One method might be to set the ExcludeSyncFolders to prevent Nickel from scanning the location where comics are stored; similarly there must be a setting in KOReader to filter out the location where ePubs / kepubs are stored.
Search the forums for more info on the ExcludeSyncFolders settings.
Of course, you'll also need to configure calibre and it's locations for storing content. I seem to remember that people have posted examples of configuring different locations based on file type.
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