From: Rafal Smigrodzki (rafal@smigrodzki.org)
Date: Wed Jun 11 2003 - 12:52:35 MDT
Aubrey wrote:
>
> All true. I mentioned one aspect of this earlier -- that there will
> always be a proportion of stuff in the lysosomal compartment that is
> digestible (and, indeed, being digested), and that is the material to
> which your logic correctly applies. But that presumably applies only
> to intact cells, not to the acellular core. I couldn't find a ref to
> your claim that the **majority** of pathologically relevant material
> in late-stage (artery-occluding) plaques is apparently digestible --
> please provide it.
### Hackam DG. Peterson JC. Spence JD. What level of plasma homocyst(e)ine
should be treated? Effects of vitamin therapy on progression of carotid
atherosclerosis in patients with homocyst(e)ine levels above and below 14
micromol/L. American Journal of Hypertension. 13(1 Pt 1):105-10, 2000 Jan
At least this is the article I was thinking about - unfortunately I read it
a long time ago, and crucial numbers flipped in my memory - the study shows
only a very modest absolute reduction of the plaque (the relative reduction
compared to pre-treatment was quite substantial).
So, well, I guess I goofed up, there is no proof that plaque in adults is
largely reversible. Still, there is no proof to the opposite, either, and
the ApoE mice, as well as presence of unmodified cholesterol in the plaque
support the equilibrium hypothesis.
I guess we should for now conclude that there is insufficient quantitative
data to decide in favor of either hypothesis.
-----------------------
>
>> ### Chinnery specified the "maintenance of wild-type mechanism", yes,
>> but AFAIK he didn't say that random fluctuations are irreversible and
>> cannot push the total number of genomes back down (except when driven
>> to homoplasmy).
>
> He said that the total number can fall due to random fluctuations, but
> not be "pushed" down. That's where the bias in directionality comes
> from: there is no push either way when the number of wild-types is
> sufficient, but there's an upward push when it isn't.
### This sounds reasonable.
-----------------------
> Ah, but it's not just as seen in real life: this is the whole problem.
> We see two clear deviations from real life in his model: (1) his model
> predicts lots of proliferation at modest heteroplasmy (say, under
> 50%),
### Can you quote Chinnery on that?
----------------------------
Thresholds don't help re
> the former, because in Chinnery's model the only reason there's a
> threshold is that there's a maximum number of mt genomes in total (wt
> plus mutant).
### I didn't get this one. Chinnery specifically predicts biochemical
threshold effects for mutations with high E (the efficiency parameter). This
would not be dependent on any maximum number of mt genomes, and does not
predict lots of proliferation at modest heteroplasmy (see Fig 7 and page 578
in the J.Theor Biol article).
---------
and (2) it predicts (for parameters chosen to give the observed
> number of COX-negative cells) a lot more heteroplasmic cells than
> homoplasmic (or very nearly) mutant cells.
### Can you quote him?
See fig 5 and p 580, where he says that within his model the levels of
mutations and COX negativity can vary independently of each other.
-------------------------
>
> Really? I thought only a few types block PCR (eg thymine dimers).
> But I'm not well up on that, so I take your word for it.
### Bulky adducts do block PCR, although I should qualify it by saying that
I don't know the relative abundance of various adducts in the mtDNA.
-----------------------------
>
>> BTW, I just read the abstract of your paper in Protoplasma - sounds
>> intriguing, but the full text is not available online. Could you send
>> me a copy?
>
> I actually don't have full-text access, even though Cambridge does get
> the journal in hard copy. If you (or anyone else reading!) can get it
> (http://link.springer.de/link/service/journals/00709/tocs/t3221001.htm
> and my article is the second in the issue), I would be most grateful!
>
### Thanks, I got it.
Rafal
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