Until very recently the USPS was legally required to pre-fund its pension plan for 75 years, which is unheard of in private business. It was an enormous drain on capital that prevented them from being able to make those kinds of investments.

https://www.reuters.com/world/us/us-senate-approves-50-billion-postal-service-relief-bill-2022-03-08/

Can’t say I’ve ever seen that for an NMR. A standard 400 MHz instrument has to be topped up with 70-100 L of liquid helium every 6-12 months.

To add to this, there’s an iterative set of interactions where ligand binding induces conformational changes on the receptor, which induces some conformational change on the ligand, and so on. That’s why in silico docking that assumes a rigid receptor often gives spurious results that don’t line up with experimentally measured binding affinities. It’s problematic since reductions in receptor degrees of freedom can impose a significant entropic cost, which can have a major influence on the Gibb’s free energy of the binding event.

We’re getting better at modeling those interactions than we used to be, but it’s still extremely challenging. The best efforts start with a large collection of known binding affinities with different ligands, which can be used to constrain the system.

To add to this, it’s also why you’re mostly likely to find halogen-containing biomolecules in aquatic species, especially marine mollusks. The dye Tyrian purple would be a classic example.

I’ll give them some wiggle room since it’s entirely possible that some minor but extremely active constituent is giving all the response (this has happened to me where I remade a compound that turned out to be inactive compared to previous preparations because it was too pure and didn’t have the active impurities of what had been made before), but it is useful to have that perspective about the potential limitations of what they’re seeing. Such are the challenges of natural product chemistry.

Will be interesting to see what the active compounds are and what their prevalence in the extracts was. Because if you assumed that they were pure compounds 5 ug/mL is probably somewhere in the 10 uM range, which is not what you’d hope for from a potential hit.

To build on what’s already been said, there is a test for unilateral vs bilateral hyperaldosteronism - adrenal venous sampling. But it is critical to get a specialist with a lot of experience because it’s a technically challenging procedure.

https://www.mayoclinic.org/medical-professionals/endocrinology/news/primary-aldosteronism-the-role-of-adrenal-venous-sampling/mac-20430855

Not exactly shocking from a DNA alkylating agent.

There are some dry cleaning systems that use supercritical carbon dioxide as the solvent. But that’s still a liquid.

https://academic.oup.com/book/42069/chapter/355917907

To begin with we would have to know what headaches are on a mechanistic level and at least when I took a neurophysiology of pain course in grad school the answer was pretty unclear.

Nope, taking breaks during the week is much more important than taking larger blocks off. The damage tends to be something of a positive feedback loop - damage accumulates, which tends to lead to inflammation, which leads to more damage. Having time when the repair mechanisms can work before the inflammation sets in will do a lot more than a big break after that cycle has already been going for a while.

Specifically about DOMS, one thing that might be worth trying is lighter movements that are similar to but not exactly the same as what you did the day before. That gets the muscle moving and increases blood flow without hitting them in quite the same way. So something like squatting with in a different style or pressing from a different angle.

That is the essence of protection/deprotection chemistry. The peptide is generally attached to the resin using a functional group is is susceptible to the same cleavage conditions as the side chain protecting groups (HF for Boc peptides, TFA for Fmoc peptides) so that global deprotection and resin cleavage happen simultaneously.

As already noted, it’s a blood-brain barrier issue. The first generation antihistamines are about as ideal as you can get for penetrating the BBB - mostly non-polar molecules with a few amines. The second and subsequent generations took inspiration from first generation metabolites that also contained carboxylic acids. The additional functionality made them especially bad at getting through the BBB while retaining their activity at the target. It’s really a rather neat piece of medicinal chemistry.

Trying to avoid burdening my last comment, there’s also a technique called native chemical ligation that can allow you to make full length proteins semi-synthetically: part of the protein is made in cells, part of it is made synthetically, then the two are stitched together. This relies on peptides called inteins that naturally cleave themselves from pro-peptides. It relies on a cysteine to act as a nucleophile and can splice two sections into a new polypeptide. So under the right conditions if you have one peptide with an intein and another with a terminal cysteine you can get them to link up. There are still some real limitations - it’s easiest when the synthetic part goes at the end so you don’t have to sandwich it with two different reactions. You also need to have a cysteine in the vicinity or be able to make a mutant that tolerates the substitution. And, as others have noted, you still have to be able to get it to fold, which is often not trivial.

That’s called solid phase peptide synthesis. You start with a single amino acid linked to a solid resin through a cleavable linker. The peptide is built up with amino acids that are selectively protected on the amine (and usually any reactive side chain functional groups) and have a free carboxylic acid. The acid is ‘activated’ into a more reactive form and added to the resin where the growing chain has a free amine to react with it. Then the reactants are washed off and the amine protecting group is chemically removed to expose a new amine and the cycle repeats. When the full peptide has been made there is a global deprotection process that also cleaves the peptide from the resin. It usually needs HPLC purification to separate it from peptides that may have missed a coupling or two.

The major power of this method is that you can readily introduce all sorts of unnatural amino acids or even entirely different kinds of chemical functionalities (e.g. esters instead of amides). While there are ways to do that biochemically, there’s much more flexibility with solid phase synthesis.

As others have noted, there are some limitations to the process. The most important is scale - because it’s being built on a resin you’re limited by the number of sites where a peptide can start from, so you’re generally going to get milligrams to tens of milligrams out. Second, there can be complications depending on how favorable it is for the growing peptide to fold in on itself, which can happen even using strong solvents like DMF. That can keep the end of the peptide from efficiently reacting, so you’ll end up with errors.

With all of that said, it’s relatively trivial to make 20-mers with automated synthesis. Once you get out to the 60-mer range it becomes challenging but not impossible. Much longer than that and you’re probably better off with biochemical synthesis, either in cells or a cell-free extract.