RNA came first. Then, ~3-4 billion years ago, DNA emerged.
Among their differences:
🔹RNA contains uracil
🔹DNA contains thymine
But why does DNA contains thymine (T) instead of uracil (U)?
https://t.co/XlxT6cLLXg
1/16
Why do B12 and folate deficiencies lead to HUGE red blood cells?
And, if the issue is DNA synthesis, why are red blood cells (which don't have DNA) the key cell line affected?
For answers, we'll have to go back a few billion years.
RNA came first. Then, ~3-4 billion years ago, DNA emerged.
Among their differences:
🔹RNA contains uracil
🔹DNA contains thymine
But why does DNA contains thymine (T) instead of uracil (U)?
https://t.co/XlxT6cLLXg
🔑Cytosine (C) can undergo spontaneous deamination to uracil (U).
In the RNA world, this meant that U could appear intensionally or unintentionally. This is clearly problematic. How can you repair RNA when you can't tell if something is an error?
https://t.co/bIZGviHBUc
DNA's use of T instead of U means that spontaneous C → U deamination can be corrected without worry that an intentional U is being removed.
DNA requires greater stability than RNA so the transition to a thymine-based structure was beneficial.
https://t.co/bIZGviHBUc
Let's return to megaloblastic anemia secondary to B12 or folate deficiency.
When either is severely deficient deoxythymidine monophosphate (dTMP*) production is hindered. With less dTMP, DNA synthesis is abnormal.
[*Note: thymine is the base in dTMP]
https://t.co/AnDUtKkbZh
So one hypothesis is that megaloblastic anemia results from a deficiency in dTMP leading to an issue with DNA elongation (i.e., addition of nucleotides)
Some (#1) but not all (#2) data support this.
There is more to it.
1. https://t.co/vysYKm4Sst
2. https://t.co/PxjmJAsvwj
To add to our explanation for how B12 and folate deficiencies hinder DNA synthesis, look back at the figure in tweet 5.
What would you anticipate increases in concentration in the setting of B12 or folate deficiency?
B12 and/or folate deficiency result in issues with dTMP production. As dUMP is the precursor, the ratio of dUMP/dTMP rises.
Result: dUTP (uracil + deoxyribose triphosphate) is incorporated into DNA where dTTP should be!
https://t.co/54Bir7QA93
But uracil doesn't belong in DNA!
In response to this misincorporation, attempts are made to repair these strands. U is removed but there isn't enough T to fill the gaps. Single and double-stranded breaks form resulting in non-functional DNA.
https://t.co/JXzqUpRyGc
Without functional DNA, cell division is halted. RBC precursors undergo apoptosis.
Result: "ineffective erythropoiesis" and anemia!
To this point we've explained the anemia but haven't yet explained why the resulting RBCs are so large. That's next.
https://t.co/y5DVkAA8vj
Remember that RNA doesn't uses thymine (it uses uracil). And only the thymine containing nucleotide (dTMP) requires B12/folate.
🔑Result: In B12/folate deficiencies, RNA synthesis is relatively unaffected!
https://t.co/lwmGWuOrFC
In the nuclei of B12/folate deficient RBC precursors, DNA synthesis is poor leaving cells stalled and unable to divide.
But, in the cytoplasm, RNA and protein synthesis continues unabated.
Result: "nuclear-cytoplasmic asynchrony"
Precursors with nuclear-cytoplasmic asynchrony are unable to divide into daughter cells. But the cytoplasm continues to expand.
When survivors eventually cast off their nucleus (and its DNA!) and appear in the peripheral blood, they will be huge.
They will be macrocytic!
There are other explanations (see link).
And I admit this doesn't really explain why RBCs are more affected than other cell lines (though all ARE affected).
AND, why are neutrophils hypersegmented?
For these unanswered questions, I seek your help.
https://t.co/huX6xJOBhp
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So the cryptocurrency industry has basically two products, one which is relatively benign and doesn't have product market fit, and one which is malignant and does. The industry has a weird superposition of understanding this fact and (strategically?) not understanding it.
The benign product is sovereign programmable money, which is historically a niche interest of folks with a relatively clustered set of beliefs about the state, the literary merit of Snow Crash, and the utility of gold to the modern economy.
This product has narrow appeal and, accordingly, is worth about as much as everything else on a 486 sitting in someone's basement is worth.
The other product is investment scams, which have approximately the best product market fit of anything produced by humans. In no age, in no country, in no city, at no level of sophistication do people consistently say "Actually I would prefer not to get money for nothing."
This product needs the exchanges like they need oxygen, because the value of it is directly tied to having payment rails to move real currency into the ecosystem and some jurisdictional and regulatory legerdemain to stay one step ahead of the banhammer.
If everyone was holding bitcoin on the old x86 in their parents basement, we would be finding a price bottom. The problem is the risk is all pooled at a few brokerages and a network of rotten exchanges with counter party risk that makes AIG circa 2008 look like a good credit.
— Greg Wester (@gwestr) November 25, 2018
The benign product is sovereign programmable money, which is historically a niche interest of folks with a relatively clustered set of beliefs about the state, the literary merit of Snow Crash, and the utility of gold to the modern economy.
This product has narrow appeal and, accordingly, is worth about as much as everything else on a 486 sitting in someone's basement is worth.
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This product needs the exchanges like they need oxygen, because the value of it is directly tied to having payment rails to move real currency into the ecosystem and some jurisdictional and regulatory legerdemain to stay one step ahead of the banhammer.