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It is a very interesting question and I would definitely try it in vitro if I could. That being said, the first study that hinted at this temperature dependency was done using rabbit reticulocytes.

This means that while wild-type viruses carrying the opal codon is clearly the fittest at high temperature, at lower temperature the fitness gap between it and other codon variants becomes much more narrow.

But at “lower” mosquito-specific temperature, other stop codons exhibit higher translational read-through, enough to partially rescue fitness. This also means opal codon has higher read-through, and over produces polyprotein, like the sense codons, leading to similar processing issues.

At vertebrate-specific “high” temperatures, the opal codon produces the optimal amount of polymerase via read-through (unlike the other stop codons) without overproducing the polyprotein (like sense codons do) because it disrupts the processing cadence.

Thank you, Laura. Based on this study and others it would seem that the temperature sensitivity of the opal codon manifests via changes in the rate of programmed translational read-through and polyprotein processing efficiency.

Having access to the beautiful SHAPE-MaP data was absolutely crucial!

Finally, here is a link to the prequel study. www.science.org/doi/10.1126/...

This work would not have been possible without the efforts of two talented mentees Tiia Freeman and Eva Alleman (currently UW MCB), and my mentors @harmitmalik.bsky.social and @memerman.bsky.social. Also big thanks to Kevin Myles and his lab at Texas A&M for carrying out in vivo experiments!

The paper also contains an unexpectedly cool finding which we discovered on a short side-quest. Check out the preprint to see if you can spot it! As always, we would love to hear your thoughts and feedback.

This in turn prevents viral dsRNA sensing by cytoplasmic RNA sensors Dicer 2 and MDA5, in mosquito and human cells, respectively. Dicer 2, in particular, exerts strong selective pressure on the opal codon, such that sense-codon substitutions are highly disfavored in RNAi-competent mosquitoes.

Building on our previous study, we demonstrate that by maintaining proper non-structural polyprotein processing, the nsP3 opal codon also helps maintain the integrity of viral replication spherules.

And now this is the first statement from a named White House official, hours before the proclamation is set to go into effect.

Despite saying “to be clear,” her first tweet in this thread contained an FAQ posted yesterday which contains NONE of the information she lists below.