Are Natural Paper Inclusions Always A Negative?

Received this amazing 528B... MNH, huge margins,
with inclusion in the left '2' viewable from the
back... (see photo)

Yes, it is considered a fault. When a Stamp is sent in for grading, points are removed for natural inclusions.

Thank you... I like to collect anomalies here and there,
and found this one interesting, given it appears to not
be an after-effect from usage (or manipulation), rather
a paper flaw prior to printing...

I'm fairly certain it's OG, so I'll just go ahead and
mount it next to its 'brother' 528B in my album...

As far as whether it detracts or devalues, or lowers a "grade", it depends upon size, location, visibility. If it is only visible from the back side, and very small (a tiny pulp or fiber), it may not detract or lower the grade. The W/F offset issues are rife with NPIs - they are fairly common on them, just sometimes you have to really be looking for them.

PSE labels them as "Production faults"

http://www.psestamp.com/appendix.chtml

Thanks for the link to PSE, stallzer. My comment about the lowering of grade is trying to emphasize how noticeable it is. If the inclusion is present, but small enough to really have to look hard to see it, it may not be called out in the cert or affect the grade. If you look at higher magnification, you will probably see one or more natural paper inclusions on most stamps. In fact, if you look at almost any stamp, at higher magnification, you will find one or more faults or irregularities.

From PSE: "U.S. stamps occasionally have one or more natural inclusion specks embedded in the paper. These vary in size, color and location. They effectively lower the value of a stamp if they are visually objectionable and so the color of the stamp can also be a factor affecting the visual effect."