mobilejdral

I spent the entire time reading it pondering the same thing.

1. The article presents that calling out to a tool like python is "expensive" because of the overhead of forking a process, loading up the python env etc, but why not just eliminate that overhead and embed WebAssembly so this "tool call" is near zero? This feels very similar to the discussion in the 90's around the overhead of threads v.s. processes or kernel space v.s. user space. Could even go further and have a running beam vm so the LLM can write elixir which is ideal for LLM's that stream out code? Elixir programs will be a lot shorter than webassembly.

2. The core argument stated is "A system that cannot compute cannot truly internalize what computation is." The idea being that it could write a program, execute it and by seeing all of the steps maybe even part way through stop and change its mind or when writing new programs write them better, aka be able to debug on the fly?

3. Not mentioned, but there is a 3rd x factor that LLM's will use this new found computation engine to do overall better at "thinking". Computing in very unexpected ways and to unexpected problems. Maybe it would do dramatically better at some benchmark because of this?

Unfortunately these are not explored and it is just an execution engine even resulting in the conclusion stating "arbitrary programs can be compiled directly into the transformer weights, bypassing the need to represent them as token sequences at all." which goes to point number 1 of if we are compiling to weights why not just optimize the tool calling?

Having worked on software that runs manufacturing plants your comment echos the idea that too many engineers have that they are "better" than manufacturing and lessons don't apply to them.

Go back to your desk and work on a PR that is going to go through a 20 step process that is constantly changing before a hopefully semi-regular release goes out to customers and tell me how you ignoring all of knowledge on how to do this well is good for your career.

For a long time I assumed folks like you were simply uneducated, but know I see it for what it is, elitism.

Depends on the microplastics, but many act as endocrine disruptors that "mimic" estrogen, tricking the body into over-activating ERa and upregulates the PEMT gene and the higher acetylcholine. It could also be that the microplastics can physically bind to or chemically inhibit acetylcholinesterase and that is the reason for the higher acetylcholine. Depending on the cause this is only a short term good thing, but could be downregulating genes.

The non-DHA omega-3 EPA are good at preventing perivascular fibrosis and thus a better glymphatic system for the removal of beta-amyloid proteins. EPA also helps produce melatonin which kick off sleep and this whole process.

Natto-serrazime is probably an excellent complement as it is on the other side and is a dissolver. (Noteworthy: Pterostilbene + Glucosamine similar to EPA reduces fibrosis)

The interesting connection is how this is needed when we are older, but not younger. When younger ERa activates more which does this all on its own. This is the connection to why 2/3 of alzheimer's are post-menopausal women and why HRT is important.

Edit: and to tie this to APOE as it is the gene most associated with Alzheimer's. e4/e4 requires more choline so someone with e4/e4 is more likely to be choline deficient. EPA/DHA usually attach to Phosphatidylcholine (PC) when in the blood/brain. PEMT is a gene controlled by ERa to make choline, but from the above less ERa activation and we make less PEMT so less choline and less PC. Choline is the precursor to Acetylcholine (primary neurotransmitter for memory and focus and essential for REM sleep). This is why Choline is known to help with Alzheimer's.

It depends on the person and their genetics. The further you get from the ERa the more complicated this gets and simply stating "Do X" wouldn't apply to everyone even if there are some incredibly common things to do. I might know all the upstream genes, their interactions, and symptoms by heart so it is pretty easy to identify, but general advice would go something like: eat well, get sleep and exercise.

ERa activation promotes PGE2 resulting in decreased 15-PGDH.

So this is one of those standard poor estrogen signaling downstream things and simply improving the estrogen signaling and you get improved cartilage. Anyone can do this today along with getting all of the other positive effects. Those with EDS who have say variants on their TNXA/B have poor production ability to start and so we do everything we can to improve their cartilage production as they can only make so much which include doing stuff like this.

I am not saying that if there was a pill on the market today that would increase plaque-clearing there wouldn't still be dementia, simply that they would probably then die from pneumonia.

One needs to also dive into neurogenesis. Elevated HPA Axis activation which brought us the oxy-androgens also gives use higher cortisol and lower α-MSH which promote neurogenesis. This elevated cortisol is one of the classic hallmarks of Alzheimer's. Estrogen signaling is also an important part of neurodevelopment. So someone with Alzheimer's usually has low α-MSH and low estrogen signaling and overall reduced neurodevelopment. Need to fix these to prevent dementia.

The various stuff that has been found to reduces dementia also improve estrogen signaling. Estrogens are an incredibly old hormone used in regulating a ton of basic cell function. Keep ERa functioning well and you get not only better amyloid plaque clearance, but healthier DNA repair, immune system, etc and better neurogenesis. A lot of stuff that improves longevity ultimately just keeps this going.

There is a Alzheimer's Choline camp which is where we know that Choline supplements is associated with improved Alzheimer's. With low estrogen signaling you have lower N-methyltransferase so less Choline in the body as it is how the body makes it. Less Choline, less SAM via BHMT, less SAM, less clearance of 2-OHE1, less ERa activation, and ... less choline in a loop. Supplement with Choline and it helps not only with the APOE e4 which consumes more Choline, but undoes this is what this theory is about.

As we are having fun with this, decrease the BHMT from less Choline and it shifts from BHMT-mediated methionine synthesis to MTR-mediated pathways, consuming 5-MTHF resulting in slower THF regeneration. Slower THF regeneration impairs the folate cycle, increasing reliance on serine as a one-carbon donor. Elevated serine flux upregulates PHGDH, which promotes IKKα-HMGB1 signaling which drives amyloid pathology and neuron death! Which brings us to probably my favorite paper from this year. "Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease" https://www.cell.com/cell/fulltext/S0092-8674(25)00397-6

I myself don't put myself in the Choline camp, but more see Alzheimer's simply as one failure mode on the metabolic estrogen axis of which is induce in certain genetic or diet configurations. In this mode it results in a number of cascading failures until death. Some genetics/diet are fairly easy to halt/undo the spiral of death which is seen in how there are some things that are known to improve Alzheimer's in some, but not all patients. I can induce Alzheimer's via the gut, diet, inflammation, adrenals, sleep, a whole host of ways, anything that starts the cascade.

An example of an unlucky genetic case is when someone has 3 CYP21A2 rather than 2, they end up with hypercortisolism and nearly always they will get Alzheimer's if there is no intervention. This is a rare genetic case, but simply a way to break the axis elsewhere with the same effect.

For this particular situation on D3 I personally (who is not your doctor) would go with vitamin D3-loaded nanoemulsion. The reason is that Vit D influences how tryptophan is converted down the 5-HTP and serotonin path or the Kynurenine path. We want higher serotonin AND specifically in the brain. The higher serotonin means better melatonin which not only increase sleep, but increase the ERα expression which we are trying to increase... in the brain.

There is a recent study on this showing how this form can provide better results in the brain. https://www.sciencedirect.com/science/article/pii/S305047402...

In general: Omega-3, bcomplex with choline etc all have studies. Really it depends on the individual and what their genetic weakest issue is. Its old and boring, but eat healthy, don't eat before bed, exercise (dance!), and get good sleep always apply.

The title is a bit link-bait. It should really be "Disrupting circadian rhythms of plaque-clearing brain cells is associated with Alzheimer's"

He found that too much of YKL-40, which is linked to Alzheimer’s risk in humans, leads to amyloid build-up, an accumulation that is a hallmark of the neurodegenerative disease.

There are countless studies that highlight how genetics or lifestyle and other factors that result in a reduction of estrogen signaling are associated with Alzheimer's. Estrogen, primarily activated at night decreases the expression of the YKL-40 gene. All of the known interventions, from vitamin D, Mg, to gut, choline, etc all can improve estrogen signaling, decreasing YKL-40 gene. One can end up with Alzheimer's from many different routes so interventions depend on the person.

If there was a pill on the market today that would only increase the plaque-clearing all this really does is move the needle, they still have reduced estrogen signaling and the next weakest part of the system would fail such as from animpaired immune system and they will probably die of pneumonia.

But we could back up and say what is the most common cause of the global reduced estrogen signaling? Often increased oxy-androgens (which increase as we age), so for example 11-ketotestosterone (11-KT) which can't convert to its estrogen form results in upregulates HSD17B2. Why do we have so much inflammation causing increased oxy-androgens from the adrenals? Senescence cells releasing inflammatory factors SASP. More time more time spent on repair resulting in identity loss and mesenchymal drift. All a fancy way of saying we get older and will probably die from whatever weakest part of the system we have genetically. Fix one thing and something else breaks instead.

And for those that want to bring in the most well known genetic mutation APOE e4: APOE e4/e4 has elevated choline demands hindering estrogen signaling as well as raising HDL and lowering LDL. Low estrogen influences Cholesteryl Ester Transfer Protein, raising HDL and lowers LDL beyond what e4/e4 does by itself. With less choline and less phosphatidylcholine, it decreases GLUT1 transporters reducing glucose entering the brain. All of the above leads to an escalating amyloid plaque burden. Then reduced deep sleep and the glymphatic system cleaning is reduced too and you have Alzheimer's.

The above was just from memory probably had an error, but the point is Alzheimer's is not "simple" like this article pretends.

Neanderthals had the FOXP2 gene, which is associated with speech and language.

And then this ties to estrogen, HRT is known to reduce the risk of dementia/AD (https://pmc.ncbi.nlm.nih.gov/articles/PMC10480684/).

PEMT (phosphatidylethanolamine N-methyltransferase) is what makes choline in the body, but it depends on estrogen.(https://pmc.ncbi.nlm.nih.gov/articles/PMC3020773/)

Tying this to APOE, specifically e4 which has an increased requirement for choline and when choline levels are low there can be a metabolic push that leads to elevated PHGDH activity and consequently, increased serine synthesis. That is a neat connection and maybe why when we study choline supplements we see positive results.

https://www.sciencedirect.com/science/article/pii/S000291652...

Think questions where there is a ton of existing medical research, but no clear answer yet. There are a dozen alzheimer's questions you could for example ask which would require it to pull in a half dozen contradictory sources into a plausible hypothesis. If you have studied alzheimer's extensively it is trivial to evaluate the responses. One question around alzheimer's is one of my goto questions. I am testing its ability to reason.

I have a several complex genetic problems that I give to LLMs to see how well they do. They have to reason though it to solve it. Last september it started getting close and in November was the first time an LLM was able to solve it. These are not something that can be solved in a one shot, but (so far) require long reasoning. Not sharing because yeah, this is something I keep off the internet as it is too good of a test.

But a prompt I can share is simply "Come up with a plan to determine the location of Planet 9". I have received some excellent answers from that.

Sure, add a way to contact you to your account and I can send you over the current understanding.

The author also asks "If you were stranded on an island (or small hostile planetoid), what books would you want to have with you?" which I also can't answer.

I would fall into the category of someone who does research as leisure. I have been slowly unraveling the genetics behind gender dysphoria. Yes I have borrowed a few biology books from libraries, but it has mostly been reading 70 years of research papers, piecing together all the evidence to make a hypothesis, comparing it to all the research data and iterating. In the last year I have also started getting a fair number of WGS (Whole Genome Sequenced) files, and I have a whole separate pile of anecdotal that just because it isn't published doesn't mean I can ignore it either. These are about as far from books as you can get. It is something I do for leisure, so my investigation has been somewhat random, following whatever I found interating at that time including dead ends. Been doing this very open ended research for years now and at this point we have a really solid understanding of it, so the edge cases are actually now the fun stuff. I never would have made anywhere near the progress I did if I had been forced to start with reading a bunch of random unrelated biology books.

3 of the 4 dna samples show signs of nonclassic CAH. This limited their reproduction abilities as 50% of babies would have CAH and die at birth until they integrated with proto-humans and had higher genetic diversity.

If you mean ring type I don't remember which one worked best, sorry.

As for my favorite EM field there is a nearby street with buried powers lines and transformer boxes at ground level. As you walk the street to the main street each box has a bigger EM sphere and I like to let my hand coast over each sphere. It isn't a sphere per say, but only in the sense that at at certain depth in the field the density (for lack of a better term) becomes high enough that I can feel it and it is like a boundary line

I have had one of these for years and the right size makes all the difference. Some fun things include the ability to feel where the metal studs are in building walls, where the electrical lines are under the ground and of course the microwave. The most interesting part is how I conceptually had thought of electrical fields as 2d (because of pictures and school), but in reality they are 3d and so it is like reaching into a sphere of various sizes, the deeper you go in this sphere the stronger the field.

Because there was general layoffs of the workers in the previous year or two? There is a fairly formulaic way that companies tighten belts. First you do layoffs, get rid of projects that will never make money, reduce headcount for orgs that grew fat, etc. At the same time you explore offshoring (especially as it keeps the same number of headcount under a vp for less cost). Then there is a round of cleaning up the management layer, making sure everyone has a minimum number of reports, moving some managers back to being leads/IC etc.

This was all formulaic and the more experienced directors and VP's back in 2022 knew this and immediately started playing the new corporate game to win in the long run.

Naltrexone in high doses takes away all pleasure by blocking opioid receptors (low doses do too, but it is different when only a few hours). So there is no reward for drinking or eating if that is why you are eating. If this is not why you eat it will be less effective.

Bupropion acts as a norepinephrine–dopamine reuptake inhibitor. Importantly it doesn't directly raise your serotonin. If you are a night owl, have trouble falling asleep etc you might have low serotonin to start and this could be bad for you.

Both of these are associated with suicidal thoughts. There is a reason HIMS requires your health info before suggesting drugs. I would flag the parent as providing dangerous information.

Actual paper: https://pubmed.ncbi.nlm.nih.gov/39235810/

Conclusions and relevance: In this cohort study, a history of upper gastrointestinal MD was associated with elevated risk of developing a clinical PD diagnosis. Increased vigilance among patients with MD for future PD risk may be warranted.

Associated is the key word. The washington post sensationalizes it to "may begin in the gut"

That is so wild to me. I only consume media there if I am sent a link. Every time I have gone there I find content that is literally optimized to use up and waste as much of my time as possible under the incentive of maximizing viewer minutes. I wonder what it would be like to spend a day in your shoes.

Some feedback: In the readme file at the top you want to describe the problems that Grace solves. This is what I read and parsed:

cloud-native version control system.

Not a problem I thought I needed to solve, but okay. Also this means I can't easily run it locally?

easy to use, easy to understand

I already understand git, so does everyone on my team, and everyone that interviews...

And it's powerful, ready to handle large repositories and large file sizes.

Is large files the main problem this solves?

Grace Server scales up by running on Kubernetes and massive PaaS services from large cloud providers.

Even when I was running Git servers for large companies this wasn't a problem I had ...

Grace Client runs in the background, making it ambient, faster, and more valuable to your everyday work as a developer.

How is that more valuable?

Grace connects you with others working in your repository, across the globe,

So like every revision control system?

in real-time

So it behaves like Google Docs? And maybe requires an internet connection?

, enabling new experiences and new ways of sharing.

Maybe this is for pair programming?

So I want to use grace if I want to pair program on large files?

Its what nature intends

A better question is if it is a fitness advantage to die. And it is. If you have two species and the first dies when something happens and the second doesn't the first will "win". The first species will have its old die out and so the young will be able to evolve faster without having to compete with everyone else that is alive, only the current generation.

We have this "kill switch" in our brains already. It is the PVN. Very much oversimplifying, but as bad things build up "inflammation", it kicks of production of cortisol to deal with it. The cortisol reduces neurogenesis and little by little our brain dies. The PVN also controls LH levels so sex hormones so rising cortisol downregulate CRH and the PVN. Puberty and menopause are just the speed changing of GnRH to match. Pain, wounds, immune system reaction, they all go through this. Imagine, at one time there was a species that wouldn't die of natural causes when it was in constant pain.

Vertebrates have the PVN, invertebrates don't. Vertebrates (nearly always) die, invertebrates generally don't.

There is a reason why all the stuff to increase life span is (generally) about healing or reducing inflammation.

I am skipping over a lot of details, but you get the point. Dieing is an evolutionary advantage, not to you, but to the species.

Can I ask you your thoughts about CYP21A2?

Been studying folks with only one working CYP21A2 due to the resulting atypical adrenal function and I noticed that their dna also contains all the genetic variants associated with Alzheimer's (some are beneficial in this case). Inquiring about the family tree of the single CYP21A2 I have yet to have someone tell me of an ancestor that died of Alzheimer's. But the family members with two good CYP21A2 (and all of the other typical Alzheimer's genetics) are the ones that end up with Alzheimer's. And for good measure, when someone has 3 CYP21A2 nearly always they will get Alzheimer's. (they also end up with Hypercortisolism).

Subclinical Hypercortisolism has a long association with Alzheimer's. A deficient CYP21A2 and the decreased incidences of Alzheimer's is not talked about other than the fact that it isn't associated with Subclinical Hypercortisolism, but Subclinical Hypocortisolism instead.

All of the known indirect early preventative measures for Alzheimer's result in shifting from Subclinical Hypercortisolism towards Subclinical Hypocortisolism.

This was not my intended area of study, but the pattern is interesting and curious for your thoughts.

Only hiring cis white men from your local network or only recruiting from the college that only allows men is by definition sexist and racist.

The point of DEI is to first try to teach and then to punish managers that are stupid and say that they have a meritocracy when they absolutely don't.

women's salaries are on average 95-99% of men's[0] - a negligible difference.

So I am guessing you would be okay if I only paid the men in my org 95-99% of what I pay women? Enforcing that they are paid the same is just giving preference to men. Didn't think so.

I have a special place in my heart for the men that whine about the one woman in their org that didn't work out, ignoring the countless men that don't work out. The idiot men that get through the interview screening are somehow okay, but heaven forbid we hire a single woman that couldn't cut it. When I ask for more details these guys eventually admit that they just hate the idea that finding a job could be slightly harder or it is plain old misogyny with the belief that all men are better than all women. This doubly applies to men who seem to not be doing amazing at their job. Not only are the other men better than them, but they get really mad when a woman does better too.

I just want to do a good job, but I have had to deal with this stuff my entire career.

There is the long standing joke around the Geeks and Jocks. The don't usually have sex with each other. Genetically they have even diverged with genetic attributes that you typically find in one and not the other. They are even more successful at having grandchildren if they mate their "own type" due to to certain genetic combinations that both parents will give to the kids. Are they two species?

It took me way to long to find the ingredient list for the Athletic Greens starting from the main page. Even on the actual page itself you have to click a button to see it. https://drinkag1.com/about-ag1/ingredients/ctr

It appeared that it was hidden on purpose and I was expecting the worst, but after seeing it I would have to disagree with your comment about it being useless. From the list I would compare it to many daily vitamins. Many are deficient in these basic vitamins (why is a separate discussion).

It isn't useless, but maybe it is simply overpriced for what it is? Most notably seems to be missing vitamin D.

In the near future you could take your dna file and upload it to a website and it would tell you what supplement is best for you, but for now as in the past there will be generic multi-vitamins that try to fit everyone. And like in the past some will lean heavily on the marketing side.

Yup, here is the first paper from a google search on that topic https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071442/ There are a number of ways to hack the hpa-axis, vitamin D being an cheap and easy one.

Worth noting that there are plenty of reasons why the hpa-axis might shift one way or another, lack of vitamin D is simply one of many. Chronic pain would be another (which low dose naltrexone often works well for).