> Bio is one of our sparsest regions 

It does seem like one of the best uses of AI -- digging through existing literature to make novel connections/ideas.

Curious if you've heard of Don Swanson's "Public Knowledge Problem" paper from the 1980's, which was roughly this line of thought?

One of the proposal papers caught my eye:

https://lacuna.tiptreesystems.com/hypothesis/why-receptor-hu...

  > " ... a ligand that binds tightly and stays bound a long time should produce a strong intracellular signal, a weak binder a faint one."

This is called "conformation": the shape it takes in the ligand binding pocket.

So it is not necessarily residence time and overall binding affinity that modulate transcriptional effect.

A very good example of this is the androgen Trestolone/MENT, which is an order of magnitude more potent than Testosterone but displays similar relative binding affinity for the androgen receptor:

https://en.wikipedia.org/wiki/Trestolone

This potency is due to the specific conformational shape it takes within the AR binding pocket.

Comments URL: https://news.ycombinator.com/item?id=50209983

Points: 2

# Comments: 0

My biomarkers were good, but combined with family history and a past history of drug abuse (primarily stimulants), it's sort of a wonder it didn't happen sooner.

The MI itself was unusual. When they placed the stent in my heart, the coronary angiogram was able to image my arteries. I had almost no measurable stenosis in my arteries: a minor 30% in one inferior artery.

I was at the gym when it happened, the prevailing theory is that I had the one artery with vulnerable plaque and it ruptured from arterial pressure.

So on the one hand, it sucks that it happened at all. But on the other hand, I'll take "you didn't die and the rest of your heart looks clear" with no complaints.

Neural Computers provide the illusion you are interacting with an underlying operating system/application, but are actually a recurring (user input) -> (predicted pixel output) loop.

In theory, it would be impossible to tell a perfect "Neural" computer apart from a "real" one. Which is kind of a wild thought.

https://arxiv.org/abs/2604.06425

  > who already have a great estimator for 10-year heart disease mortality risk in the coronary calcium score

CAC scores only show calcified plaque, not vulnerable plaque, which is the sort likely to rupture and cause an event.

You can go get a scan and receive a CAC score of 0, walk away thinking you're perfectly healthy, and then die tomorrow because the scan couldn't detect the massive amounts of non-calcified plaque lining your arteries.

The only non-invasive way to measure vulnerable/soft plaque is via CCTA

See, for example, "Atherosclerotic Plaque in Patients with Zero Calcium Score at Coronary Computed Tomography Angiography"

It measured nearly 1 in 10 patients with a 0 CAC score as having vulnerable plaque:

https://pmc.ncbi.nlm.nih.gov/articles/PMC5967134/

  > "The frequency of atherosclerotic plaque in the coronary arteries in 367 patients with zero CS was 9.3% (34 individuals)"

https://developers.openai.com/api/docs?lang=curl

    openai responses create \
      --model gpt-6-astra \
      --input "Write a short bedtime story about a unicorn." \
      --raw-output \
      --transform 'output.#(type=="message").content.0.text'

    curl https://api.openai.com/v1/responses \
      -H "Content-Type: application/json" \
      -H "Authorization: Bearer $OPENAI_API_KEY" \
      -d '{
        "model": "gpt-6-astra",
        "input": "Write a short bedtime story about a unicorn."
      }'

Comments URL: https://news.ycombinator.com/item?id=50185519

Points: 1

# Comments: 0

  > Having kicked opiates cold turkey in the past, I felt nostalgic for three simple days of traditional nausea, sweatiness, and bone-deep ache.

There is no way to explain the hell on earth that is benzo/GABA-ergic drug withdrawal, and I would not wish it on my worst enemy. It is an order of magnitude more intense than opiate withdrawals, and the timeline is weeks/months rather than days.

Like the author, I managed to quit via a year-long Ashton protocol taper.

The irony is that benzos were the one class of drugs I wasn't abusing for recreation. I was using mega-doses of Etizolam to cope with PTSD flashbacks, and only discovered I had become physically addicted after flushing it all and winding up in the ER.

I would counter that education, at least in the USA, does not adequately prepare one for life, the real world, and effectively finding employment.

What ACTUALLY mattered in my life turned out to be:

1. Who you know, and by proxy, what kind of a person you are

2. The value of "just showing up", every day

3. How important personal relationships/networking are, and just how SMALL the world is for how vast its size

Knowledge and skills are things you can sort of just pick up as you go along, but being given any kind of opportunity in the first place is not quite so easy.

Makes a great option for mobile on-device or browser app TTS.

It's small enough to be run on modern phones realtime, I use it for listening to PDF's/EPUB as Audiobooks

https://huggingface.co/hexgrad/Kokoro-82M

  > because the wilderness is behind 3 confirmation screens

Today's youth will never re-live the experience of having someone tell you to "follow them to hidden area" and then one-hitting you with a rune weapon the second you crossed into wildy + taking all your shit.

The agent pathing seemed to clip a bit through the sides of mountains at times though -- or maybe that is just a bug of GM camera following player?

https://i.imgur.com/CNAUczi.png

The further away I got from the implementation details, the fuzzier the semantics became. To the point that now I could not in good faith say I understand the system I have built from the ground-up and worked on the last ~4-5 years.

The solution to this, in my mind, is not to revert back to reviewing implementation details. The economics of that from a business/productivity perspective don't play out well.

The only viable solution in my mind is adapting code/languages themselves to the shift by making programs formally verifiable. That way you can be sure that the code "does what it says on the tin", and provably so.

I feel so strongly about this I've written on it:

https://gavinray97.github.io/blog/design-by-contract-and-eff...

  > Self-improving code would be code that runs itself and improves itself.

  > "... for the harnesses we have seen in these campaigns, average success rate is hovering around 10%"