391,431,458,489,516,560,598,631,669,719,756,782,810,833,867,898,919,955,989,1018,1041,1044,1028,1050,1069,1080,1090,1126,1153]},{name: 'Female', data : [1,2,4,4,5,7,11,13,15,17,18,18,20,20,21,23,27,28,31,34,39,45,51,58,66,68,77,89,101,103,109,118,127,137,136,152,165,176,191,211,232]}], credits: { enabled: false } });
The strength of TWAS resides in the scientific influence and impact of its global network. In order to extend its reach and impact, the Academy is committed to making its ranks of Fellows and Young Affiliates as diverse as possible. From 2013-2016, women accounted for more than 24% of the new Fellows elected.
* Due to a change in the election schedule, no TWAS Fellows were elected for the year 2017. Learn more.
TWAS: a deeper look
Field by Region
Field by Gender
Gender by Region
TWAS is a global science academy dedicated to building science in the developing world. Some 85% of its elected Fellows are from developing countries, and they work across all fields. In recent years TWAS has expanded representation to countries that had few or no members: Fellows have been elected from such countries as the Central African Republic, the Democratic Republic of the Congo, Finland and Kazakhstan, while Young Affiliates have been selected from Costa Rica, Mauritius, Papua New Guinea and Yemen.
TWAS: a worldwide network
Representation in Least Developed Countries
Underrepresented Developing Countries
The boundaries and names shown and the designations used on these maps do not imply official endorsement or acceptance by the United Nations.


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Markov Decision Processes (MDPs) - Structuring a Reinforcement Learning Problem
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What's up, guys? In this post, we're going to discuss Markov decision processes, or MDPs. This topic will lay the bedrock for our understanding of reinforcement learning, so let's get to it!
Components of an MDP
Markov decision processes give us a way to formalize sequential decision making. This formalization is the basis for structuring problems that are solved with reinforcement learning.
To kick things off, let's discuss the components involved in an MDP.
In an MDP, we have a decision maker, called an agent, that interacts with the environment it's placed in. These interactions occur sequentially over time. At each time step, the agent will get some representation of the environment's state. Given this representation, the agent selects an action to take. The environment is then transitioned into a new state, and the agent is given a reward as a consequence of the previous action.
Components of an MDP:
This process of selecting an action from a given state, transitioning to a new state, and receiving a reward happens sequentially over and over again, which creates something called a trajectory that shows the sequence of states, actions, and rewards.
Throughout this process, it is the agent's goal to maximize the total amount of rewards that it receives from taking actions in given states. This means that the agent wants to maximize not just the immediate reward, but the cumulative rewards it receives over time.
It is the agent's goal to maximize the cumulative rewards.
Alright, let's get a bit mathy and represent an MDP with mathematical notation. This will make things easier for us going forward.
MDP notation
We're now going to repeat what we just casually discussed but in a more formal and mathematically notated way.
In an MDP, we have a set of states \(\boldsymbol{S}\), a set of actions \(\boldsymbol{A}\), and a set of rewards \(\boldsymbol{R}\). We'll assume that each of these sets has a finite number of elements.
At each time step \(t = 0,1,2,\cdots\), the agent receives some representation of the environment's state \(S_t \in \boldsymbol{S}\). Based on this state, the agent selects an action \(A_t \in \boldsymbol{A}\). This gives us the state-action pair \((S_t,A_t)\).
Time is then incremented to the next time step \(t+1\), and the environment is transitioned to a new state \(S_{t+1} \in \boldsymbol{S}\). At this time, the agent receives a numerical reward \(R_{t+1} \in \boldsymbol{R}\) for the action \(A_t\) taken from state \(S_t\).
We can think of the process of receiving a reward as an arbitrary function \(f\) that maps state-action pairs to rewards. At each time \(t\), we have $$f(S_{t}, A_{t}) = R_{t+1}\text{.}$$
The trajectory representing the sequential process of selecting an action from a state, transitioning to a new state, and receiving a reward can be represented as $$S_0,A_0,R_1,S_1,A_1,R_2,S_2,A_2,R_3,\cdots$$
This diagram nicely illustrates this entire idea.
Let's break down this diagram into steps.
At time \(t\), the environment is in state \(S_t\).
The agent observes the current state and selects action \(A_t\).
The environment transitions to state \(S_{t+1}\) and grants the agent reward \(R_{t+1}\).
This process then starts over for the next time step, \(t+1\).
Note, \(t+1\) is no longer in the future, but is now the present. When we cross the dotted line on the bottom left, the diagram shows \(t+1\) transforming into the current time step \(t\) so that \(S_{t+1}\) and \(R_{t+1}\) are now \(S_t\) and \(R_t\).
Transition probabilities
Since the sets \(\boldsymbol{S}\) and \(\boldsymbol{R}\) are finite, the random variables \(R_t\) and \(S_t\) have well defined probability distributions. In other words, all the possible values that can be assigned to \(R_t\) and \(S_t\) have some associated probability. These distributions depend on the preceding state and action that occurred in the previous time step \(t-1\).
For example, suppose \(s' \in \boldsymbol{S}\) and \(r \in \boldsymbol{R}\). Then there is some probability that \(S_t=s'\) and \(R_t=r.\) This probability is determined by the particular values of the preceding state \(s \in \boldsymbol{S}\) and action \(a \in \boldsymbol{A}(s)\). Note that \(\boldsymbol{A}(s)\) is the set of actions that can be taken from state \(s\).
Let's define this probability.
For all \(s^{\prime } \in \boldsymbol{S}\), \(s \in \boldsymbol{S}\), \(r\in \boldsymbol{R}\), and \(a\in \boldsymbol{A}(s)\), we define the probability of the transition to state \(s^{\prime }\) with reward \(r\) from taking action \(a\) in state \(s\) as:
\begin{equation*} p\left( s^{\prime },r\mid s,a\right) =\Pr \left\{ S_{t}=s^{\prime },R_{t}=r\mid S_{t-1}=s,A_{t-1}=a\right\} \text{.} \end{equation*}
Alright, we now have a formal way to model sequential decision making. How do you feel about Markov decision processes so far? Some of this may take a bit of time to sink in, but if you can understand the relationship between the agent and the environment and how they interact with each other, then you're off to a great start!
Like we discussed earlier, MDPs are the bedrock for reinforcement learning, so make sure to get comfortable with what we covered here, and next time we'll build on concept of cumulative rewards. I'll see ya there!
Welcome back to this series on reinforcement learning! In this video, we'll discuss Markov decision processes, or MDPs. Markov decision processes give us a way to formalize sequential decision making. This formalization is the basis for structuring problems that are solved with reinforcement learning. We will detail the components that make up an MDP, including: the environment, the agent, the states of the environment, the actions the agent can take in the environment, and the rewards that may be given to the agent for its actions. Sources: Reinforcement Learning: An Introduction, Second Edition by Richard S. Sutton and Andrew G. Bartow http://incompleteideas.net/book/RLbook2020.pdf Playing Atari with Deep Reinforcement Learning by Deep Mind Technologies https://www.cs.toronto.edu/~vmnih/docs/dqn.pdf 🕒🦎 VIDEO SECTIONS 🦎🕒 00:00 Welcome to DEEPLIZARD - Go to deeplizard.com for learning resources 00:30 Help deeplizard add video timestamps - See example in the description 06:04 Collective Intelligence and the DEEPLIZARD HIVEMIND 💥🦎 DEEPLIZARD COMMUNITY RESOURCES 🦎💥 👋 Hey, we're Chris and Mandy, the creators of deeplizard! 👀 CHECK OUT OUR VLOG: 🔗 https://youtube.com/deeplizardvlog 👉 Check out the blog post and other resources for this video: 🔗 https://deeplizard.com/learn/video/my207WNoeyA 💻 DOWNLOAD ACCESS TO CODE FILES 🤖 Available for members of the deeplizard hivemind: 🔗 https://deeplizard.com/resources 🧠 Support collective intelligence, join the deeplizard hivemind: 🔗 https://deeplizard.com/hivemind 🤜 Support collective intelligence, create a quiz question for this video: 🔗 https://deeplizard.com/create-quiz-question 🚀 Boost collective intelligence by sharing this video on social media! ❤🦎 Special thanks to the following polymaths of the deeplizard hivemind: Tammy Prash Zach Wimpee 👀 Follow deeplizard: Our vlog: https://youtube.com/deeplizardvlog Facebook: https://facebook.com/deeplizard Instagram: https://instagram.com/deeplizard Twitter: https://twitter.com/deeplizard Patreon: https://patreon.com/deeplizard YouTube: https://youtube.com/deeplizard 🎓 Deep Learning with deeplizard: Fundamental Concepts - https://deeplizard.com/learn/video/gZmobeGL0Yg Beginner Code - https://deeplizard.com/learn/video/RznKVRTFkBY Intermediate Code - https://deeplizard.com/learn/video/v5cngxo4mIg Advanced Deep RL - https://deeplizard.com/learn/video/nyjbcRQ-uQ8 🎓 Other Courses: Data Science - https://deeplizard.com/learn/video/d11chG7Z-xk Trading - https://deeplizard.com/learn/video/ZpfCK_uHL9Y 🛒 Check out products deeplizard recommends on Amazon: 🔗 https://amazon.com/shop/deeplizard 📕 Get a FREE 30-day Audible trial and 2 FREE audio books using deeplizard's link: 🔗 https://amzn.to/2yoqWRn 🎵 deeplizard uses music by Kevin MacLeod 🔗 https://youtube.com/channel/UCSZXFhRIx6b0dFX3xS8L1yQ 🔗 http://incompetech.com/ ❤ Please use the knowledge gained from deeplizard content for good, not evil.
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Reinforcement Learning Series Intro - Syllabus Overview
Expected Return - What Drives a Reinforcement Learning Agent in an MDP
Policies and Value Functions - Good Actions for a Reinforcement Learning Agent
What do Reinforcement Learning Algorithms Learn - Optimal Policies
Q-Learning Explained - A Reinforcement Learning Technique
Exploration vs. Exploitation - Learning the Optimal Reinforcement Learning Policy
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Deep Q-Learning - Combining Neural Networks and Reinforcement Learning
Replay Memory Explained - Experience for Deep Q-Network Training
Training a Deep Q-Network - Reinforcement Learning
Training a Deep Q-Network with Fixed Q-targets - Reinforcement Learning
Deep Q-Network Code Project Intro - Reinforcement Learning
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Kari Burns
Kari Burns Pundit
Help me about radio channel icon ideas?
Elaine Villevoye
Elaine Villevoye Pundit
>>IT'S EASY<<
Diomar Bulygo
Diomar Bulygo Teacher
Acknowledging the good in your neighbors and neighborhood Cancer Prevention through Overall Wellness Dangers of Distracted Driving/ Texting While Driving Heart Health & Cardiovascular Disease Prevention There is a growing desire world-wide to understand the sometimes misunderstood country of China and benefit from studying the most widely spoken language in the world. More and more people both young and old are learning the language to increase business opportunities and for personal reasons. In fact, quite a few prominent individuals have decided to learn Chinese and broaden their horizons. Among them are former Australian Prime minister, Kevin Rudd; the U. President Obama's daughter, Malia Obama and the successful entrepreneur, Mark Zuckerberg. They all chose to study Chinese as their second language. The study of the language opens the doorway to a variety of important fields including Chinese politics, history, economy and other business opportunities. In 2010, 750,000 people from around the world took the Official Chinese Proficiency Test. The individuals who began studying the language were very diverse, varying in both industries and backgrounds. There is a huge growth worldwide in the number of non-Chinese, heritage people learning Mandarin. In fact, recently President Obama announced a new initiative aimed at having 1 million American school children learn Mandarin Chinese over the next five years. The Chinese economy is quickly becoming the world's largest economy once again, which makes it crucial for Westerners to better understand Chinese culture, and prepare American students to deal with China in future jobs. Obama announced the new initiative while standing aside Chinese President Xi Jinping, who said 2016 "will be a year of tourism between China and the United States. " He said 50,000 students will participate in an exchange program between the two countries within the next three years. It's easy to see why knowing Mandarin and understanding China is so important when you factor that they have 1. 28 billion people, which equals one fifth of the global population. Presently, China is the second largest economy in the world, along with world powerhouses such as the U. In 2014, China's top three trading partners were the U. at $521 billion, Hong Kong at $401 billion and Japan. The demand for learning Chinese as a second language has gone up dramatically, which has made the services that teach the language very popular. According to the Chinese Ministry of Education, more than 330 official institutions are teaching Chinese as a foreign language around the world. The majority of the students are from other countries. Unfortunately, it's impossible for everyone wishing to learn Chinese to take a course in the country of origin. That's why online services offering one-on-one tutoring are very valuable. These services aim to promote Chinese language and culture, support local Chinese teaching internationally, and facilitate cultural exchanges. Students who enroll in these types of programs are able to speak directly with someone from China, so they see great results in just a few weeks. All the teachers are authentic Mandarin speakers, which helps with pronunciation. Learning Chinese benefits anyone in "the West" or from countries that make up China's largest trading partners' such as U. Now more than ever, it's crucial to learn this language and gain better knowledge of one of the oldest cultures in the world.
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Read 3 reviews and enjoy exclusive savings on Luxury Gold's 8 Day Indulgence in Eastern Canada. Rich in European architecture and striking natural phenomena, you've made it to eastern Canada. A mix of English and French cultures, indulge in all the elegance this romantic...read more journey has to offer. From the sweeping skylines of Toronto to the thundering thrills of the Niagara Falls, you'll be equally inspired by both the natural elements and urban areas of this striking part of the world. Along the way you'll stay at the best hotels, including the Fairmont Château Laurier in Ottawa and Fairmont Le Château Frontenac in Quebec City, both praised for their decadent décor and prime locations.
2 Toronto Sightseeing And Niagara Falls Up Close.
3 Kingston And The Canadian Capital Of Ottawa.
5 The Old Walled City Of Quebec.
Ottawa: Meet a retired member of the Royal Canadian Mounted Police, colloquially known as 'The Mounties', and learn first-hand about Canada's iconic national police force.
Quebec City: As a guest at the iconic, luxury Fairmont Le Château Frontenac, enjoy an exclusive guided tour of this historic building, learn about the history of the château, and gain access to areas not accessible to the general public.
Quebec: Visit the Morrin Centre before it opens to the public to learn about the historic contribution and present-day culture of local English speakers.
Toronto: Take in panoramic views of the city from the CN Tower.
Niagara Falls: Greet the howling spray, wind and thunder at the base of the Falls on-board your cruise.
Quebec City: On a sightseeing tour, a Local Expert will bring to life this beautiful and historic city that will feel as if you've set foot on European soil.
Montreal: Visit Saint Joseph's Oratory, home to one of the world's greatest organs and enjoy an exclusive recital.
Enjoy the comfort of Luxury Gold's air-conditioned 40-seat coach with double the standard legroom, onboard restroom and and complimentary bottled water for you to enjoy while travelling.
Hotel and restaurant tips are included - you'll never have to worry about how much to give, nor search for foreign currency.
We also include all taxes and porterage charges at hotels. Stay connected with friends and family with our complimentary coach and hotel Wi-Fi (where available).
Ottawa: Join us for a Highlight Dinner at the Courtyard Restaurant - a culinary experience that will delight your taste buds.
Quebec City: Dine at Chez Rioux & Pettigrew, a modern eatery and bar showcasing creative, seasonal dishes that celebrate artisanal meats and local seafood.
Montreal: Celebrate with wine and good cheer at Gibbys in Old Montreal.
Toronto: The Omni King Edward Hotel showcases the old-world charm and vibrancy of the city.
Ottawa: You will be treated to a spectacular stay with unparalleled luxury at the Fairmont Château Laurier.
Quebec City: The urban resort of the Fairmont Le Château Frontenac will entice you with its breathtaking views of the St Lawrence River and Old Quebec.
Montreal: Fairmont The Queen Elizabeth Hotel has welcomed queens, princes and princesses, heads of state and international business leaders.
8 Day Indulgence in Eastern Canada reviews from past clients of Global Journeys.
An excellent tour overall, highly knowledgeable tour director, well planned itinerary, luxurious hotel stays, and excellent tour inclusions - exclusive guided tours, themed dinners, breakfasts and a lot of flourishes. I would highly recommend this tour for anyone particularly planning to go to Canada. This tour has been wonderfully organised for us by Hannah at Global Journeys and we are already planning our next trip with her. Hannah has always been prompt in replying to my emails and always...read more keeps us updated. Thanks so much again Hannah.
Dealing with Georgie who we have not met, has been a joy. Nothing too much trouble and all arrangements efficiently carried out. All flight details perfect, and the Insight Vacation tour of Quebec very very good. Very short, but still an overview of the area, and each night in an excellent centrally placed hotel. A well organised and efficient tour.
Trip prices are per person, and reflect applicable discounts. Discounts are subject to availability, exclusive to Global Journeys and may be withdrawn at any time without notice. Trip prices are correct at the time of the products going live, however are subject to confirmation at the time of booking. All trip information is correct at time of trips going live, however are subject to change by Luxury Gold. Full terms & conditions are available here.


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Tag: Graceless
Limbo Kids – Graceless – Single Review
By Tim September 5, 2014 March 15, 2015 New Release, Release Reviews
Limbo Kids is a band from England I last looked at almost two years ago.
Limbo Kids – Graceless – artwork
At the time a duo, the line-up has now extended to four. Given the change in members and a slightly different sound to the material, which is now much lighter in feel, it is of little surprise that there was a slowing down in activity, although a three track single did appear last year.
Now firmly back on track Limbo Kids have a new single set for release on the 29th September – Graceless, which finds the band with a sense of greater confidence. Retaining an element of the shoegaze, they have zipped up the tempo and lightened the mood to provide a dance beat driven sound, with enhanced synths, giving the music a more spacious feel and a wider appeal.
It will be interesting to hear how things develop over the next few months.
Tagged Graceless, Limbo Kids, new release, release review, Single review


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Q: Tiling a large QGraphicsItem in a QGraphicsView I am currently using a QGraphicsItem that I am loading a pixmap into to display some raster data. I am currently not doing any tiling or anything of the sort, but I have overriden my QGraphicsItem so that I can implement features like zooming under mouse, tracking whick pixel I am hovering over, etc etc.
My files that are coming off the disk are 1 - 2GB in size, and I would like to figure out a more optimal way of displaying them. For starters - it seems like I could display them all at once if I wanted - because the QImage that I am using (Qpixmap->QImage->QgraphicsItem) seems to fail at any pixel index over 32,xxx (16 bit).
So how should I implement tiling here if I want to maintain using a single QGraphicsItem? I dont think I want to use multiple QGraphicsItems to save the displayed data + neighboring data "about" to be displayed. This would require me to scale them all when the person moused over and tried to scale a single tile, and thus causing me to also have to reposition everything, right? I guess this will also require having some knowledge about what data to exactly get from the file.
I am however open to ideas. I also suppose it would be nice to do this in some kind of threaded way, that way the user can keep panning the image or zooming even if all the tiles are not loaded yet.
I looked at the 40000 chip demo, but I am not sure that is what I am after - it looks like it basically still displays all of the chips like you normally would in a scene, just overrode the paint method to supply less level of detail...or did I miss something about that demo?

A: It's not too surprising that there would be difficulty handling images that size. Qt just isn't designed for it and there are possibly other contributing factors due to the particular OS and perhaps the way memory is managed.
You very clearly need (or at least, should use) a tiling mechanism. Your main issue is that you need a way to access your image data that does not involve using a QImage (or QPixmap) to load the entire thing and provide access to that image data since it has already been determined that this fails.
You would either need to find a method (library) that can load the entire image into memory and allow you to pull regions of image data out of it, or load only a specific region from the file on disk. You would also need the ability to resize very large regions to lower resolution sections when trying to "zoom" out on any part of the image. Unfortunately, I have never done image processing like this so am unfamiliar with what library options are available, Qt likely won't be able to help you directly with this.
One option you might explore however is using an image editing package to break your large image up into more manageable chunks. Then perhaps a QGraphicsView solution similar to the chip demo would work.

redpajama_set_name: RedPajamaStackExchange


Taxes: Please review Tax Relief for Victims of Terrorist Attacks (PDF 130 kb).
Third Party Expenses: ITVERP accepts only one application per victim. If you are applying on behalf of other family members, you must include their expenses in your request for reimbursement.
Repayment: This applies in cases of overpayment to applicants, fraudulent Information, or ineligibility of the claimant.


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Television was introduced to Sri Lanka on 13 April 1979 with the establishment of the Independent Television Network (ITN). In less than two months, it was nationalised on 5 June 1979. Under the Sri Lanka Rupavahini Act of 1982, ITN and the Sri Lanka Rupavahini Corporation (SLRC) monopolised the television industry until the 1980s.
Today, private television outlets are among the top most watched channels in the country. Audience concentration in the sector of television is 77%. Though concentrated, TV remains a competitive space as the top three channels operate almost at eye level with respect to viewership.
Channel Eye / Nethra TV
DAN TV
Independent Television Network (ITN)
Rupavahini
Shakthi TV
Swarnavahini


Yesterday was the last day of work before Christmas break. In honor of that we had a party for the kids. It was a lot of fun. I was expecting destruction and chaos...but it really wasn't that bad.
We ate pizza, drank soda, ate candy, decorated cookies, played games...and my favorite activity was decorating one kid from each class as a Christmas tree. The student that we decorated from my class was a good sport because those kids did a number on him.


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Johannesburg Gets a Taste for Japan's Kobe Beef
Braeside Butchery owner Caroline McCann in Johannesburg. (Darren Taylor for VOA News)
Johannesburg, South Africa is one of Africa's top cities in business and wealth. Its financial area is often called the richest square mile on the continent. As its wealth increases so does the tastes of its residents.
Right now, demand is rising in Johannesburg for Kobe beef. Top cooks and professional meat cutters say it is the best beef in the world. It is definitely the most costly.
The beef comes from Wagyu cattle in Japan's Kobe region. The beef's fat content makes it rich and melt-in-your-mouth tender.
At Braeside Butchery in Johannesburg, butchers slice through carcasses -- the remains of the dead cow. Caroline McCann is the owner of the meat store. She is a "huge fan" of Kobe beef.
The Japanese taught her how to cook it: drop thin pieces into boiling miso soup for a very brief time.
"And with chopsticks just three to five times put the meat through the broth, and enjoy. And you do! It is just delightful. It's incredibly creamy; almost like eating a slab of butter, so it's very rich; you certainly can't eat a lot of it."
Caroline McCann has visited Japan. She says the meat currently costs more than $1,000 dollars a kilo on international markets.
McCann says Kobe farmers understand that the better they feed and treat their animals, the better their beef will taste.
"It's kind of the ultimate diet. So they ((the cows)) have this wonderful massage once a day and then they get fed beer every day. Most people I know would put their hands in the air and beg to be a Wagyu." (Laughing) "And so what they get is they get roughly a liter, liter and a half, of hops every day. So it's high carb, high sugar, which also helps them to bulk up."
An order is ready in the kitchen of a restaurant in Sandton, a wealthy area of Johannesburg. Businessman Dennis Atwood is eating Kobe-style steak.
"It is of the best in the world. It's dry on the outside and quite pleasant to eat. The flavor is certainly intense."
Caroline McCann says Kobe-style beef is something that wealthy people from all over the world want.
"The people that are looking for this are the same people that are very well traveled, very well read, very well informed; they would have eaten at some of the ((world's)) top restaurants.
She says there also are a lot of people from elsewhere in Africa, who visit Johannesburg for business, and they too want to eat Kobe beef.
"So a lot of people from Ghana and Kenya and Congo, who come with significant money, come with a significant understanding of food internationally, and they're also actively seeking out this kind of product."
Very soon, Caroline McCann says she is set to import Kobe-style beef from Australia, where Wagyu-crossbreeds are growing.
She plans to sell the beef for 1,300 rands, or more than $100 dollars a kilo… But it will obviously sell for much more at restaurants.
I'm Marsha James.
Darren Taylor reported this story from Johannesburg. Marsha James adapted it for VOA Learning English. Caty Weaver was the editor.
butchery – n. the work of a butcher: the job of preparing meat for sale
carcass – n. the body of a dead animal
ultimate – adj. greatest or most extreme
beg – v. to ask (someone) in a very serious and emotional way for something needed or wanted very much
bulk up – phrasal verb to gain weight often by becoming muscular
crossbreeds – v. to make two different kinds of animal breed together


Gideon Iliya who has been an outstanding player for DFA since last year wins the DFA player of the month of March after being nominated three times without winning. Gideon was presented with the award in Diamond FA 4th showcasing game by a Norwegian Scout Mr. Yousoupha Fall. Congratulations to the great DFA Midfielder.


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Most Read Bi Masturbation Sex Stories
It's just sex
It was a very fun and sexually charged year. But then year one was over and soon the sophomore year began. Anyway, I had gotten a little bit of a reputation of fucking and moving on from one girl to another. I'm not saying I was a stud or anything, just that I had good enough looks to keep me busy for the first year.
4.3 2598 words 12 mins college & first time & friendship
Jerking Off with My Best Friends
We were playing video games all day when Clive opened is phone and his gay porn from the day before started playing. We were shocked because Clive always insisted he was straight. It turned me really on because I was also secretly bi. Clive said that he was just checking it out. And I said: "I would like to check you out", while having a throbbing 12 inch boner, which was clearly visible.


Some people know that fat is important for body but if the amount of fat is too high, it will increase the risk of serious disease. To know whether your body fat percentage is normal or nonstandard, you need to measure it. Calculating body fat percentage can be complicated if you do not know how to take it. There is simple way to measure body fat percentage and it is also accurate; dexa scan. This method utilizes x-ray technology to measure body fat. Some popular university has this technology; you can also ask your doctor where you can find it. This method is quite pricey but it is equal to the result.
Place your tape just under your adam aple, do not press your neck, just relax and measure it. If the result is not exact, you just calculate it up to the nearest half inch.
Mesure your waist circumference is not complicated, you just need to place tape under your belly buton. It is recommended to ask someone help to measure it while you hang your arms.
This is also important in measuring body fat percentage because women carry more fat especially on their hips. You just need to place tape and measure the circumference; it is best for you do not wear pants while taking this measurement.
This is easy, you just need to stand and lay on the flat surface. Keep your head up, your body stand straight. Place the ruler up your head and mark it. Then you measure height from the floor to ruler mark.
This kind calculator can you find on website. Make sure your measurement is accurate to get the exact result as well.
It is the simple way to measure your body fat percentage. Calculating body fat percentage is not hard task and you can do it by yourself but it will be more accurate if you see professional exert to take it such as using dexa scan.


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Kuurne–Brusel–Kuurne je jednodenní cyklistický závod konaný v Belgii. Koná se den po závodu Omloop Het Nieuwsblad poslední neděli února nebo první neděli března a uzavírá úvodní víkend belgické cyklistické sezóny. Závod je součástí UCI ProSeries na úrovni 1.Pro. Tom Boonen je nejúspěšnějším účastníkem závodu díky svým 3 vítězstvím.

Historie

Úvodní ročníky
První ročník závodu se konal v roce 1946 a začínal ve městě Kuurne, známém svým textilním průmyslem, směřoval do Bruselu a následně se vrátil zpět do Kuurne. V 50. letech sloužil jako úvodní závod belgické cyklistické sezóny. Když se začal Brusel stávat nepřístupných pro cyklistický závod, byl závod přeplánován směrem do Vlámských Arden. Zároveň byl také přejmenován na "Omloop der beide Vlaanderen". V roce 1979 se však organizátoři rozhodli vrátit zpět původní název Kuurne–Brusel–Kuurne.

Počasí
Vzhledem k zimními termínu závodu je často závod poznamenán špatnými povětrnostními podmínkami. Tři ročníky musely být zrušeny kvůli sněžení nebo mrazu, a to 1986, 1993 a 2013. Ročník 2010 se konal v extrémních podmínkách, protože zbytky orkánu Xynthia provázené silným větrem a prudkým deštěm zasáhly Belgii. Závod musel být zkrácen o 20 km kvůli spadlému stromu na silnici. Vítězem se stal Nizozemec Bobbie Traksel. Do cíle dojelo pouze 26 jezdců z původních 195. V roce 2004 se Kuurne stalo úvodním závodem sezóny po zrušení Omloopu Het Nieuwsbladu kvůli sněhu, který stihl přes noc roztát.

Seznam vítězů

Vítězství dle zemí

Odkazy

Reference

Související články
 Peter Sagan
 Omloop Het Nieuwsblad

Externí odkazy

Cyklistické závody v Belgii

redpajama_set_name: RedPajamaWikipedia


January 15, 2010 in "Black Rock Coffe Bar chris swann elaine swann swannconcepts.com music multimedia etiquette talble manners mac g1"
In Oceanside California, Black Rock Coffe Bar is now open and everything on the menu is free! That's whats up! Sorry Starbucks I'm jumping ship!


It's bigger, faster and darker than the original movie, so perhaps it's not surprising that it is receiving a bigger screen debut than "Spider-Man" or "Harry Potter."
In "X2: X-Men United," the sequel to 2000's hit film "X-Men," rival gangs of mutants unite to battle a common enemy.
Charles S. Dutton, who directs and stars with Meg Ryan in the upcoming Paramount Pictures feature "Against the Ropes," will star in Dark Castle Entertainment's supernatural thriller "Gothika" for director Mathieu Kassovitz.


text:
"Have you seen my dick?"
Once upon a time, Eli Roth's debut film Cabin Fever (2002 / trailer) was high on my list of films I wanted to see, but then I saw Roth's Hostel (2005 / trailer), a totally non-scary and stupid and overtly xenophobic film — Hey! That foreign guy must be evil! He eats salad with his fingers! — and Cabin Fever quickly got deleted from the list. But after Eli Roth's rather effective acting turn in Inglorious Basterds (2009 / trailer), however, the thought arose to give Cabin Fever a chance. First films are often better than the second, after all.
As the cookie is apt to crumble, however, the sequel Cabin Fever 2: Spring Fever fell into my hands first — but then, it ain't like Cabin Fever 2: Spring Fever features any plot points that require seeing the preceding film to understand, assuming that you at least know the first flick was about a highly contagious, body-rotting and deadly disease.
The birth of the sequel was anything but an easy one, as any trash-film aficionado is probably aware of from all the reports that have popped up on the web over the years. Ti West, a new shooting star of the American horror film scene who had made some waves with his third film The House of the Devil (2009 / trailer), was pulled in to helm the flick, for which he also supplied the story. Once he finished filming way back in 2007, the powers that be weren't happy with the final product, which they then reshot in parts and re-cut, the end result being that Ti West wanted his directorial credit removed and the film to be credited to good ol' Alan Smithee. But since he was not a member of the Director's Guild, the producers denied his request and released the film as his product, though he himself has completely disowned it. Considering its reception after Cabin Fever 2: Spring Fever was finally pulled down off the shelf, dusted and released, the chance of a "Director's Cut" seems relatively slim...
Probably about as slim as the film's plot, actually: water gets infected by sickness, teens at prom drink water, everyone dies — bloodily, gushingly, hilariously. And interwoven in-between, a rather pointless subplot involving Deputy Winston (Giuseppe Andrews of 2001 Maniacs [2005 / trailer]), the cop from the first film, that may include one or two hearty laughs (the gusher at the restaurant, for example) but only proves itself ever-so-slightly necessary as the dues ex machina required for the film's end-of-days final — and it also serves to make the last bit about the strippers all the more obviously tacked on as an afterthought.
Cabin Fever 2: Spring Fever sort of picks up directly after the events of the first film with an infected Paul (Rider Strong of Tooth & Nail [2007 / trailer]) pulling himself out of the water and stumbling onto a road where he promptly explodes when hit by a school bus. A nifty animation credit sequence follows that not only sets the parodist tone of the film that follows but also narrates how the infected water makes its way to the local water bottling plant, is bottled and finally delivered to the school. Some time is spent on the introducing the future infected, and for a change some of them almost look the right age for being in high school; some future dead are more likeable than others, but virtually all of them end up at the high school prom. (Thus making the film's title, Cabin Fever 2: Spring Fever, rather an anachronism: not only does nothing occur in a cabin, but spring is more-or-less over.)
At the prom, all hell breaks loose once the infection sets in just as truckloads of unidentified exterminating governmental agents lockdown the school and begin to eradicate the infected. The film's nominal figures of identification are John (Noah Segan of Brick [2005 / trailer], Deadgirl [2008 / trailer] and All about Evil [2010 / trailer]), his best friend Alex (Rusty Kelley) — who dies dickless — and Cassie (the intriguing-looking Alexi Wasser of Growth [2009 / trailer]), and they run around a lot as they try to avoid both the infected and the exterminators — and deal with their own infection.
The bloodbath of the prom is full of gross-out laughs though the projectile puking does get tiresome, but there are many a mean laugh elsewhere in the film, including a few doozies involving a pissing janitor, a fat chick losing her virginity in a swimming pool, and Alex's shower-not-a-grower dick. As mentioned before, the tacked on stripper scene — though also funny in an uncouth, boundary-pushing way — is rather pointless, but the final animation scene does nicely tie up all the loose threads... but for one totally forgotten one that gets tied after the final credits have rolled.
Neither tension nor intelligence are to be found anywhere in Cabin Fever 2: Spring Fever, and the film is hardly imperative viewing, but for what it is — a tasteless, below-the-belt, blood-and-guts-heavy parody — it works well enough: there is indeed a lot of viscera and a never-ending stream of tasteless laughs and gross-out scenes. Thus, the flick actually makes for fun viewing, particularly when stoned.
Short Film: A Great Big Robot from Outer Space Ate...
R.I.P.: Leslie Nielsen
Der Fälscher von London / The Forger of London (Ge...
R.I.P.: Ingrid Pitt


What's the only thing better than watching the boys in blue and white out on the hallowed King Power turf? Being out there yourself of course!
And that's exactly what Leicester City supporters have the chance to do on Friday 17th May 2019 thanks to our free to enter play on the pitch competition for Foxes fans.
Maybe you'll recreate a Jamie Vardy rocket of your own!


he company history goes back to the second half of the nineteenth century when Andrzej Stepkowski's plant, manufacturing platter products, was established. After the war, however, due to post-war distraction, its activity was dropped.
few years later, Andrzej Stepkowski, having same initials as the plant founder, inspired by his family history and being aware of the possession of original samples and models, in 1967 reopened the company as ARTISTIC PRODUCTS A. STÊPKOWSKI. Quite soon, in 1974 Central Association of Crafts spotted the company's products at the Polish Exhibition of Arts and Crafts and awarded the company with a silver medal.
. Stepkowski's products are handmade, based on the original designs while their range has been expanded over the years in respond to customer's tastes and requirements. Our wide range of articles covers silver and brass coated trays, epergnes, boxes, sugar bowls made of metal and ferruled, decanters ferruled with silver elements, mirrors, candlesticks, fruit knives, icons etc. - total over 250 models and designs.
We also have great experience in renovating old items of historic value. It means silver coating, adding missing parts (e.g. legs, handles, covers) etc.
ur products have been appreciated by our customers who look for original and valuable presents on special occasions like: weddings, birthdays, anniversaries etc. They are excellent interior supplement of an elegant house, a mansion, a restaurant or a hotel. The A. Stepkowki Company sells its products at the Polish market as well as foreign ones; we have exported them to Sweden, Germany, USA, Spain, Italy and Austria.
e welcome and invite lovers of beautiful, stylish products and professionals involved in interior designing, owners of restaurants, shops and companies, wholesale stores both Polish and foreign ALL OF YOU WHO ARE INTERESTED IN "BEAUTY WITH A SOUL".


Abstract. The method to Subtract, Multiply and Divide two Field Numbers over the Extended Galois Field GF(p^q) is a well needed solution to the field of Discrete Mathematics as well as in Cryptology. In this paper the addition of two Galois Field Numbers over Extended Galois Field GF(p^q) has been reviewed and Subtraction, Multiplication and Division of two Galois Field Number over Extended Galois Field GF(p^q) has been defined.


text:
Current approaches for multiple myeloma
Mechanisms of autologous GVT in MM
Commentary Free access | 10.1172/JCI125431
Autologous graft versus myeloma: it's not a myth
Shuai Dong and Irene M. Ghobrial
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Irene M. Ghobrial, Harvard Institute of Medicine Room 240, 4 Blackfan Circle, Boston, Massachusetts 02115, USA. Phone: 617.632.6777; Email: Irene_Ghobrial@DFCI.harvard.edu.
Find articles by Dong, S. in: JCI | PubMed | Google Scholar |
Find articles by Ghobrial, I. in: JCI | PubMed | Google Scholar
First published November 19, 2018 - More info
J Clin Invest. 2019;129(1):48–50. https://doi.org/10.1172/JCI125431.
Copyright © 2019, American Society for Clinical Investigation
First published November 19, 2018 - Version history
Bone marrow transplantation generates T cell–dependent control of myeloma in mice
Slavica Vuckovic, … , Mark J. Smyth, Geoffrey R. Hill
Research Article Immunology Transplantation
Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk*MYC myeloma–bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell–dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell–dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes.
Slavica Vuckovic, Simone A. Minnie, David Smith, Kate H. Gartlan, Thomas S. Watkins, Kate A. Markey, Pamela Mukhopadhyay, Camille Guillerey, Rachel D. Kuns, Kelly R. Locke, Antonia L. Pritchard, Peter A. Johansson, Antiopi Varelias, Ping Zhang, Nicholas D. Huntington, Nicola Waddell, Marta Chesi, John J. Miles, Mark J. Smyth, Geoffrey R. Hill
Graft-versus-tumor (GVT) effects have been thought to mostly result from allogeneic transplants; however, there is a growing body of research that supports a possible autologous GVT effect. In early clinical studies, a positive correlation between lymphocyte count recovery after autologous transplantation and overall survival has been observed. However, mechanistic studies to identify the mediators of autologous GVT responses have been lacking. In this issue of the JCI, Vuckovic et al. observed a T cell–dependent autologous GVT effect in the Vk*MYC myeloma model. Moreover, the authors showed that CD8+ T cells mediate myeloma control through IFN-γ secretion, which could be further augmented with a CD137 agonist, suggesting a therapeutic approach for enhancing autologous GVT.
Multiple myeloma (MM), characterized by the accumulation of malignant antibody-producing plasma cells, is the second most common blood cancer after non-Hodgkin lymphoma (NHL) in the United States (1). Thanks to the understanding of disease biology, an increasing number of individualized treatments are available that have largely improved patient outcomes. Despite the large number of experimental therapeutics being tested for myeloma, such as immunotherapies, histone deacetylase (HDAC) inhibitors, chimeric antigen receptor (CAR) T cell therapy, MM remains incurable. For transplant-eligible patients, high-dose therapy (HDT) followed by autologous stem cell transplantation (SCT) is the standard of care (1). While allogeneic transplantation can provide a potential cure due to the graft-versus-tumor (GVT) effect, this approach is prohibitive because of the high risk of treatment-associated mortality, including the development of graft-versus-host disease (GVHD). Especially for patients with MM, allogeneic SCT does not confer superior overall survival (OS) compared with autologous SCT. Therefore, allogeneic SCT is not considered a first-line treatment for MM and is only done in clinical trial settings. On the other hand, post–autologous transplant patients who received maintenance therapy with the immunomodulatory (IMiD) agent lenalidomide had remarkably improved survival rates compared with those who did not, suggesting that the host's immune system can be improved to keep the cancer at bay (2).
There is a significant body of evidence suggesting that the immune system has a critical role in myeloma disease control. IMiDs have been shown to improve the function of NK cells and T cells, both of which contribute to disease regression (3, 4). With the immunomodulatory effects of IMiDs, it remains elusive whether patients are capable of generating spontaneous antitumor immunity. An array of early clinical studies have reported a positive correlation between lymphocyte count recovery after autologous SCT and OS, suggesting an autologous GVT effect. Many of these studies were done retrospectively and involved a wide range of diseases, including MM, B cell/T cell NHL, Hodgkin lymphoma (HL), mantle cell lymphoma, acute myeloid leukemia, metastatic breast cancer, and ovarian cancer (5). These studies found that, among the autograft immune effector cells, CD4+ T cells (in MM), NK cells (in diffuse large B cell lymphoma), and cytotoxic DCs (in classical HL) are associated with better clinical outcomes. For post–autologous SCT MM patients, it was reported that a higher CD4+ T cell count and an increase in the ratio of CD4+ to CD8+ T cells were associated with superior outcomes (6). However, mechanistic studies on the factors that mediate autologous GVT have been lacking.
In this issue, Vuckovic et al. used the Vk*MYC murine myeloma model to examine spontaneous T cell antimyeloma immunity in the autologous transplant setting (7). Bone marrow transplantation (BMT) with myeloma-experienced BM performed in myeloma-bearing mice induced clone-specific, T cell–dependent disease control. This effect was generated by memory T cells within the myeloma-experienced graft as well as by priming of naive T cells. Compared with the mice that received myeloma-free BM, CD8+ T cells from mice that received myeloma-experienced BM had distinct T cell receptor (TCR) repertoires and greater clonotype overlap. These CD8+ T cells induced antimyeloma immunity through IFN-γ secretion, which could be further enhanced by a CD137 (also known as 4-1BB) agonist and PD-1 blockade. Furthermore, Vuckovic and colleagues showed that secretion of IL-17A from donor BM directly stimulated myeloma cells through the IL-17 receptor to promote tumor growth and immune evasion, which was independent of Th17 cell differentiation (Figure 1).
Autologous GVT effects are mediated by IFN-γ–expressing CD8+ T cells. Expansion of CD8+ T cells from autologous, myeloma-experienced BM promotes antimyeloma effects. Of the transplanted CD8+ T cell population, CD44+ cells are the most effective at killing myeloma cells, suggesting that antigen experience is critical for antitumor immunity. Th17 cells support myeloma cells via IL-17A secretion, though this effect is not the result of enhanced Th17 cell differentiation. The antimyeloma effects of CD8+ T cells are mediated by the secretion of IFN-γ, and this immunity can be enhanced by treatment with a CD137 agonist and PD-1 blockade.
In contrast to clinical observations, Vuckovic et al. found that CD8+ T cells, rather than CD4+ T cells or NK cells, are critical for autologous GVT (7). This observation raises the question as to whether this discrepancy is due to the murine model and/or the tumor clone used. Could this CD8+ T cell dependency be a specific phenomenon for the Vk*MYC model? Is it possible that specific antigens with this clone triggered a CD8+ T cell response? The authors emphasized that the observed antimyeloma immunity was clone specific. Had the T cells experienced a different myeloma cell clone, would the observed outcome be different? It will be worthwhile to confirm this observation in a different murine myeloma model. In addition, the authors examined the TCRβ chain diversity and clonal types. It is likely that this particular TCRβ chain profile reflects the myeloma cell clone used in the study. Is TCRβ clonality the key for the autologous GVT effect? Given the heterogeneity of human disease, are similar profiles observed in patients? What are the factors influencing the clonality? How can we incorporate this information into predicting disease control or relapse?
Vuckovic and colleagues also reported that the most effective antimyeloma CD8+ T cells were within the CD44+ subset, suggesting that antigen experience contributes to antitumor immunity (7). Mice that received myeloma-experienced CD44+ T cells were found to have an expansion of CD8+ T cells but not CD4+ T cells. It is not surprising that both activated DNAM-1+PD-1+CD8+ T cells as well as exhausted DNAM-1–PD-1+Tim-3+CD8+ T cells were observed upon engraftment of CD44+ T cells. Nonetheless, it is impressive to see that, despite having an exhausted phenotype, these CD44+ T cells still exhibited superior antimyeloma immunity. Guillerey et al. recently reported that the exhaustion marker TIGIT was upregulated on CD8+ T cells during disease progression (8). This TIGIT expression was also the reason for disease relapse in autologous transplantation in the Vk*MYC mouse (9). However, Vuckovic and colleagues did not mention TIGIT in this study. Is TIGIT also expressed in the myeloma-experienced graft? What could have contributed to the differences in disease control? Paradoxically, it has been reported that human effector CD8+ T cells derived from naive cell subsets possess better quality for adoptive immunotherapy compared with those derived from memory cell subsets (10). Perhaps the transgenic expression of antigen receptor and forced expansion "aged" the memory T cells differently in the human setting. Nonetheless, it will be extremely intriguing to see whether the myeloma-experienced T cells from human patients also exhibit superior antimyeloma immunity.
Since Th17 cells have been suggested to induce myeloma progression through IL-17 production (11), Vuckovic and colleagues undertook the task to elucidate the role of IL-17 after autologous transplantation. In this setting, myeloma development was impaired following IL-17 neutralization, confirming the negative impact of IL-17 on disease control (7). The effect of IL-17 is probably not due to its action on the donor graft, as the study by Vuckovic et al. showed that transplantation with IL-17 receptor–deficient donor BM did not notably reduce disease burden. When both donor and recipient BM were lacking the IL-17 receptor, there was a systemic increase in IL-17 levels, which further induced the activation of multiple pathways involved in myeloma survival and immune evasion. However, the study did not rule out the possible effect of IL-17 on the recipient's BM compartment.
IFN-γ is thought to be an integral part of antitumor immunity. However, depending on the context, it can either be immune activating or immune suppressing. IFN-γ can promote antitumor immunity through direct cytotoxic effects on tumor cells, activation of macrophages, and inhibition of FoxP3+ Treg function (12, 13). Vuckovic and colleagues showed that IFN-γ is critical for the CD8+ T cells to control myeloma. On the other hand, IFN-γ has also been shown to induce PD-L1 expression on ovarian cancer cells, leading to immune evasion (14). Additionally, our group recently observed that myeloma cells can produce IFN-γ, which leads to Treg expansion (15). These data again highlight the dual effects of IFN-γ in myeloma-immune microenvironment crosstalk. Nonetheless, Vuckovic et al. demonstrated that IFN-γ–producing, CD8+ T cell–dependent antimyeloma immunity can be further enhanced by treatment with a CD137 agonist. The agonist produced activation and exhaustion profiles, including PD-1 upregulation, similar to those seen in mice transplanted with myeloma-experienced BM. Moreover, the addition of PD-1 blockade with the CD137 agonist further improved T cell–mediated myeloma control.
In summary, these data provide important insight into spontaneous host antimyeloma immunity and the crosstalk between myeloma cells and the T cell compartment. Although it remains to be determined whether this phenomenon can be translated to the human setting, this study suggests a possible new targeting strategy to improve post-transplantation recovery and perhaps clear minimal residual disease. Furthermore, it will be intriguing to examine whether the autologous GVT effect is myeloma specific or can also be found in other hematological malignancies.
We acknowledge Mark Bustoros (Dana-Farber Cancer Institute) for helpful comments and suggestions regarding this Commentary.
Conflict of interest: IMG has a consulting/advisory role with Celgene, Takeda, Bristol-Myers Squibb, Janssen Pharmaceuticals, and Amgen. IMG has also received research funding and honoraria from Celgene, Takeda, Bristol-Myers Squibb, Janssen Pharmaceuticals, and Amgen.
Reference information: J Clin Invest. 2019;129(1):48–50. https://doi.org/10.1172/JCI125431.
See the related article at Bone marrow transplantation generates T cell–dependent control of myeloma in mice.
Kumar SK, et al. Multiple myeloma. Nat Rev Dis Primers. 2017;3:17046.
Roeven MW, Hobo W, Schaap N, Dolstra H. Immunotherapeutic approaches to treat multiple myeloma. Hum Vaccin Immunother. 2014;10(4):896–910.
Haslett PA, Corral LG, Albert M, Kaplan G. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med. 1998;187(11):1885–1892.
Reddy N, et al. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol. 2008;140(1):36–45.
Porrata LF. Autologous graft-versus-tumor effect: reality or fiction? Adv Hematol. 2016;2016:5385972.
Schmidmaier R, Oversohl N, Schnabel B, Straka C, Emmerich B. Helper T cells (CD3+/CD4+) within the autologous peripheral blood stem cell graft positively correlate with event free survival of multiple myeloma patients. Exp Oncol. 2008;30(3):240–243.
Vuckovic S, et al. Bone marrow transplantation generates T cell–dependent control of myeloma in mice. J Clin Invest. 2019;129(1):106–121.
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Guillerey C, et al. TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma. Blood. 2018;132(16):1689–1694.
Minnie SA, et al. Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade. Blood. 2018;132(16):1675–1688.
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Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–969.
Overacre-Delgoffe AE, et al. Interferon-γ drives treg fragility to promote anti-tumor immunity. Cell. 2017;169(6):1130–1141.e11.
Abiko K, et al. PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. Clin Cancer Res. 2013;19(6):1363–1374.
Kawano Y, et al. Blocking IFNAR1 inhibits multiple myeloma-driven Treg expansion and immunosuppression. J Clin Invest. 2018;128(6):2487–2499.
Version 1 (November 19, 2018): Electronic publication