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Rafael Nadal will hope to continue his push towards a 19th Grand Slam title when he plays in the quarter-finals of the US Open on Wednesday.
Three-time US Open winner Nadal faces Argentina's Diego Schwartzman, who has never reached a Grand Slam semi-final.
France's Gael Monfils plays Italy's Matteo Berrettini in the last eight.
In the women's event, Belinda Bencic, who eliminated Naomi Osaka, meets Donna Vekic, with Canada's Bianca Andreescu up against Elise Mertens of Belgium.
Nadal, 33, is the only player seeded in the top 12 to be in action on the Arthur Ashe Stadium on Wednesday and meets Schwartzman after the 20th seed knocked out world number six Alexander Zverev on Monday.
Spaniard Nadal has been in impressive form and lost only three games in the last two sets of his four-set win over 6ft 6in Marin Cilic, a player almost a foot taller than 5ft 7in Schwartzman.
Diego Schwartzman (right) came from a set down to beat world number six Alexander Zverev on Monday
"It will be a big challenge, I have to play my best," Nadal said. "I'm happy for Diego, he's a close friend and I hope to play a great match.
"He is playing amazing - he is one of the players with the best talent on tour."
Monfils reached the final four at Flushing Meadows three years ago, while 23-year-old Berrettini will be playing in his first Grand Slam quarter-final.
On Tuesday, Monfils watched on as partner Elina Svitolina moved into the last four of the women's event, beating Britain's Johanna Konta 6-4 6-4.
"We're pushing each other and we're now trying to join each other in the semi-finals - now it's time for him to step up his game," the Ukrainian joked.
Nineteen-year-old Canadian Andreescu, a winner over former world number one Caroline Wozniacki in the third round, had never got past round two in a Slam before this tournament.
"It feels awesome. I've been working and dreaming of this moment for a really long time, so it feels pretty damn good to be in the quarters here," she said.
"I'm really happy, but the tournament's not done yet and I can do even better. I've never felt this confident before. This year has been the best of my life."
However, Andreescu's opponent, Mertens, the 25th seed, has been in fine form, not losing more than three games in any set in four matches.
Bianca Andreescu's previous best performances at Grand Slams were reaching round two at the Australian Open and the French Open earlier this year
In the first match on Arthur Ashe Stadium at 17:00 BST, Bencic, a 7-5 6-4 winner over 2018 champion and world number one Naomi Osaka on Monday, takes on Croatia's Vekic.
Bencic, 22, was out of action for five months in 2017 after having wrist surgery and her ranking dropped outside the top 300 before she worked her way back up.
"When you're injured you wonder if you can ever play at this level again," said Bencic. "All true athletes have to overcome obstacles, injuries, tough times and it made me a stronger person, a better player."
On a match against her friend Vekic, Bencic added: "It will be great that one of us will be in the semi-finals. I'm very happy for her. But definitely I want to win."
Jamie Murray (left) and Neal Skupski are the 15th seeds in the men's doubles
In the men's doubles quarter-finals, British pair Jamie Murray and Neal Skupski take on unseeded Americans Jack Sock and Jackson Withrow.
Britain's Luke Bambridge, along with Japan's Ben McLachlan, play the top-seeded Colombians Juan Sebastian Cabal and Robert Farah, who won the doubles title at Wimbledon in July.
It is a busy day for Murray as he is also in mixed doubles semi-finals action, partnering American Bethanie Mattek-Sands. Last year's champions will play third seeds Samantha Stosur and Rajeev Ram.
