Game mechanics questions for experienced players

I have two quick questions:

1- Does in-game fatigue effect every player, or just D-linemen? We rotate D-linemen due to fatigue, but no other players. I am just wondering if everyone else sees performance drop off (just to a smaller level) as the game wears on.
2- Let's say I am running a base 4-3 defense, but pull a lineman in my nickel or dime package. Would it be better to run with DE3 ends, since there are only 3 linemen, or DE4 ends, because the game penalizes me for playing guys out of their "scheme"?

TIA

1. As far as I've heard and can tell fatigue only effects the D-line and HB's. If your HB has too many carries in a season then they may perform worse.

2. You currently cannot change your depth chart for different packages so if you're running a 4-3 I would assume it would be best to stick to DE4 ends, although, I'm not sure how much of a penalty, if any, you'd receive for swapping to the DE3's.

Yep, Kingswood is correct. Fatigue is only a factor for d-linemen and running backs. With running backs, there are a couple of things to consider. First is overall use - if you use a running back at the high end of NFL usage, you can "burn him out" and his performance will suffer in future seasons. The exact algorithm is a state secret, but as with other things, you know your NFL and can probably see examples of when this has happened. (Glance toward Larry Johnson.) Second, if you use a running back a lot more than his previous season's usage, his performance in that season will suffer. The reason for this is that we don't want someone finding a running back he had 50 carries for 400 yards, and then that guy gets 300 carries for 2,500 yards or so in Sandbox. If you use that guy sparingly over the season, he'll perform well (+/- randomness, scheme, and competition), but the more you keep using him, the more his performance will decline (via another state-secret algorithm).

In terms of nickel defenses, your linemen won't face an out of position penalty that's specific to the nickel. We keep them in their proper position. But keep in mind that if you pull a DT it'll likely weaken your run defense more and if you pull a DE it'll likely weaken your pass rush. So the other performance algorithms will still apply.