ray__

The physical rotation/tumbling of molecules in an MRI is also very important, because the strong magnetic field is the thing inducing the "up"-vs-"down" split in the first place, and if the molecular motion is happening at a certain frequency with respect to the external magnetic field there are other interactions that can come into play which can affect the coherence of the nuclear spins (i.e. they can fall out of sync). Thankfully, the rotation of a small molecule like pyruvate is very fast (might higher then the "spin" frequency-a.k.a the Larmor frequenct of 13C at the magnetic field strengths involved in MRI) so the physical tumbling of pyruvate doesn't really come into play when trying to measure its signal. It can be another story for molecules that don't tumble quickly, like the ones that make up tissues, fat, etc.

Obviously this requires a little bit of tinkering and the end result isn't nicely packaged like a factory Apple product would be, but it only took about half an hour to put together and I haven't had any issues with the driver board yet. And it was way cheaper than a "Retina" display from Apple or LG.

Another consideration is that most protein structure prediction methods only generate the backbone, and the sidechains are modeled in afterwards. Enzyme efficiency requires sub-A level structural precision in the sidechains that are actually doing the chemistry involved in catalysis, so it could also be the case that the current backbone-centric methods aren't good enough to predict these fine-tuned interactions.

  In the long term, a balance is assumed to be established between the amount of injected PLL-FPBA and cleared PLL-FPBA. Thus, the long-term toxicity of the complex formulation needs to be thoroughly evaluated for clinical translation.

Citations 13-40 provide a pretty good overview of the history of glucose-responsive insulins. These ideas are awesome and I hope they can be successful some day, but I also get the impression that engineering improvements (and cost reductions) in insulin pump technology will provide more immediate quality-of-life improvements for the broader Type-1 Diabetic population.

Even the largest successful government coverups (MKULTRA, Iran-Contra, etc.) required far fewer people to be "in the know" than would be required for something like a crashed or observed alien spacecraft. In addition to this, the people who would have to be in the know would not be a community of high-ranking intelligence officers who are dedicated to their mission. It would be janitors, construction workers, commercial radar operators, and the like. There is no way that people like this could be motivated to keep an existential threat like this under wraps.

¹ https://en.wikipedia.org/wiki/Literate_programming

"Leapfrogging ahead of these research institutes with a practical demonstration has been Harold Katcher. Katcher’s method is proprietary."

Wow, a proprietary method that outdoes decades of scientific research? Haven't heard that one before. I understand that there has been little progress in this space, but that's because no one knows what causes aging (or if it can be halted at all). There's no single smoking gun, and there is likely no single easy solution. I also understand that our scientific institutions aren't perfect–and that the big ship of science can sometimes take a while to turn away from a tantalizing hypotheses, like the amyloid hypothesis-but that doesn't mean that you should trust Harold Katcher instead.

Presumably, longer proteins require more splicing, so impaired RNA splicing could account for a deficit of longer proteins as we age.

Why is this "presumably true"? Intuitively, impaired splicing would produce longer proteins, because introns aren't excised as effectively. Even this take is far too simplistic–there are innumerate feedback and control mechanisms involved in mRNA splicing. I'm sure the author has a better grasp on molecular biology than this hot take suggests based on his credentials, but the treatment of this topic by the author is concerning.

As an aside, wow, that preprint spent over three years in review, and the figures and text are way different. A lot of work and stress must have gone into it.

A machine learning approach for predicting toxicity would have a far greater impact on public health than AF2 does.

Consideration 1: Amyloid itself is a structural characterization of protein assemblies. Amyloid structures generally form in intrinsically disordered (ie unfolded under normal conditions) proteins as a low-energy conformation that is self-templating and derives its stability from a large number of interactions between many copies of the same protein. Amyloid is not really related to protein function in a direct way. The biological roles of disease-associated amyloid-prone proteins (some famous ones are Aβ, Tau, and TDP-43) can be quite varied in the non-amyloid state. These proteins are also associated with neurodegenerative disease through orthogonal means, namely through genetic analysis of disease-related mutations, so it isn't just the fact that these protiens wind up in amyloid fibers that leads us to believe that they're associated with neurodegenerative disease. So, we know because of genetic analysis that these proteins are associated with disease, they can all form amyloid, but we aren't losing any consistent biological function due to their dysregulation–this strongly suggests that the amyloid or otherwise dysregualted state of these proteins is problematic on its own.

Consideration 2: Recent structural work has tied different amyloid isoforms to different disease pathologies. I work in an adjacent field to this and these results were really what changed my mind about the validity of the amyloid hypothesis despite years of doubting/discounting it (often in a public way, often to the detriment of my own career–turning the corner on this was a bit challenging). See this paper and the first 5 citations in it (https://www.nature.com/articles/s41586-021-03911-7) for a good example of direct structural links between amyloid structure and disease pathology, and the associated comment (https://www.nature.com/articles/d41586-021-02611-6) for a good overview.

Consideration 3: The presence of amyloid plaques in patients in the real world is generally assessed by histological analysis or other methods that don't capture information at the molecular level. This, combined with the two points above that seem to point to some shared structural features of amyloid-prone proteins being disease causative, suggests to me that studying amyloid (or maybe more specifically the behavior of amyloid-prone proteins) is still a worthwhile endeavor.