"John H." <johnh from goawayplease.com> wrote in message
news:13laqukj08fmg6f from corp.supernews.com...
>> Fair warning: I've had very little time(<2 weeks) to research and think
> about this so don't be surprised if I am blundering along here.
>> I'm trying to track down the following:
>> Whether or not there are differing transporters into the rod and cone
> cells, and the RPE cells, for the pro-vitamin A carotenoids\retinoids and
> the non-pro ones, lutein and zeaxanthin.
>> Can anyone help???
>>> The retinoids go off into the visual cycle, in STGD(stargardt) there is an
> accmulution of retinoids in both the ROS and in the lipofuscin in the RPE.
> There is also some evidence to suggest a lack of L and Z in the RPE for
> STGD patients. I suspect that the ABCA4 product, Rim protein, may have a
> preferential transport of retinoid products, particularly those with PE
> component, but I'm beginning to wonder if there if there is another
> transport function here, that of L and Z into the RPE, being depleted
> either by the lipofuscin products, which clearly have a significant
> retinoid component, or if the Rim protein also serves a role of
> transporting L and Z into the RPE. The problem is that Rim protein, as
> currently understood, appears to be a specific product of the rod and cone
> cells.
>> The current paradigm for STGD goes like this:
>> The Rim protein(protein from ABCA4) is dysfunctional, it transports shed
> ROS to the RPE for "reprocessing" and the product of the same is purportly
> then transported back to the ROS. Yet if Rim protein is a product of rod
> and cone cells, and in STGD the lipofuscin is present in the RPE, not the
> rods and cones, and if RPE cells first die, this seemingly precipitating
> photoreceptor death, then shouldn't we expect to see aggregations
> primarily in the rods and cones, not the RPE? It don't make sense.
>> It might go like this: the Rim protein has two ATP binding clefts, the
> transport across cell membranes is ATP dependent, so perhaps the relevant
> alleles impact on ATP capture or hydrolysis. So the ROS fragments are
> transported to a RPE cd36 receptor where they can be scavenged, but it may
> be the case that further ATP is required for transport to the lysosomes
> within the RPE to initiate degradation. I am too ignorant about
> biochemistry to know whether or not ATP can be transported through a cell
> membrane via an ABC transporter and even if that is possible do lysosomes
> require ATP from this source or are these ATP independent processes. We're
> awating genetic testing results but for now I'm assuming ATP involvement
> because there is good evidence to suggest that enhancing mitochondrial
> function can not only prevent aggregation but in AMD at least even reduce
> pre-existing aggregates.
>> It may not even be an ATP issue, allele variation may be related to the
> tranporter segment that binds the retinoid proteins. The incomplete
> transport may then allow oxidation via light which exposes hydrophobic
> cores, allowing aggregation, preventing adequate transport, perhaps even
> "clogging" the RPE cd36 scavenger receptor, so the process goes downhill
> from there. Fascinating problem, very fucking difficult, driving me nuts.
>> So then, can anyone point me to a good article on how the ROS is
> constructed, what are its constitutents, and are L and Z present in the
> photoreceptor cells or are L and Z very much located in the RPE?
>> Sort of an academic exercise, asked by friends to help with their daughter
> recently diagnosed with STGD. My role there mostly over but now I'm
> perservating on the bloody thing. See, a little brain damage goes a long
> way ... to Hell and back. Hey Glen, if you got this far, I really could do
> with a lesson in the finer subtleties of statistical analysis! I suspect
> that after this I'm also going to need a DRD2 antagonist ....
Hi John. I'm not sure I can help the sort of subtleties you might have in
mind. Remember, behavior analysts eschew the use of statistics but, of
course, I published in journals that require inferential statistics so I
have used them - usually repeated measures ANOVA. I know that you were
probably just making conversation, but far be it from me to pass up a chance
to bad mouth inferential statistics. One of the weird things about p-values
is that if you reject the null-hypothesis, the p-value becomes, in a sense,
meaningless! This is because a p-value gives the probability of obtaining
differences between two groups that are equal to or more extreme than what
you obtained GIVEN THAT THE NULL-HYPOTHESIS IS TRUE! But if you reject the
null-hypothesis on the basis of the p-value, what is the quantitative
meaning of the p-value? Many people think that the p-value "gives the
likelihood that the data you obtained are due to chance," but that is the
equivalent of saying that it is the probability that the null-hypothesis is
true given the data. But, as I have just described, that is not what a
p-value gives - it gives the probability of obtaining the data given that
the null hypothesis is true! This does not mean that a small p-value should
not cause you to reject the null-hypothesis, but as I said in a previous
post, rejecting the null hypothesis becomes increasingly likely as a
function of sample size! I am increasingly becoming enamored with Beyesian
statistics thanks to the unfortunately-absent Michael Olea. That guy is
really smart (but I think praise makes him somewhat uncomfortable). Beyesian
statistics do, in fact, give you the p that your hypothesis is true given
the data. Another thing that people think is that, if the p-value is really
small, repeating the experiment is likely to reproduce the results of the
first, but this is not true, as far as I can see. The only way to show that
a finding is reliable is to replicate it. But a lot of journals discourage
the submission of experiments that solely function as replications!
Anyhow...speaking of smart, you should be proud of your scientific
abilities. BTW, I don't think that I ever saw the abbreviation DRD2 and had
to Google it. I suspected it was a DAergic D2. Do you think you need a D2
antagonist for migraine or psychosis? I know what you mean though - I have
thought about certain topics on and off for decades, and sometimes cannot
abandon the problem for months at a time.
Good luck in your endeavors,
Glen
>> Someone take these dreams away .... they keep calling me(Dead Souls, Joy
> Division)
>>> John.
>>>