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Ideally, the easiest method should be the first on the list. Click the "Start" icon on the bottom-left part of the screen. In the Cortana search box, type "device manager" (without quotes). Click the Device Manager when it appears to open it.
The shortcut for the Quick Access menu in Windows 10 is pressing the Windows key + X. A menu will appear on the left side of the desktop. Select Device Manager to launch it.
Open the "Run" window by opening the Start Menu and entering the word 'run' in the search box. Alternatively, you can use a shortcut by pressing 'Windows key + R'. In the "Run" window, type 'devmgmt.msc' and press Enter or the "OK" button.
Open Control Panel by searching for it in the Start Menu or navigating "File Explorer" then clicking on "Desktop" and then double-clicking on "Control Panel". While on the Control Panel, locate the search box on the top-right part of the window and search for "device".
Click "Device manager" from the results. Two options named "Device Manager" will appear and you can select either.
Another way to open device manager is through the Computer Management console. To do this, click on the File Explorer icon on the taskbar. After opening File Explorer, select "Desktop" on the left-hand-side then right-click on "This PC"or whatever you named your computer. On the context menu that appears after right-clicking, select "Manage" which will open the Computer Management window. Select "Device Manager" from the system tools.
You can alternatively access device manager on windows 10 from Computer Management by opening "File Explorer", clicking on "This PC" and then "Manage" on the toolbar located at the top.
The Settings charm is a shortcut for opening the Settings program in Windows 10 and Windows 8/ 8.1. In Windows 10, press the Windows key + I to open the Settings charm. In the top-right corner, there is a search box where you should type 'device manager' and then press Enter to execute the search. Open Device Manager from the search results.
This is a more complicated technique of how to find device manager on windows 10. You can open Command Prompt by searching 'cmd' or 'command prompt' in the Start Menu or typing 'cmd' from the Run box. Type "devmgmt.msc" (without quotes) in the Command Prompt console after opening. Press Enter to execute the command and launch the device manager.
Open the Start Menu from the icon on the bottom-left. In the Cortana search box, type 'power' or 'powershell'. Click on Windows PowerShell from the search results. On the console that appears, type the term devmgmt.msc and press Enter to run the command.
Right-click on any empty space on the desktop and select New > Shortcut from the context menu. On the next window that asks about the item location, type devmgmt.msc and click the "Next" button.
The next window requires you to name the shortcut. Type "Device Manager" or any other name that is easy to remember. Click "Finish" to save the shortcut.
By doing regular cleanups, system checkups and restricting heavy tasks that utilize a lot of RAM and strain the computer's processor, you can prevent device issues. Manually optimizing your computer can be a laborious task and you might miss some things. It is best to use PC optimization software like Windows Care Genius which has the capability to speed up PC performance, clean junk files to free up space, optimize Windows system along with 19 other useful features. Windows Care Genius checks the stability of the PC, scans and analyzes PC status, eliminates website tracking from cookies and browsing history and allows you to schedule periodic clean-ups.


text:
Saying Goodbye to 'The Jerry Springer Show' After 27 Seasons
Why Led Zeppelin Won't Reunite
Here Are a Few Things 7-Eleven Kept on a Down Low About the Slurpee
Magnifico! Bohemian Rhapsody Hailed Most Streamed Song of 20th Century
This Is How Muhammad Ali Influenced Hip Hop Music
The Gore and Glory of '90s Grunge: Musicians Who Left Too Soon
Retro music August 14, 2020
A big chunk of the '90s music scene is all about grunge rock. A fusion of punk music and heavy metal—the genre filled radio stations with angsty songs that resonate to the ideals of the rebellious teens.
As a result, artists sprung from underground musicians to international rock stars, becoming instant celebrities overnight. The irony between the grunge's anti-mainstream roots and the sudden burst to fame became the foundation of that period's cultural revolution.
Despite being filthy rich, these musicians' lives weren't as glamorous as portrayed in the media. While their legacy lives beyond the '90s, it still seems too sudden how some of the grunge movement's front-liners left their fans too soon. It is also shocking how most of them departed from this world which, in some cases, was an escape from the nightmare their lives had become.
Kurt Cobain was one of the most famous faces of the grunge is Nirvana's frontman. The band is probably one of the first to break free from the underground music scene with MTV's release of the band's "Smells like a Teen Spirit" music video.
Kurt Cobain was very open about the struggles he faced while growing up
One of the most iconic music videos in the world of grunge, it perfectly highlighted the look of the '90s—worn-out Chuck Taylors, unwashed hair, and a subtle hint of irony with the presence of cheerleaders.
Cobain had a tough life growing up – he witnessed his parents' divorce and also suffered domestic abuse at the hands of his step father. Cobain was only 27 when he took his own life, leaving his then-wife and one of grunge rock's muses, Courtney Love, and their daughter, Frances Bean behind.
Kristen Pfaff
Another member of the 27 Club, Kristen Pfaff was a bassist for the bands Janitor Joe and Hole. Coincidently, Pfaff was one of Cobain's close friends who overdosed on opium two months after the untimely demise of the Nirvana frontman. Pfaff's death was the second shock to the industry that year.
Kristen Pfaff was a bass guitarist for the band Hole whose lead singer was Courtney Love, Kurt Cobain's widower
Prior to becoming a grunge bass guitarist, Pfaff was a women's studies graduate and an active supporter of women's rights. She became a counselor for assault victims. After her death, Hole dedicated their tour and also their only compilation album, "My Body, the Hand Grenade" to Pfaff.
With his signature voice and style, grunge fanatics will never forget Layne Staley, the lead vocals for Alice in Chains. One of the grunge era's iconic frontmen, he died of accidental drug overdose exactly eight years after Kurt Cobain's death. He was only 34 at the time.
Layne Staley was found dead in his home 14 days after his assumed day of death. He died of accidental cocaine overdose
Alice in Chains' debut album, "Facelift," was released on 1990 and was a certified double platinum. The second single from the album titled "Man in the Box," which was written by Staley himself, became a huge hit because of its distinctive sound. Though his rise from a subculture musician in Seattle was colorful, years leading to his death were not. He started avoiding the public eye from 1997, with reports saying he only consumed Ensure for his sustenance.
He died on April 19, 2002 with his body partially decomposing that authorities needed to compare dental records to make sure it was Staley's. Jerry Cantrell, Alice in Chains' lead guitarist, dedicated his solo album "Degradation Trip," to Staley, which was released two months after his accidental death.
One of the most recent losses of the grunge rock industry is Soundgarden and Audioslave vocalist Chris Cornell. Regarded as one of the foundations of the '90s grunge movement, Cornell was known for his amazing four-octave vocal range and belting techniques, as well as his wide contribution to the music industry. The two-time Grammy-award winner also ranked 9th in the Rolling Stone's "Best Lead Singers of All Time" list.
Chris Cornell was found dead in a hotel room's bathroom on May 18, 2017. He took his own life by hanging
Died at the age of 52 on May 18, 2017, Cornell took his own life in his hotel room in MGM Grand, Detroit. This was after his performance with his former band, Soundgarden on the Fox Theatre the day before.
Prior to his death, fans already knew about of his struggles with mental health issues and substance abuse. He was very open about his addiction and even admitted to going to rehab before.
On the day of Cornell's supposed 53rd birthday, one of his close friends and lead singer for Linkin Park, Chester Bennington, also ended his life, cutting his brilliant career short.
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redpajama_set_name: RedPajamaCommonCrawl


Antigua and Barbuda are located in the middle of the Leeward Islands in the Eastern Caribbean roughly 17 degrees north of the Equator. Antigua is the largest of the English-speaking Leeward Islands and is about 14 miles long and 11 miles wide encompassing 108 square miles. Its highest point is Boggy Peak (1319ft) located in the southwestern corner of the Island. To the south are the islands of Montserrat and Guadaloupe and to the north and west are Nevis, St.Kitts, St.Barts and St.Martin.
The skyline of the capital St.Johns on Antigua is dominated by the magnificently evocative white Baroque towers of St.Johns Cathedral. The towers are the first sight of Antigua for about half of the islands visitors each year many of whom arrive by boat. St.Johns is a lively hub for shopping and dining and has a recently completed cruise ship dock.
There are 365 beaches on Antigua, one for each day of the year, and the great majority rest inside the calm, protected waters of the islands Caribbean side. The temperatures generally range from the mid-seventies in the winter to the mid-eighties in the summer and with annual rainfall averaging only 45 inches this makes it the sunniest of the Eastern Caribbean Islands and the northeast trade winds are nearly constant.
The majority of Antiguans are of African lineage and are descendants of slaves that were brought to the island to work in the sugarcane fields. Antigua was first inhabited by Meso-Indians called Siboney (stone people) whose settlements date at least 2400 BC and the Arawaks, who originated in Venezuela and gradually migrated up the chain of islands now called the Lesser Antiles, succeeded the Siboney. The Carib Indians massacred the Arawaks, a peace-loving and agricultural people, and were master of the sea, very skilful canoe drivers and most of all they were very fierce and aggressive.
Sir Christopher Columbus landed on Antigua in 1493 and named the island for the Church of Santa Maria de la Antigua in Seville and the island was Sir Christopher Codrington established the first, largest sugar estate in Antigua in 1674 and leased Barbuda to raise provisions for his plantations. By the middle of the 18th century the island was dotted with more than 150 cane-processing windmills and today almost 100 of these picturesque stone towers remain. At Bettys Hope, Codringtons original sugar estate visitors can see a fully-restored sugar mill.
With a complex coastline of safe harbours and a protective nearly unbroken wall of coral reef it was the perfect place to hide a fleet and in 1784 Admiral Horatio Nelson sailed into Antigua and established Great Britain's most important Caribbean base and set up Nelsons Dockyard there.
The Bird family controlled the islands from the mid-1940s to 2004 and the country joined the West Indies Federation in 1958. When the Federation broke up the island became one of the West Indies Associated States in 1967 with self-governing internal affairs and full independence was granted on 1 November 1981.
Barbuda is a flat, coral island with an area of only 68 square miles and lies approximately 30 miles due north of Antigua. Barbuda can be reached easily by a 20 minute flight from Antigua or a three hour boat trip and the nation also includes the tiny (0.6 sq miles) uninhabited island of Redonda, now a nature reserve. The smooth coastline is edged with long, pink and white sand beaches protected by barrier reefs and the pristine pink beaches of the southwestern shore beach stretch as far as ten miles without interruption.
Barbuda is one of those very few islands in the Caribbean that remains, and probably will remain for some time, so undeveloped as to seem positively deserted at times. The graceful Fregata Magnificens, or Frigate Bird, has a marked preference for the northwest lagoon and the island Frigate Bird Sanctuary is a must visit and the waters off shore have an abundance of shipwrecks and beautiful reefs.
The history of the island has been intimately tied to that of Antigua for centuries and the first early attempts to settle Barbuda were failures. It wasn't until 1666 that the British established a colony strong enough to survive the ravages of both nature and Caribs and in 1680 Christopher Codrington and his brother were granted a lease to land in Barbuda and with subsequent leases that granted them additional rights to the substantial wreckage along Barbuda reefs the Codringtons became the preeminent family.
On Barbudas highest point are the ruins of the Codrington estate, Highland House, and on the islands south coast still sits the 56-foot high Martello castle and tower, a fortress that was used both for defence and as a vantage from which to spot valuable shipwrecks on the outlying reefs.
The islands of Antigua and Barbuda are refreshingly different, romantic and flamboyant. Maybe you will find that something missing in your life when you land here.
Foreign investment is encouraged and there are no barriers for investors, buying real estate on the island of Antigua is a very straight forward process.
You will need to appoint the services of a lawyer to act on your behalf. Typically lawyers will charge 1% to 2% depending on the purchase price.
As a non Antiguan purchasing real estate in Antigua you will need to apply for a non citizens license.
A non citizens license can take up to four months to be granted depending on your legal representation and the speed of the application process.
Non-Citizens license 5% of the value (applicable to non-Antiguans).
Government transfer tax 2.5 % (Stamp Duty)of the value of the property.
Legal costs vary depending on the purchase value and are typically between 1% and 2%.
There is no capital gains tax in Antigua. The only taxes incurred on the property after purchasing is the annual property tax of 0.03% and the 7.5% stamp duty when selling.
Citizens of USA, Australia, New Zealand, South Africa and Irish nationals require a valid passport but visas are not required for stays of up to one month.
UK nationals require a valid passport and a visa is not required for stays of up to six months.
Canadians do not require a passport providing they hold other documents with proof of identity such as a birth certificate, drivers licence with photo or a citizenship card/naturalisation certificate. A visa is not required for stays of up to one month.
All other nationalities must check with the Consulate/Embassy in their home country before travel as to the requirements for entry into Antigua and Barbuda.
All nationalities must hold confirmed onward or return tickets and sufficient funds to cover their period of intended stay. Since January 2007 all US citizens travelling to and from Antigua and Barbuda by air require a passport, by 1st January 2008 the requirement will be extended to include all land and sea border crossings as well.


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The North East Aircraft Museum
Monkwearmouth, Tyne and Wear
3.5 miles from Monkwearmouth, UK-N6
In the first Hangar, a man is seen hiding behind an aeroplane, poltergeist activity is reported, and strange sounds such as banging and laughing are heard. In Hangar 2, the ghost of a man thought to have been murdered by a jealous husband is said to remain here. In Hangar ...
Souter Lighthouse
A couple ghosts have been reported here including Isobella Darling (a former occupant, now known for her activity in the kitchen) and a former lighthouse keeper named John. (Submitted by Chris Berglund)
Marsden Grotto
A former gang member and smuggler named John the Jibber was actually an informer. His gang locked John in a barrel and hoisted him up, waiting for him to die slowly. John is still heard groaning throughout, and poltergeist activity is also reported. (Submitted by Chris Berglund)
Willington Mill
Wallsend, Tyne and Wear
A woman named Kitty supposedly got caught in one of the machines and died. She is seen and felt throughout the location. (Submitted by Chris Berglund)
The Angel View Inn
Low Eighton, Tyne and Wear
8 miles from Monkwearmouth, UK-N6
Activity here is common, but no one knows the source. One team of ghost hunters encountered poltergeist activity, balls of light, and drastic cold spots. Messages also come up on spirit boxes. (Submitted by Chris Berglund)
Lumley Castle
Monkwearmouth, County Durham
The former owner of property, Lily of Lumley, was said to have been murdered by two priests and dropped down a well; her apparition is seen around the castle and sometimes coming out of the well. A playful man named Black Jack likes to move objects, children have been heard ...
Newcastle Castle Keep
"The Poppy Girl" is the nickname for a woman who was thrown in the castle prison, before suffering a horrific death. Visitor become aware of her presence because they will pick up the smell of flowers passing by. Another woman is seen in the chamber, monks are heard chanting, disembodied ...
The Manor House Hotel
West Auckland, County Durham
23.9 miles from Monkwearmouth, UK-N6
The ghosts here include a young boy found in Room 6; he is said to cry out looking for his mother. Meanwhile, a female spirit, nicknamed Betty, is also said to wander around looking for her son. In Room Seven, a large man is reported. Also, a medium has picked ...
Hall Garth and Country Club Hotel
Monkwearmouth, Darlington
A nun was said to have been bricked up alive here. Most activity stems from Room 2; usually the faucets will turn on and off by themselves. (Submitted by Chris Berglund)
Haunting Experiences: Ghosts in Contemporary Folklore
Diane Goldstein
A Ghost in My Suitcase: A Guide to Haunted Travel in America
Mitchel Whitington
Picture Yourself Ghost Hunting
Christopher Balzano
The Green Dragon
Activity is common in the cellar; staff feels as if they are not alone and sometimes report being touched. (Submitted by Chris Berglund)
Thornaby Centre
Thornaby, England
The ghost of an airman is said to be here; some of the electrical equipment acts up by itself as if someone is controlling it. (Submitted by Chris Berglund)
Preston Hall - Stockton-on-Tees
The ghost of a highwayman, a woman walking her dog, and most commonly, a grey lady have been seen. (Submitted by Chris Berglund)
Lord Crewe Arms Hotel
Monkwearmouth, Northumberland
The spirit of Dorothy Forster is said to be here, whose brother, Tom Forster, was part of the 1715 Jacobite Rebellion. (Submitted by Chris Berglund)
Raby Castle
Monkwearmouth, England
Charles Nevill, who plotted the Rising of the North in the Baron's Hall is reported in that room. Henry Vane the Younger is seen in the library without his head and the first Lady Barnard is also seen here. (Submitted by Chris Berglund)
Darlington Civic Theatre
Ghosts ranging from stagehands, former managers, and crying children have been reported here all throughout the theatre. Recently, a photograph captured two ghosts sitting in the distance lending to the belief that there's more ghosts here than previously thought! (Submitted by Chris Berglund)
The Pot and Glass
28 miles from Monkwearmouth, UK-N6
Staff and visitors say that a friendly ghost is here, but not much is known about it. (Submitted by Chris Berglund)
Blackwell Grange Hotel
Darlington, Darlington
A painting was acquired of a woman in a tartan outfit. The woman in the painting is said to have been attached to the painting and now haunts this building as revenge for husband's slaughter. (Submitted by Chris Berglund)
Brinkburn Priory
Former monks are seen in groups or heard chanting. In the cellar, a dark and violent entity has shoved people around. Other apparitions of a young girl and a woman in grey have also been seen. (Submitted by Chris Berglund)
The Schooner Hotel
Alnmouth, Northumberland
Unexplained noises are heard in room 28; this includes screams, whispers, and conversations. In room 17, a ghostly child is said to ride a tricycle. It is believed that there are at least 60 ghosts here. (Submitted by Chris Berglund)
Haunting Experiences: Encounters with the Otherworldly
Michelle Belanger
Ghost Hunting: How to Investigate the Paranormal
Haunted Route 66: Ghosts of America's Legendary Highway
Richard Southall
Ancient Unicorn Inn
Bowes, County Durham
Two young lovers share the same grave nearby; the boy died after getting ill and the girl died heartbroken. Both of them are seen by their burial place. A young boy in the cellar and a bearded man are also seen here. The ghosts are mischievous, but it a good ...
Monkwearmouth, North Yorkshire
It would seem as if every room here has some form of activity. In the library, an upset girl is seen; in the alcove, a vicar or priest likes to appear; in the tunnels, a nurse frequently shows up (said to be the most commonly seen ghost here). Temperature drops, ...
Tan Hill Inn
A ghost of former manager named Mrs. Peacock will interfere whenever people start brawls. (Submitted by Chris Berglund)
Chillingham Castle
Chillingham, Northumberland
Shadows have been seen in the courtyard, one ghost in the chamber is unseen, but gives off an eerie feeling, a conversation between two unseen men carries on in the chapel, and in the 'Inner Pantry', a woman in white approaches people begging for water, but vanishes soon after. (Submitted by ...
Busby Stoop Inn
Thomas Busby was hanged for his crimes, but always loved his seat at this location. After his death, anyone who sits in this chair meets an untimely and always tragic death; the chair has been hung on the wall to prevent anyone from accidentally sitting in it. (Submitted by Chris Berglund)
Bamburgh, Northumberland
Don't be surprised if you take a photograph and a mysterious figure or form shows up; it's quite common here. People commonly report a woman in a pink (or green) dress said to be a princess who leapt to her death after she found out her lover had married someone ...
Bamburgh Beach
Witches used to live in the dunes and would sacrifice people for Satanic rituals. Other people have died violently here through other means, and a burial site was even uncovered. While Roman Polanski was filming Macbeth here, many extras were shocked to see hands coming out of the sand... And ...
Appleby Castle and Keep
Appleby-in-Westmorland, Cumbria
The Keep is the oldest building still in existence today and little has changed in over 900 years. It is one of the few remaining intact Norman Keeps in Great Britain. This castle has a rich and varied history. It has been held by the Kings of Scotland and England. Parts ...
Nunnington Hall
A very strict mother loved her son, but locked her stepson in the attic. The stepson eventually disappeared (either escaping or being murdered), and soon the other child fell to his death. The heartbroken mother soon lost her sanity and long after her death, she and the two children are ...
Brougham Hall
Brougham, Cumbria
The hall and grounds are reportedly haunted by sounds of soldiers battling in the middle night, world war soldiers marching and various people who were employed at the property including a woman called Emily and a boy who died there. Henry Brougham who lived there in the nineteenth century was ...
Scarborough Castle
The beheaded ghost of Piers Gaveston is reported here. He is said to lunge at visitors and has a very malicious behavior. (Submitted by Chris Berglund)
Jedburgh Castle
Jedburgh, Scottish Borders
The ghost of former prisoner Edwin McArthur is said to threaten visitors and invokes a sense of dread. Other former prisoners may be here as well. (Submitted by Chris Berglund)
The jail is known to have a high level of paranormal activity where former prisoners still cry out and make contact with visitors. A piper can also be seen or heard playing outside of the castle on the battlefield. (Submitted by Chris Berglund)
York Guild Hall
York, York
The ancient City of York is famed for being one of (if not the) most haunted cities in Europe . York Guild Hall is one of York's most historic and haunted locations, with its tales of ghostly black monks, dis-incarnate voices and shadowy figures. The York Guild Hall was built ...
Dryburgh Abbey Hotel
Newtown Saint Boswells, Scottish Borders
A woman who drowned herself in the nearby river is said to haunt here. In the ruins of the nearby abbey, monks can also be heard chanting. (Submitted by Chris Berglund)
Levens Hall
Monkwearmouth, Cumbria
The most commonly reported ghosts include that of a gypsy who cursed the building's grounds and that of a dog who many visitors mistake for being alive. (Submitted by Chris Berglund)
East Riddlesden Hall
Riddlesden, West Yorkshire
The Grey Lady occupies a chamber named after her; another spirit named the Blue Lady is thought to have drowned in the pond. Shadows are a commonly witnessed phenomenon, objects vanish and reappear, and people never feel alone. (Submitted by Chris Berglund)
Thirlestane Castle
Lauder, Scotland
One of the Dukes who occupied here is still reported to haunt the location. It is believed to be John Maitland. (Submitted by Chris Berglund)
The reports here include am Edwardian-era figure who walks through walls, a child that can be seen and heard upstairs, and various shadows seen throughout the building. (Submitted by Chris Berglund)
Parkside Social Club
Haworth, England
A Victorian girl has been seen and heard running up and down the stairs. She is said to frequent the pool room which is why some people avoid it. (Submitted by Chris Berglund)
Ghostly Encounters: True Stories of America's Haunted Inns and Hotels
Frances Kermeen
Ghost: Investigating the Other Side
Katherine Ramsland
Real Ghosts, Restless Spirits, and Haunted Places
Brad Steiger
The Black Bull
Haworth, West Yorkshire
A poltergeist has a reputation to throw glasses around. Two people in period clothing are also seen here. Submitted by Chris Berglund
Old Silent Inn
Stanbury, England
A former landlady's presence is reported here. She is said to have been an avid lover of the wild cats, ringing a bell to let them know that food was ready. The ringing of the bell is still heard to some. (Submitted by Chris Berglund)
Bolling Hall
Bradford, West Yorkshire
It is said that the ghost of an elderly woman appeared to a sleeping Earl who had plans of massacring the town of Bradford; her presence convinced him to call off the mass killing. People report drastic emotional changes throughout the hall, coins fall from the ceiling, people feel breathing ...
Pendel Hill is the equivalent of Salem, Massachusetts. Villagers fell ill and milk went sour leading everyone to believe that this was the work of witches. Accusations flew and (possibly) innocent people were hanged. Since then, strange people have appeared in photos and some guests have been strangled by an ...
Lower Well Head Farm
Monkwearmouth, Lancashire
This was the site of a series of witch trials in 1612. 10 mysterious murders resulted in the conviction and torture of around a dozen people who still remain here. Dark figures are seen outside; inside, people have reported hearing the sounds of something being dragged. A little girl is ...
Tynedale Farm
Newchurch-in-Pendle, Lancashire
The house here was owned by a descendant of Alice Nutter, executed in the 1612 witch trials. Phantom monks are reported here as well as that of a servant girl who travels between here and Lower Wellhead farm. (Submitted by Chris Berglund)
Grand Theatre, Lancaster
A lady in grey, believed to be Sarag Siddons, is seen here. In her lifetime, Siddons played Lady Macbeth here, but after death she might be the one that is reportedly seen throughout. A male spirit named Harald is also believed to be here. (Submitted by Chris Berglund)
Three Mariners
A female spirit is said to occupy the ladies' toilets; a man murdered somewhere in the 16th or 17th century is also seen here. (Submitted by Chris Berglund)
Lancaster Castle was used as a prison for accused witches and heretics before meeting their fate by execution. On the premise, the ghosts of an elderly lady, a middle-aged woman, a monk, and child running about have all been reported. (Submitted by Chris Berglund)
Lady Le Gros
Beverley, England
A Victorian gentleman, said to be the former landlord, was playful and had a habit of appearing and disappearing. Since a new landlady took over the pub, it is said that a psychic was brought here and laid his spirit (as well as others) to rest. Sadly, it was bulldozed in ...
Haunted Cemeteries: Creepy Crypts, Spine-Tingling Spirits, and Midnight Mayhem
Ghost Dogs of the South
Randy Russell
Haunted Too: Incredible True Stories of Ghostly Encounters
Dorah L. Williams
» Cemeteries near Monkwearmouth, UK-N6
» Find museums in Monkwearmouth, UK-N6


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Prediction of anticancer molecules using hybrid model developed on molecules screened against NCI-60 cancer cell lines
Harinder Singh1,
Rahul Kumar1,
Sandeep Singh1,
Kumardeep Chaudhary1,
Ankur Gautam1 &
Gajendra P. S. Raghava1
BMC Cancer volume 16, Article number: 77 (2016) Cite this article
In past, numerous quantitative structure-activity relationship (QSAR) based models have been developed for predicting anticancer activity for a specific class of molecules against different cancer drug targets. In contrast, limited attempt have been made to predict the anticancer activity of a diverse class of chemicals against a wide variety of cancer cell lines. In this study, we described a hybrid method developed on thousands of anticancer and non-anticancer molecules tested against National Cancer Institute (NCI) 60 cancer cell lines.
Our analysis of anticancer molecules revealed that majority of anticancer molecules contains 18–24 carbon atoms and are dominated by functional groups like R2NH, R3N, ROH, RCOR, and ROR. It was also observed that certain substructures (e.g., 1-methoxy-4-methylbenzene, 1-methoxy benzene, Nitrobenzene, Indole, Propenyl benzene) are more abundant in anticancer molecules. Next, we developed anticancer molecule prediction models using various machine-learning techniques and achieved maximum matthews correlation coefficient (MCC) of 0.81 with 90.40 % accuracy using support vector machine (SVM) based models. In another approach, a novel similarity or potency score based method has been developed using selected fragments/fingerprints and achieved maximum MCC of 0.82 with 90.65 % accuracy. Finally, we combined the strength of above methods and developed a hybrid method with maximum MCC of 0.85 with 92.47 % accuracy.
We developed a hybrid method utilizing the best of machine learning and potency score based method. The highly accurate hybrid method can be used for classification of anticancer and non-anticancer molecules. In order to facilitate scientific community working in the field of anticancer drug discovery, we integrate hybrid and potency method in a web server CancerIN. This server provides various facilities that includes; virtual screening of anticancer molecules, analog based drug design, and similarity with known anticancer molecules (http://crdd.osdd.net/oscadd/cancerin).
One of the major challenges in the field of drug discovery is to design effective drugs against cancer. Existing drugs have their limitations that includes, side effects of drugs, high toxicity, drug resistance towards current anticancer drugs [1]. There is a pressing need to improve the drug arsenal to fight against this deadly disease. Experimental techniques used for drug discovery are costly and time-consuming. Thus, there is a need to develop in silico techniques for designing anticancer drugs.
In the past, attempts have been made to develop computational methods to design/predict anticancer molecules. Recently, various studies modelled the drug behaviour against multiple cancer cell lines using different genomics features. Based on the genomic data i.e., DNA copy number, gene expression, mutations and methylation the drug sensitivity is predicted. Either single gene features predict the drug sensitivity or multigene features [2–9]. In spite of advances in genomics, modelling the behaviour of thousands of drug is still a challenging task. The other approach is quantitative structure-activity relationship (QSAR) based models, where chemical features are used to predict inhibitors against specific cancer drug targets [10–18]. Most of the QSAR-based models have been developed for predicting inhibition activity of a specific class of molecules against a given drug target [19–23]. Recently, QSAR-based models have been developed for inhibition activity prediction of any class of molecule (irrespective of molecules class) against cancer drug target EGFR [24]. In contrast, limited attempt have been made to develop methods for predicting the anticancer activity of molecules against cancer cell lines. Kumar et al. developed one such method against 16 pancreatic cancer cell lines, which consider cancer cell as a whole for the anticancer activity irrespective of drug targets [25].
Development Therapeutics Program (DTP) stores thousands of molecules tested against NCI-60 human cancer cell lines [26]. Researchers have exploited this massive dataset for various studies like a prediction of anticancer molecules. Josefin and coworkers showed that molecules with similar activity profiles or structure often show similar mode of action (MOA) [27]. Recently, Li et. al. have developed a method called CDRUG [28], for predicting the potential anticancer molecules using the NCI-60 data. They developed similarity-based approach using relative frequency-weighted fingerprints, Tanimoto coefficient, and MinMax Kernel and achieved area under the curve (AUC) value of 0.88. CDRUG is based upon thousands of fingerprints generated using jCompoundMapper [29] and offers little understanding of the algorithm. Further, JCompoundMapper package generates only chemical graph fingerprints with no substructure-based fingerprint. In this study, a systematic attempt has been made to develop a method for predicting anticancer molecules. Here, we have used a large dataset containing 8565 anticancer and 9804 non-anticancer molecules obtained from NCI-60 [28]. Using this large dataset, we identify important fingerprints/substructures that play a significant role in the classification of anticancer and non-anticancer molecules. We developed a hybrid method by combining the machine learning and similarity-based method developed on the above dataset for classification of anticancer and non-anticancer molecules.
Dataset used in this study was taken from Li and Huang study [28], which consists of 8565 anticancer and 9804 non-anticancer molecules. This dataset is compiled from the NCI-60 DTP project, and it is available at http://bsb.kiz.ac.cn/site_media/download/CDRUG/Benchmark.rar. In NCI-60 DTP project, two-stage screening of molecules was carried out. In the first stage, all the molecules were screened on 60 cell lines at 10−5 molar (15 μg/ml). Molecules showing significant growth inhibition were further tested on NCI-60 at five different concentrations. The results of screening were analyzed by NCI COMPARE algorithm [30].
Fingerprint calculation
PaDEL software [31] was used to calculate fingerprints, which calculates ten types of fingerprints viz. CDK, Estate fingerprints, MACCS fingerprints, PubChem fingerprints, substructure fingerprint and Klekota-Foth fingerprints and their respective counts. The details about PaDEL package and different fingerprints are available at PaDEL website.
Fingerprint or feature selection
In this study, we used an MCC-based approach for feature selection, where mean of each fingerprint in active and inactive dataset was calculated using the eqs. 1 and 2 [32].
$$ {\mathrm{F}}_{\mathrm{i}}^{\mathrm{A}}=\frac{{\displaystyle {\sum}_{\mathrm{j}=1}^{\mathrm{NA}}}{\mathrm{D}}_{\mathrm{i}}^{\mathrm{j}}}{\mathrm{NA}}\cdot $$
$$ {\mathrm{F}}_{\mathrm{i}}^{\mathrm{I}}=\frac{{\displaystyle {\sum}_{\mathrm{j}=1}^{\mathrm{NI}}}{\mathrm{D}}_{\mathrm{i}}^{\mathrm{j}}}{\mathrm{NI}} \cdot $$
Where F Ai and F Ii represent mean of ith fingerprint in active (A) and inactive (I) molecules respectively. NA and NI is the number of molecules in active and inactive datasets respectively. D ji is the value of ith fingerprint for the jth molecule (value is either 0 or 1). For active molecules, j varies from 1 to NA and for inactive molecules j varies from 1 to NI. Next, we classify the anticancer and non-anticancer molecules based on the compound score (Cscore) of a single fingerprint. If the value of fingerprint is 1, Cscore is the difference between F Ai and F Ii , else the Cscore is the difference between F Ii and F Ai . Following equation was used to calculate Cscore
$$ {\mathrm{C}}_{\mathrm{score}}^{\mathrm{j}}=\left\{\begin{array}{c}\hfill {\mathrm{F}}_{\mathrm{i}}^{\mathrm{A}}-{\mathrm{F}}_{\mathrm{i}}^{\mathrm{I}},\ \mathrm{if}\ {\mathrm{D}}_{\mathrm{i}}=1\hfill \\ {}\hfill {\mathrm{F}}_{\mathrm{i}}^{\mathrm{I}}-{\mathrm{F}}_{\mathrm{i}}^{\mathrm{A}},\ \mathrm{if}\ {\mathrm{D}}_{\mathrm{i}}=0\hfill \end{array}\right. $$
Where Cj score is a compound score of the jth molecule for ith fingerprint. Each molecule is having, Cscore more than threshold was classified as active, otherwise classified as inactive molecule. This technique was repeated for each fingerprint at the different threshold. Finally, the performance of each fingerprint is computed in terms of MCC value.
Calculation of similarity
In order to compute similarity between two molecules, we calculated Tanimoto similarity score between two molecules using following equation
$$ {\mathrm{T}}_{\mathrm{s}}\left(\mathrm{X},\mathrm{Y}\right)=\frac{{\displaystyle {\sum}_{\mathrm{i}}\left({\mathrm{X}}_{\mathrm{i}}\wedge {\mathrm{Y}}_{\mathrm{i}}\right)}}{{\displaystyle {\sum}_{\mathrm{i}}\left({\mathrm{X}}_{\mathrm{i}}\vee {\mathrm{Y}}_{\mathrm{i}}\right)}} $$
Where Ts is the Tanimoto similarity score between compound X and Y; X i and Y i is fingerprint i of compound X and Y, respectively; N is total number of fingerprints. In this study, we computed two types of Tanimoto similarity scores called Ts1 and Ts0. The Ts1 was calculated for fingerprint present (value 1) in the molecule and Ts0 based upon the fingerprint absent (value 0) in the molecule.
Potency score
The potency score of a query molecule was computed using following steps:
First, we computed Tanimoto similarity score Ts1 between query compounds with each of anticancer molecules and selected highest Ts1 called HaTs1.
Similarly, we also computed highest similarity score HaTs0 between the query and most similar anticancer molecules based on Ts0.
Above steps were repeated to compute similarity scores HnTs1 and HnTs0 between the query and most similar non-anticancer molecule.
Finally, potency score was computed using following equation
$$ {P}_s= max\left({\mathrm{H}}^a{\mathrm{T}}_{\mathrm{s}1},{\mathrm{H}}^{\mathrm{a}}{\mathrm{T}}_{\mathrm{s}0}\right)\hbox{-} max\left({\mathrm{H}}^{\mathrm{n}}{\mathrm{T}}_{\mathrm{s}1},{\mathrm{H}}^{\mathrm{n}}{\mathrm{T}}_{\mathrm{s}0}\right) $$
Where P s is the potency score of the query molecule and max is the maximum or highest score. If HaTs1 has q high score as compared to HaTs0, then it is the maximum score (max) of the anticancer molecule. Similarly, max score of non-anticancer molecules was selected based on the highest score of either HnTs1 or HnTs0. The advantage of using potency score instead of normal Tanimoto score is that it provides the structural similarity information of query molecule with anticancer, as well as with non-anticancer molecules.
Frequency of functional groups
Functional groups were identified using the ChemmineR package of R [33]. The percent of compounds having specific functional groups was calculated using eq. 6. We also calculated the mean count of functional groups in compounds were compute using the eq. 7.
$$ {\mathrm{F}}_{\mathrm{G}}=\frac{{\displaystyle {\sum}_{\mathrm{i}=0}^{\mathrm{n}}}{\mathrm{P}}_{\mathrm{i}}^{\mathrm{j}}}{\mathrm{n}}\times 100 $$
$$ {\mathrm{M}}_{\mathrm{G}}=\frac{{\displaystyle {\sum}_{\mathrm{j}=1}^{\mathrm{n}}}{\mathrm{C}}_{\mathrm{i}}^{\mathrm{j}}}{\mathrm{n}} $$
Where MG is the mean count of a functional group (G) in total number (n) of anticancer or non-anticancer compounds. C ji is total count of a functional group (G) for the jth compound with i value ranges from zero to maximum number of occurrence of functional group in a compound. The FG is the mean frequency of a functional group (G) in total number (n) of anticancer or non-anticancer compounds with P ji stands for presence or absence (value is either 0 or 1) of a functional group.
For a comparison of potency score method with machine learning methods, we also developed models using various classifiers in WEKA package [34]. We also compare the performance of our method with SVM package [35]. For improving the overall performance, we developed the hybrid method by doing an average of the normalized potency score and SVM score. Since, the scale of potency score and SVM value are different, we normalized these values between −1.0 and 1.0.
We have adopted the five-fold cross-validation technique to evaluate the performance of our models. In this technique, the compounds were randomly divided into five parts, where four parts were used for training and remaining part for testing. This process is carried out five times in such a way that each part was used once for testing. For obtaining unbiased results, the whole process of five-fold cross-validation was repeated 20 times. We report the final results as the average of 25-fold cross-validations. The performance of the method was assessed using various standard parameters like sensitivity, specificity, accuracy, and Matthews correlation coefficient (MCC) [36]. The receiver operating characteristic (ROC) graph was plotted using the ROCR package in R [37].
The study doesn't involve any human, plant or animal subject. All the experiments were carried out using computational techniques.
We tried to find out the predisposition of various functional groups in anticancer and non-anticancer molecules. Functional groups were identified using the ChemmineR package of R [33] and percentage of groups in compounds were computed using eq. 6. It was observed that certain functional groups (e.g., ROH, RCOR, RCOOR, ROR) have higher frequency and are predominantly present in anticancer molecules. These groups may be responsible for the anticancer activity of these active molecules as shown in Fig. 1. These functional groups can be further explored in designing of promiscuous anticancer molecules. We also calculated the total count of functional groups present in anticancer and non-anticancer molecules. It was observed that ROR group frequency range from 0 to 15 (maximum ROR was observed in a compound) as shown in Additional file 1: Figure S1. Further, we tried to find out the pharmacophore of most active molecules, which could be responsible for the anticancer activity. We aligned the top 20 molecules (in terms of activity) by PharmaGist software [38] and selected the most significant alignment (PharmaGist score of 77.61). This alignment identified total 18 features, which include twelve hydrogen bond acceptors, four aromatic, one hydrophobic and one hydrogen bond donor as shown in Fig. 2.
Functional groups present in anticancer and non-anticancer molecules along with their mean frequency
Pharmocophore alignment of most active anticancer molecules generated using PharmaGist
Maximum common substructures (MCS)
We also determined the maximum common substructures in anticancer molecules using the LibMCS module of Chemaxon (http://www.chemaxon.com/). The analysis shown in Fig. 3 depicts the frequently occurring Maximum Common Substructures (MCS). The number beneath each MCS represents the total number of molecules in which that particular substructure was present according to MCS module. The 1st substructure is 1-methoxy-4-methylbenzene i.e., (methyl group is present at para position). The 2nd substructure is a part of known tyrosine kinase inhibitors like Imatinib and Nilotinib. The 6th substructure is indole structure, which is used for designing inhibitors against kinases especially EGFR [39]. The 3rd, 4th, 5th, 6th, 7th, 8th and 9th substructures are acetophenone, 1-methoxy benzene with partial double bond at meta position, nitrobenzene, indole, propenyl benzene, butyl benzene and dimethylaniline. We also calculate frequency of occurrences of these MCS in anticancer and non-anticancer compounds using substructure search option of jcsearch module of Chemaxon (Additional file 1: Table S1). The most popular common substructure 1-methoxy-4-methylbenzene found in 1115 (13.02 %) anticancer and 577 (5.89 %) non-anticancer (5.89 %) compound. Most of MCS have higher frequency in anticancer compounds as compare to non-anticancer compound.
Maximum common substructures found in anticancer molecules along with the number of molecules having that particular substructure
Analysis of fingerprints
In order to identify the best fingerprints, which are more abundant in anticancer or non-anticancer molecules, we used the MCC-based feature selection technique as described in Methods section. In brief MCC based feature selection involves two major steps; in first step the performance of each fingerprint is computed in terms of MCC; in 2nd step, fingerprints are ranked based on their MCC score [32]. In this study, we selected fingerprints having MCC score greater than 0.2 for the development of the model. It was observed that PubChem fingerprint number 12 is among the best fingerprints that can classify anticancer and non-anticancer molecules with an accuracy of 71.69 %. This fingerprint represents the presence of > = 16 carbon atoms in a compound. The best ten fingerprints along with their classification performance of anticancer and non-anticancer compounds are shown in Table 1. The detailed results of 126 fingerprints are given in Additional file 1: Table S2. It was observed that few CDK fingerprints are also efficient in distinguishing anticancer and non-anticancer molecules.
Table 1 The individual performance of best 10 selected fingerprints using MCC based approach
Potency score based classification
In the current study, we compute the performance of models using five-fold cross validation technique with 20 runs as described by Li et. al. We selected the best fingerprints out of 9365 fingerprints for accurate, unbiased and quick development of classification method using MCC feature selection. First, we develop potency score based method using top 50 fingerprints having the highest MCC score. The best 50 fingerprints based method achieved 86.94 % accuracy with 0.74 MCC. Next, we developed method using best 100, 150 and 200 fingerprints and achieved 89.48 %, 90.1 %, 90.16 % accuracy respectively (Table 2). It was observed that using more than 150 fingerprints; there is no increase in performance of the method. Finally, we selected the fingerprints having MCC greater than 0.2 and obtained 126 fingerprints. We used these 126 fingerprints for developing prediction models and achieved 90.94 % accuracy with 0.82 MCC.
Table 2 The performance of potency score based method developed using different sets of fingerprints
Models based on machine learning techniques
In order to discriminate anticancer and non-anticancer molecules, we developed classification models using various machine learning techniques. The performance of models developed using different classifiers implemented in WEKA (i.e., Random forest, IBK, Naïve Bayes) and SVMlight [35, 40] has been shown in Table 3. The SVM-based models achieved highest accuracy 90.40 % with MCC 0.81 among all classifiers. The Random forest, IBK and Naïve Bayes based method achieved the highest accuracy in the range of 74.92–87.47 %. The models based on SVM and Random Forest achieved the best performance at the center of threshold and had broad range of MCC across various thresholds. The Random forest method achieved best performance using 100 trees; best SVM model trained using RBF kernel with parameter g = 0.1, c = 6 with j = 1; IBK method achieved best performance using kNN score of 3 with Manhattan distance algorithm.
Table 3 Comparative performance of models developed using 126 fingerprints at various thresholds has been shown in this table
Performance of hybrid models
As shown in both potency score based method and SVM-based model achieved maximum accuracy. The potency score method performs better, when query molecule is similar with anticancer molecules but perform poorly in case level of similarity is low. In case of SVM, the performance of the model is unaffected by similarity with known molecules. As shown in ROC curve at lower false positive rate (FPR), potency score performs better than SVM and at higher FPR, SVM perform better than potency score based method (Fig. 4). In order to take the advantage of potency score and SVM method, we developed the hybrid method. In case of hybrid method, first we compute SVM potency score of a query molecule and normalize these scores between −1.0 and 1.0. The average of normalize values is computed to obtain the hybrid score and used for predicting anticancer molecule. We developed a hybrid method using 126 best fingerprints and achieved highest MCC 0.85 with 0.98 AUC. The detail result of hybrid method are shown in Additional file 1: Table S3.
ROC plot of potency score, SVM and hybrid method developed using 126 fingerprints
Comparison with existing method
We compared the performance of our methods with existing method CDRUG. The CDRUG developed by Li et. al. achieved 65 %, 74 %, 81 % sensitivity at false positive rate (FPR) 0.05, 0.1, 0.2 respectively (Table 4). At 65 % sensitivity, both potency score method and SVM achieved 0.02 FPR and hybrid method achieved 0.01 FPR. As shown in Table 4, our models perform better than existing method CDRUG.
Table 4 Comparative performance of CDRUG (existing method) and our models based on potency score, SVM and hybrid approach
Description of the web server
In order to serve the scientific community, we developed a web server called "CancerIN" for predicting the anticancer potency of an unknown molecule and it's GI50 across different cancer cell lines. This web server consists of three modules for designing, library screening and chemical analogs screening.
Draw molecule
This web server provides a user-friendly interface with options to draw a chemical compound using Marvin applet as shown in (Fig. 5a) [41]. The output consists of a 3D structure of query molecule with physicochemical properties and hybrid score. The five most similar anticancer molecules along with their NSC ID, PubChem ID, Mean_logGI50, Tanimoto similarity score, Potency score and physicochemical properties are also displayed. The details button provides the GI50 and LogGI50 score of similar molecule against different NCI-60 cancer cell lines. The user can select and further load either query molecule or any five similar molecules for further modifications based upon the structural similarity (Fig. 5c). The modified molecule can be further used as query molecule for increasing its potential anticancer activity.
Various modules of CancerIN showing the input format and output display: a The Marvin draw applet for drawing molecules, b The input form for generation of analogs, c The output page of draw molecule module, and d. The result page of scan library showing the list of query molecules and the most similar anticancer molecules
Scan library
This web server also provides the provision to scan a chemical library in SMILES format [42]. The output consists of query molecule and five most similar anticancer molecules along with their other details as described above in tabular format (Fig. 5d).
Chemical analogs
We have also provided facility for the users to screen analogs generated from different combination of scaffold, building blocks and linkers using SmiLib [43] package (Fig. 5b) and subsequent prediction of their anticancer potency score. The results consist of query molecule and five most similar anticancer molecules in a tabular format.
For the screening of thousands of molecules, we have developed CancerIN standalone, written in Python. The standalone version can screen thousands of molecules in less than 10 min. The input consists of a single file having chemical structures (SMILE format) of molecules for screening. The standalone version can be easily updated by replacing the underlying data file. The user can easily increase or decrease the number of fingerprints used for final prediction. The source code allows the scientific community to utilize the novel similarity-based method for prediction of various types of molecules.
In brief, the CancerIN web server predicts the anticancer capability of a single molecule, a library of chemicals or analogs. Since, our method also consider similarity, it also displays the GI50 of the similar anticancer molecule across different cancer cell lines. A careful analysis of the anticancer efficacy of five similar molecules aids in understanding the anticancer efficacy of query molecule against various cancer cell lines. The standalone version of CancerIN allows the users to scan a vast library of molecules for the screening of potential anticancer molecules. This standalone is available at CancerIN website http://crdd.osdd.net/oscadd/cancerin.
Discussion and conclusion
The continuous development of novel anticancer drugs is imperative in order to tackle multi-drug resistance in cancer. At the same time, the development of an anticancer drug is very time-consuming, expensive and labor-intensive task. However, an integrated approach consisting of both computational and experimental approaches would be of great significance. Computational approaches are very helpful to identify or to narrow down potential lead molecules in a very short period without involving much money. Subsequently, the experimental approach may be used to validate these predictions. In this study, we developed QSAR models by considering the whole cell for anticancer activity for any class of molecules. The aim of the present study was to develop an efficient in silico method for screening of anticancer molecules against NCI-60 cancer cell lines. Thus, our method is a general method for predicting anticancer molecules irrespective of drug target or cell line. The performance of potency score method introduced in this study is comparable with models developed using machine-learning classifiers (e.g., Random forest, SVM, IBK and Naïve Bayes). We further improve the performance of our method by combining potency-score based model and SVM based method. In past, a method CDRUG has been developed on same dataset of chemicals for predicting anticancer molecules. Our best models outperform existing method CDRUG. Finally, we integrated these models in a web server for the betterment of scientific society working in this field.
area under the curve
FPR:
false positive rate
MCC:
Matthews Correlation Coefficient
MCS:
maximum common substructures
MOA:
QSAR:
quantitative structure-activity relationship
SVM:
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Authors are thankful to funding agencies, Council of Scientific and Industrial Research (project OSDD and GENESIS BSC0121), Govt. of India.
Bioinformatics Centre, Institute of Microbial Technology, Sector 39-A, Chandigarh, India
Harinder Singh, Rahul Kumar, Sandeep Singh, Kumardeep Chaudhary, Ankur Gautam & Gajendra P. S. Raghava
Harinder Singh
Kumardeep Chaudhary
Ankur Gautam
Gajendra P. S. Raghava
Correspondence to Gajendra P. S. Raghava.
HS initiated work and did all primary work including a compilation of datasets. RK and HS developed web server and identified active substructures. SS developed scripts for selecting best descriptors. HS and KC developed & evaluated prediction models. AG improved the overall presentation of the manuscript. GPSR coordinated the project and assisted in interpreting data. All authors have read and approved the manuscript.
Counts of Functional groups present in anticancer and non-anticancer molecules. Table S1. Shows frequency of occurrence of MCS in anticancer and non-anticancer compounds according to LibMCS module of Chemaxon. Structures were search using jcsearch module of Chemaxon with substructure search option. Table S2. The individual performance of best 126 selected fingerprints using MCC based approach. Table S3. Performance of hybrid method developed using 126 fingerprints on different sensitivity. (DOC 356 kb)
Singh, H., Kumar, R., Singh, S. et al. Prediction of anticancer molecules using hybrid model developed on molecules screened against NCI-60 cancer cell lines. BMC Cancer 16, 77 (2016). https://doi.org/10.1186/s12885-016-2082-y
Cancer inhibitors
Classification of cancer inhibitors and non-inhibitors
Active substructure
Active functional groups
QSAR
SVM light


Identify and develop safer, more effective treatment paradigms for patients with hematological malignancies.
LLS has formed a partnership with Celgene to create the first of such RFPs that will build the foundation of this new LLS initiative. This initiative will identify and fund priority research areas, with support from biotech and pharmaceutical partners in order to address significant unmet medical needs. The near-term goal of this program is to advance the scientific and medical understanding of the various hematological malignances.
The LLS is not currently accepting applications for the Quest for CURES.
With evolving technologies and emerging treatment options, this RFP is focused on defining subgroups of patients with a given diagnosis, understanding the role and improving detection of minimal residual disease (MRD) in hematological malignancies and using this information to guide treatment intervention. In addition, understanding which patients are more likely to transition from a pre-malignant state to full malignancy may provide new routes for early therapeutic intervention.
b. Identification of the spectrum of mutations, chromatin modifications and/or changes in immune function in elderly patients that identify those at high risk of transitioning from chronic pre-leukemic disorders to acute leukemias.
This RFP represents a new LLS research grant paradigm; QFC projects should, if successful, have a measurable impact on the diagnosis or treatment of patients with hematologic malignancies over the next 5 to 10 years. Proposals must include specific timelines, milestones and deliverables that researchers believe are achievable with their proposed funding. The range of funding available is from $200,000 to $400,000 annually, for research to be completed in a period of 2 years. Additional funding, for projects that have demonstrated exceptional progress in the initial 2 years may be available; subject to review by LLS and Celgene.
Additional funding is not guaranteed for any of the projects, but is contingent on the achievement of the project goals. The LLS Research Department staff will work with researchers to monitor progress and provide insight and expertise to each project.
Both Celgene and LLS are committed to supporting early stage, foundational research as well as new therapy development. Researchers and institutions should note that Celgene considers each funded project as having the potential for further development as a therapeutic or diagnostic for patients.
In addition to LLS's standard terms and conditions for academic grant awards, QFC also includes the following requirements. In partnership with Celgene and their funding, academic institutions and researchers will have to agree to provide Celgene with first rights to negotiate for intellectual property deriving from or reduced to practice during each project. Should Celgene choose to negotiate for rights to IP, Celgene shall have an exclusive period for this negotiation. If an agreement is not reached the Institution and researcher may not enter into an agreement with terms any less favorable than what was last offered by Celgene for a certain period of time. Please inquire with LLS for disclosure of those time periods. Also, if after said period of time, the Institution has not entered into another agreement, Celgene shall have the right to elect to enter into another exclusive dealing period. During the period of the grant and the periods when Celgene exercises its rights the institution is prevented from disclosing intellectual property rights outside normal activity or enter into negotiations with a third party. These specified periods for negotiation will be spelled out in the contract and available for review during the application process. Each applicant to the QFC is required to have his or her institution certify agreement with the IP terms and Celgene Rights at the time of application submission. For questions regarding this policy, please contact researchprograms@lls.org .
LLS is the world's largest voluntary health agency dedicated to blood cancer. The LLS mission: Cure leukemia, lymphoma, Hodgkin's disease and myeloma, and improve the quality of life of patients and their families. LLS funds lifesaving blood cancer research around the world and provides free information and support services to patients and their families.
Celgene is a global biopharmaceutical company committed to improving the lives of patients' worldwide by delivering innovative and life-changing drugs for our patients. With more than 300 clinical trials, Celgene has focused on delivering novel therapies for patients with incurable hematological malignancies, including multiple myeloma, myeylodysplastic syndromes, chronic lymphocyte leukemia (CLL), non-Hodgkin's lymphoma (NHL), and myelofibrosis.


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Home / Los Angeles / Upcoming Events in Los Angeles
Upcoming Events in Los Angeles
The Most Exciting Upcoming Events in Los Angeles
Springtime is finally upon us, which means that the good people of LA are starting to get outside and experience everything their city has to offer. And there is a lot it has to offer, whether it be concerts, comedy shows, lectures, cook-offs, or a range of other activities & events.
There can be a lot to choose from, and we know that better than anyone, but that shouldn't mean you get caught up in making the decision and miss what's going on right now.
To help with the decision & give you an idea of what's going on, we put together a list of some of the most interesting & highly anticipated events being put on in Los Angeles.
Vince Staples: March 30th at The Novo
With yet another critically acclaimed record (2018s "FM!") under his belt, Vince Staples is hitting the road, coming all the way from Long Beach to rock with the crowd in Los Angeles. The rising experimental rapper JPEGMAFIA, along with Channel Tres, will be Vince's support acts.
Masters of Taste: April 7th at the Rose Bowl
If you've wanted to sample all the quality food that LA has to offer, you'd probably end up having to move back to where you lived before you moved to the city. Thanks to the Masters of Taste, though, you can achieve this dream in a single afternoon.
During this festival, over 2,500 hungry & thirsty patrons walk onto the field of the Rose Bowl to enjoy unlimited tasting from the city's top chefs, restaurants, cocktail bars & breweries.
Admission will cost you, but considering the quality you'll get to enjoy it's a can't-miss deal for the many foodies (including yourself, perhaps) that are a part of the LA melting pot.
Earth Day LA: April 11th at Grand Park
Even though we've done a lot of damage to it already, it's our responsibility to save it, and we can't do that properly unless we have the knowledge to do so.Thankfully, the people who organize Earth Day LA are ready to teach the people everything they know. They'll be offering tips on going green, displaying the latest in environmentally conscious technology, and showing people all the different types of drought-resistant plants
They'll also be hosting performances, displaying recycled-art projects from kids, and even giving away free plants to people living in the city. Speaking of free, that's the cost of this event!
TCM Classic Film Festival: April 11th-14th at various locations
If you've taken your fair share of film classes and are wholly convinced that the glory days of cinema passed many moons ago, you'll be able to experience those classics the way they were intended to be shown: in the theater.
Individual tickets are available for each movie, although priority is given to people who purchase one of four tiers of passes they offer to the whole festival. You can find out more about these pases & other details on their website, which is hyperlinked in the section title.
LA Art Book Fair: April 12th-14th at The Geffen Contemporary at MOCA
For a cultural experience during that weekend that's slightly less expensive (read: free), The Geffen Contemporary at MOCA & Printed Matter are hosting the LA Art Book Fair.
This event is an international gathering to celebrate the most prominent & exciting voices in the art publication world. The full list of exhibitors, selected from a pool of thousands of applications, will be revealed in the middle of March.
Krush Groove: April 20th at The Forum
Local hip-hop heads might already know, but for the uninitiated, Krush Groove is an annual concert put on by famed radio station 93.5 KDAY, which champions the "golden age" of hip-hop by putting the greats on constant rotation.
With Krush Groove, fans get the chance to see these greats on stage. This year, acts like The Dogg Pound, Bone Thugs-N-Harmony, Too Short, Ice Cube, DJ Quik, Warren G, and more will be performing at the event.
Photoville LA: April 26th-28th & May 2-5 at the Annenberg Space for Photography
Attendees of this free event will get to enjoy an exhibition of photographs from a wide assortment of local & international photographers. To add an extra twist, all the photographs are displayed in repurposed shipping containers, photo cubes, and other special installations.
Guests will also get to enjoy various family-friendly activities, workshops, talks, food & beverage options, and a community beer garden.
Bikini Kill: May 2nd at Hollywood Palladium
People with even a slight interest in the iconic riot grrrl music scene should be jumping for joy at the sight of a Bikini Kill show date. With the exception of a smaller show in 2017, this will be one of the first major concerts the band has done in over two decades.
Even if you aren't familiar, the band's powerful feminist messages & infectious energy will be sure to have you hooked on first listen, so you should try to score some tickets regardless.
Melinda Gates: May 7th at Aratani Theatre
For those who want an extra dosage of girl power, Melinda Gates will be giving a talk at the Aratani Theatre to discuss her book "The Moment of Lift: How Empowering Women Changes the World."
In the book, she discusses various steps that need to be taken to ensure gender equality, including access to education & careers, bodily autonomy, maternity leave, and other measures. She also discusses various figures she believes have greatly contributed to the fight for equality.
Ariana Grande: May 10th at The Forum
2018 was a tough year, but there weren't many people that had a tougher go of it than Ariana Grande. One of her concerts was brutally attacked, her ex-boyfriend Mac Miller died of an overdose, and she had to cut off her recent engagement to top it all off.
Through all this, though, she's released two quality albums ("Sweetener" and "thank u, next,") that shine light on all the facets of her struggles & triumphs. After performing on the 6th and 7th at the Staples Center, she'll be bringing her Sweetener tour to The Forum on the 10th.


This year's Brighton Pride event raised a record-breaking amount for community causes, organisers said.
The LGBT+ event saw hundreds of thousands of people flock to the city for the Community Parade, Pride Festival headlined by Britney Spears and the new LoveBN1Fest on August 3 to 5.
The £250,000 raised by the event will be distributed as grants to LGBT+/HIV organisations and community groups through the Rainbow Fund, the Pride Social Impact Fund, Pride Cultural Development Fund and new Pride Solidarity Fund.
Paul Kemp, Brighton Pride CIC managing director, said; "We are immensely grateful for the support of everyone who purchased tickets for the official Pride events, as well as our sponsors all of whom have helped us raise this record amount for good causes across our city.
Organisers said all tickets revenue raised from Brighton Pride events goes directly to the operational and running costs of producing the Pride Festival, LGBTQ+ Pride Community Parade, Pride Village Party and community fundraising for the Rainbow Fund and Pride Social Impact Fund.
Over the last six years Pride has raised more than £700,000 for charities.
The new Sunday community day in Preston Park – LoveBN1Fest – helped raised even more funds with £20,000 being allocated from the Social Impact Fund for good causes around Preston Park and the St James Street area.


Save time without sacrificing flavor with these recipes that can go from your freezer your dinner table no time at all. These 20 Chicken Freezer Meals are perfect for busy nights or those nights where you just don't want to cook!
If you love Chicken Freezer Meals Make sure you check out our 10 Freezer Meals in 30 Minutes Meal Plan!
Also, be sure to check out our NEW Freezer Cooking Meal Plans are now available. You can buy these new plans that include the Detailed Shopping List, Full Recipes, and even Step by Step Instructional Videos. These are some of our family favorite dinner ideas!
The fresh lemon flavor brightens this dish while a side of pasta brings it together.
With vegetables included in the dish, this complete meal takes minutes to prepare.
This make-ahead casserole easily thaws and bakes, a quick budget-friendly meal.
An international-flavored casserole full of spice and protein.
Creamy, tangy, satisfying and personalized your way.
Eat it now, freeze it for later. Tough decision.
A go-to appetizer that you can have on hand for impromptu entertaining.
Large enough for a crowd, serve up a bowl of comfort for your next dinner.
Nothing could be simpler than chicken going to the grill straight from the freezer. Why didn't I think of that?
Cooked ahead of time in a homemade sauce, this a great freezer meal for those busy evenings.
This dish is not only quick to throw in the freezer but it's absolutely delicious when grilled up.
The recipe makes two pans – one to eat and one to freeze. To enjoy later. You're welcome.
Cook up a batch and freeze it for easy school night tacos, enchiladas, taquitos, chicken, burritos – you name it!
Freezer friendly meal, potluck dish, or meal to help a family/friend in need – comfort food for anytime of the year.
Perfect for storing in the freezer to keep on hand for those days when you don't have time to cook, but still want a home cooked meal!
With part BBQ sauce and part hot sauce, Spicy BBQ Wings are simple and delicious.
Super tasty and oh so easy to make – just dump all of the ingredients into your Crockpot and voila!
A go-to, easy dinner meal, freeze half for later or feed a group – your choice.
A creamy, spicy chili which goes from freezer to Crockpot in no time flat.
Homemade version of a beloved favorite, these are great frozen, thawed overnight, and reheated the next day for lunch.
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Thank you for applying to adopt a cat from Foal Farm.
Our main concern is that our cats should go to permanent new homes where they will be cared for and happy, for the rest or their lives. We give you all the available advice and information regarding the cat you have chosen, and also offer you help and advice after adoption.
To try to reduce the number of cats returned to us, we would therefore ask you to answer the questions below so that we can match each cat to a suitable owner.
Please think carefully about your decision, as we consider that you either know you can cope with a cat or you can't – and FOAL does not automatically give refunds.
Foal Farm may refuse the right to adopt a cat without giving reason. All animals remain the property of FOAL, and are adopted at our discretion.


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Many people want to know: Why is there a lighthouse perched on the top of our bike shop building? We absolutely love all things nautical, alongside our love for bikes. Come inside and all will be made clear as day, once you've see how we decorated!
As we were constructing our new building, we decided that we wanted to incorporate an uncommon eye catching feature not typically seen in the middle of a city in Colorado. Thus was born our lighthouse, the crowning touch. To answer many a curious visitor's questions: yes, there is a working light inside, and yes, there is a way to the top of the lighthouse (the view is spectacular!). We are so sorry, but there are no tours are given of the lighthouse as it is a little difficult climb.
Next time you're traveling down Colorado Avenue near 7th Street, look up and check out our lighthouse. We're pretty sure it's the only one.
We get a lot of comments and questions about the mural on the side of our building. It was painted by a talented local artist named David Gonzales during the summer of 1998. It depicts an old-time bi-plane flying over wind swept sand dunes with a curious group of cyclist riding below. Many people don't realize that this is a tribute to the Wright brother's achievement of the first manned, powered and controlled flight in 1903.
Wilbur and Orville Wright were first fascinated with bicycles, and began the Wright Cycle Company in 1896 in Dayton, Ohio. They sold hundreds of their Wright Special's for $18 each, and those funds financed much of their work and experimentation in aviation. Many of their tests on aerodynamics and wing forms were conducted on top of bicycles that were used to produce the necessary breeze. Story has it, that Wilbur one day at his bike shop while fiddling with an empty inner tube box got the idea for the moveable bi-plane wing. The box was rigid vertically, but could be twisted into opposing angles. The discovery of this design was a major step to the development of the first airplane.
On December 17th 1903 history was made and the world forever changed with that first flight. The roots of aviation will forever be tied to the bicycle and the two inventive bicycle mechanics from Ohio. We pay tribute to both with our mural. Next time when coming into our shop, pause and take a look and reflect on how our lives have been made better by both of these incredible inventions.
One day some customers saw me playing with our dog Bosco while perusing around the bike shop and during our conversations, they asked me if I wanted another one. I was indeed curious and asked if they were getting rid of a Maltese (that breed is so expensive). They replied yes, and that they were moving and wouldn't be able to keep her.
That is how we became pet parents of our sweet Zoie. She was an older pup at 9 years old, she weighed less than 3 pounds, and had a hunched back as a result of being in a crate for those 9 years. Poor girl, she could not even hold her head up straight; the day after we got her we rushed her to our vet. Her teeth were infected, her jawbone was also infected, and we discovered many other issues as well. We decided to have her fixed because we found out that dogs that are fixed live much longer and have less health problems. Nothing could be done with her hunch back, and it made her walk funny, but she was never in pain again. Our vet said the blood infection would have killed in a few more days without proper care.
She immediately grew to over 6 pounds! She was healthy, happy, and loved for the last 6 years of her life! She slept on our bed, and we made her home made dog food. She loved being held and was a great playmate for Bosco. She traveled all over the USA, spending a month in Key West, going on lots of fishing and camping trips. She was so happy to go to the bike shop every day. She just loved life so much. At almost 15 years old, on October 22, she suffered a stroke and passed away in my arms. I continued to tell her how much we love her and kissing her. I always prayed she did not remember her first 9 years of neglect and abuse, and only remembered her last 6 years with us.


This is your basic Hot Rolled round bar. It comes in 20 foot lengths, or cut to your specifications. We generally stock these in our smaller diameter sizes.
This is a 1045 grade bar, available in 20 foot lengths or cut to size. We stock this grade from 1/2" diameter to 12" diameter.
This is the most commonly used grade. It is usually slit edge in the thinner sizes and flat bar in the larger sizes. The standard is 20 foot lengths but we can cut to your exact measurements as well.
These are the 1/8" through 1/4" hot roll flat bars. They come in 20 foot lengths or cut to your exact size.
These are the most common sizes of Rebar. The standard length is 19'06".
This uses a numbered system to determine its size.
These bars come in 20 foot lengths or cut to size.


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Directed by: Sohail Khan
Producer by: Sohail Khan, Sunil A Lulla
Starring: Salman Khan, Daisy Shah, Tabu, Danny Denzongpa & Ashmit Patel.
Music Dir: Sajid-Wajid
The most awaited film of Salman Khan "Jai Ho". This was not the initial name of the movie. At first, it was being called as "Mental". The leading role is being played by Salman Khan while he will be seen with a new comer co-star, Daisy Shah. Besides that, there will be many other actors one can see in this movie such as Sunil Shetty, Ashmit Patel, Genelia D'Souza etc who have played small roles in it but their presence have increased the value of the movie. The direction of this movie has been given by Salman Khan's younger brother Sohail Khan.
The story of the movie is quite interesting. It starts with Salman Khan, who has been shown in this movie as an ex-army officer. He was expelled from the army due to not obeying his senior's order but the fact was Salman Khan refused his senior's order as they were not according to justice.
As a common man, Salman also didn't like any unjustice act being done with someone. He always helped those who needed someone to stand for them as according to Salman, you don't need a uniform to help others. The story of this movie also revolves around a war that has been started between Salman and a boy. Salman gets within a small fight with this boy who turns out to be the son of great politician and from here the war between family's starts. Now who will win this war, what will happen, for this you will have to watch the movie.
Now lets talk about the acting. This movie is purely Salman Khan type movie. He has played his role so well, even better then Dabangg, and for sure, no one would have done a better job then Salman for this kind of a movie. Daisy Shah, who is playing the lead actress role in this movie, is professionally a dancer who have done dance performances in the background of Salman Khan�s songs in some movies. Salman may have liked her and picked her up for this movie. So it's a life changing movie for Daisy Shah. Her acting is rated as "OK" in this movie. The reason she might not have expressed her acting skills to the fullest may be that her role was quite limited. Her chemistry with Salman is good and her dance performances in the movie are also good as she is a dancer by profession. Besides Salman and Daisy Shah, if we talk about the acting of other actors then this review will get too much boring.
Sohail Khan, as a director, has done a good job, he has targeted a common man and the issues revolving around him that will surely attract the audience as they will be relating it to themselves.
We personally didn't found the music of this movie very attractive. And We don't think that there is any song in the movie that will help in making this movie more popular.
Over all, this movie "Jai Ho" is a typical Salman Khan movie in which you will not only see action which includes 8 sec punch, throwing people and breaking walls, but some comedy and emotions also adds up value to this movie. Screen play is weak in this movie but Salman Khan's acting has surely covered it well. The first half of the movie is more entertaining while the second half has serious scenes and is packed with tons of action.
The basic theme of the movie is that when someone helps you don't just thank him/her, help 3 others so that they could also help others. This movie is good to watch and We will rate this movie as 3.5 stars.
Click Here For Movie Krrish 3


58 4pfqA 029763 13303 13301 13083 8 77 11279 1890 497 2014-07-03 n Chain A, Crystal Structure Of Hypoxanthine Phosphoribosyltransferase From Brachybacterium Faecium Dsm 4810, Nysgrc Target 029763.
74 4mchA 029520 6858 6854 6626 3 76 6121 600 16 2014-03-31 n Uridine Phosphorylase From Vibrio Fischeri Es114 Complexed With 6-hydroxy-1-naphthoic Acid, Nysgrc Target 029520.
77 4lyyA 029677 15525 15521 15327 5 98 13647 1913 224 2014-03-31 n Hypoxanthine Phosphoribosyltransferase From Shewanella Pealeana Atcc 700345, Nysgrc Target 029677.
84 4m6dA 032671 6317 6311 6266 6 86 5779 489 113 2014-03-31 n Aptamer Minf-lysozyme Complex.
85 4m1qA 029814 4389 4387 4055 9 78 2300 1653 158 2014-03-31 n L-lactate Dehydrogenase From Bacillus Selenitireducens Mls10, Nysgrc Target 029814.
87 4lnhA 029520 6616 6613 6476 4 76 5948 618 16 2014-03-31 n Uridine Phosphorylase From Vibrio Fischeri Es114, Nysgrc Target 29520.
95 4marA 029804 6974 6971 6789 3 70 5648 988 426 2014-03-31 n Purine Nucleoside Phosphorylase From Meiothermus Ruber Dsm 1279 Complexed With Sulfate.
96 4m1eA 029364 6101 6098 5988 7 68 4686 1302 69 2014-03-30 n Purine Nucleoside Phosphorylase I From Planctomyces Limnophilus Dsm 3776, Nysgrc Target 029364.
99 4m7wA 029767 6830 6829 6698 10 98 5642 968 432 2014-03-30 n Purine Nucleoside Phosphorylase From Leptotrichia Buccalis C-1013-b, Nysgrc Target 029767.
100 4m3nA 029804 7546 7539 7278 3 70 6127 1005 428 2014-03-30 n Purine Nucleoside Phosphorylase From Meiothermus Ruber Dsm 1279, Nysgrc Target 029804.
106 4m0kA 029775 12079 12070 11606 9 59 9618 2303 471 2014-03-30 n Adenine Phosphoribosyltransferase From Rhodothermus Marinus Dsm 4252, Nysgrc Target 029775.
109 4lzaA 029700 14354 14349 14083 8 79 12165 3026 419 2014-03-29 n Adenine Phosphoribosyltransferase From Thermoanaerobacter Pseudethanolicus Atcc 33223, Nysgrc Target 029700.
116 4mzzA 033256 107 98 98 30 97 0 57 41 2014-03-28 n Bovine 3 Glu-osteocalcin.
177 4jhmA 206359 6155 6152 5930 6 84 5923 147 1 2013-05-13 n Putative Mandelate Racemase/muconate Lactonizing Enzyme From Pseudovibrio Sp.