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Wimbledon champion Petra Kvitova became the fifth top 10 seed to exit the US Open in the first week when she was knocked out by Serbian world number 145 Aleksandra Krunic.
But there were no such problems for men's top seed Novak Djokovic and eighth-seeded Andy Murray, both former champions in New York, who remained on course for a mouth-watering quarter-final showdown.
Third seeded Kvitova lost the third round tie yesterday 6-4, 6-4 to the pint-sized 21-year-old from Belgrade, who came through qualifying and had never won a match at a major before this year's event.
Kvitova joins second seed Simona Halep, fourth-seeded Agnieszka Radwanska, Angelique Kerber, the sixth seed, and eighth-seeded Ana Ivanovic in failing to make the fourth round.
The 24-year-old Kvitova dropped serve five times and committed 34 unforced errors against the 5ft 4in (1.63m) Krunic who divides her time between the pro tour and studying for a university economics degree.
"It was an honour to play on the same court as Petra, she's a great champion. I watched both her wins at Wimbledon," said Krunic.
"I wanted to be myself on court, play as long as possible. I didn't expect to win. I hoped to win a set."
Krunic said she tried not to think about nerves even as a 4-2 lead in the second set was swallowed up by Kvitova who pulled level at 4-4.
But the slender Serbian broke for 5-4 and claimed her famous win on a second match point when another Kvitova forehand sailed wide.
"On match point I thought 'Don't serve a double fault.' I just wanted to keep the ball in until she missed," added Krunic who will next face either former world number one Victoria Azarenka of Belarus or Russian Elena Vesnina for a quarter-final berth.
Djokovic, the 2011 champion, brushed aside America's Sam Querrey for the eighth time in nine meetings, with a 6-3, 6-2, 6-2 win taking the world number one into the fourth round at a major for the 22nd consecutive time.
"Sam is big server, very powerful. But he doesn't move that well so I wanted to keep him moving around the court, mix up the pace and get as many returns as possible back," said Djokovic after an 85-minute win which was never in doubt from the time he raced into a 5-0 lead in the first set.
Djokovic will next face John Isner, the