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I have a matrix that is [500x500]. I have another matrix that is [2x100] that contains coordinate pairs that could be inside the first matrix. I would like to be able to change all the values of the first matrix to zero, without a loop.

mtx = magic(500);
co_ords = [30,50,70;  30,50,70];
mtx(co_ords) = 0;
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You can do this using the function SUB2IND to convert your pairs of subscripts into a linear index:

mtx(sub2ind(size(mtx),co_ords(1,:),co_ords(2,:))) = 0;

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