There are two kinds of rejects. Manuscripts being of some merits yet requiring additional significant studies are rejected but with the permission of resubmission. In this case, the authors may resubmit a revised manuscript with a cover letter stating original manuscript number and illustrating point-by-point responses to the comments provided in the Reject/Resubmit decision letter. Manuscripts rejected without a resubmission option are not allowed to resubmit. However, if the authors choose to submit a substantial revision as a new submission, a point-by-point response letter is not allowed, because it will be treated as a new submission.