--- Log opened Sun Sep 21 00:00:46 2025
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03:33 < fenn> paraoxone is some nerve gas that is degraded by an enzyme named paraoxonase
03:34 < fenn> paraoxonase-1 aka PON1 is found on the surface of small lipid transport particles returning their cholesterol to the liver to be reused. these small particles have a high surface area and are exposed to greater lipid peroxidation per unit lipid than on the forward journey when the particle is larger and full of lipids
03:35 < fenn> "coincidentally" PON1 has lipid peroxide degrading activity via hydrolysis
03:37 < fenn> PON1 is associated with reduced atherosclerosis and heart disease
03:40 < fenn> PON1 is activated by PPAR-γ (and thus all the things that activate PPAR-γ), omega-3 fats, polyphenols such as found in olive oil, capers, wine, green tea, turmeric, chocolate, berries, coffee, pomegranate, etc. as well as isothiocyanates found in radish, mustard, crushed bok choy or kale or broccoli, and sulforaphane in broccoli
03:49 < fenn> wow crazy stuff https://en.wikipedia.org/wiki/Project_Coast
04:03 < fenn> why should polyphenols activate a detoxifying enzyme?
04:04 < fenn> i could understand isothiocyanate (a toxin)
04:04 < MuaddibLLM> [gpt-5] Polyphenols activate PON1 through multiple complementary pathways (PPAR-γ/PKA/cAMP, Nrf2/ARE, AhR, SREBP2) because both serve as cellular antioxidant/anti-inflammatory defenses - it's evolutionarily logical for dietary antioxidants to upregulate endogenous detoxifying enzymes. https://pmc.ncbi.nlm.nih.gov/articles/PMC9311866/
04:08 < fenn> MuaddibLLM: huh? not logical
04:08 < MuaddibLLM> Not because they’re “antioxidants,” but because many polyphenols act as mild electrophiles/ROS-cyclers that trip Keap1-Nrf2 and sometimes PPARγ xenohormetic stress-signaling, which in turn upregulates detox/HDL programs like PON1 - classic hormesis, not charity; quick review: https://pmc.ncbi.nlm.nih.gov/articles/PMC9311866/
04:16 < fenn> doesn't answer the evolutionary or system design "why" question
04:41 < hprmbridge> kanzure> https://x.com/ergoCONSULT_/status/1969623551226400967
04:56 < fenn> "That was probably Thiel-thot Cathy Tie in disguise" does he know
04:58 < L29Ah> who is our Thiel-thot on duty today?
04:58 < hprmbridge> kanzure> you know, it's odd that the race for a new race is so public and that so few people are even trying.
08:44 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=ac4c8dd5 Bryan Bishop: whale SIRT6 transcript >> http://diyhpl.us/diyhpluswiki/transcripts/longevity-comparative-biology-gorbunova/
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10:46 < hprmbridge> kanzure>  https://cdn.discordapp.com/attachments/1064664282450628710/1419379347135135814/GuXz0lXbEAIUbHG.jpg?ex=68d18b87&is=68d03a07&hm=3903b1d59db9d483bcb965a078d49250a7d9155386d0f0c3ab361376ee21cf7a&
10:48 < hprmbridge> alonzoc> A lot of the bio grads I knew at uni instantly jumped to "thats immoral" the moment anything about improving the human condition beyond new drugs was brought up
10:50 < hprmbridge> alonzoc> Mix that along with the fact that many go "how will I benefit personally from improving future generations" and you just get people willing to cross that taboo line and who have some motive beyond the self.
12:14 < kanzure> "Ah, so what I want, the one thing that we can't do is make this oscillatory wave measurement on the cell sorter. I actually feel like there's a lot of really interesting things that could be done if we were able to like hold a cell long enough to make this measurement and then sort it I had a colleague Phil Romero that made droplet microfluidic devices We had this plan actually to kind of ...
12:14 < kanzure> ...like measure it several times as it went down the channel but then he left the university so now I have to find a new guy that knows how to do microfluidics for that. But that would be extremely cool if we could sort based on that property.
12:42 < kanzure> er, who here has ~things about hyaluronic stuff?
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13:08 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=c30738e0 Bryan Bishop: various changes: >> http://diyhpl.us/diyhpluswiki/transcripts/scalingbitcoin/hong-kong/segregated-witness-and-its-impact-on-scalability/
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14:01 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=f8aa78b9 Bryan Bishop: explain why extra peripheral nervous system nerve fibers and roots, add hair color >> http://diyhpl.us/diyhpluswiki/mitochondria/
14:49 < hprmbridge> kanzure>  https://cdn.discordapp.com/attachments/1064664282450628710/1419440475055591589/m_dmw041f01.png?ex=68d1c475&is=68d072f5&hm=0bfd48ceebb0140e2214780392ca9e4de15b8d46b72d58cd014b5216ea8650f8&
14:49 < hprmbridge> kanzure>  https://cdn.discordapp.com/attachments/1064664282450628710/1419440541833101345/m_dmw041f02.png?ex=68d1c485&is=68d07305&hm=f900fc827f783f68f5efc6dbabbc4afa571582b5106f072b4ae02b2324dd3841&
14:55 < kanzure> "Cloning without prior approval: a response to recent disclosures of noncompliance" https://pubmed.ncbi.nlm.nih.gov/10141719/
14:56 < kanzure> not only did they demand they delete the human embryo splitting data, but they also made him resign :(
15:02 < kanzure> from the unethics committee https://www.fertstert.org/article/S0015-0282(04)01038-6/pdf
15:03 < kanzure> if they were all for it, then why didn't they protect the researchers?
15:04 < kanzure> "While some of these applications may be unethical, they could be prohibited without also prohibiting embryo splitting" looool the achille's heel of ethics committees!
15:11 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=650f985a Bryan Bishop: add genetic routes for increased dizygotic twinning, speculate about monozygotic twinning >> http://diyhpl.us/diyhpluswiki/genetic-modifications/
15:32 < kanzure> https://diyhpl.us/wiki/transcripts/genetically-encoded-oscillatory-waves/
16:03 < hprmbridge> kanzure> jrayhawk: https://nutritioninvestigator.org/notes-on-articles/
16:25 < hprmbridge> kanzure> "using both an opsin and calcium sensor, scientists can thus "read" and "write" to neurons at the same time by using two separate lasers." two-photon optogenetics.
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16:54 < hprmbridge> kanzure> "The world uses an estimated 100 million mice in laboratory research experiments each year. "
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17:27 < hprmbridge> kanzure> that spinal nerve fusogen article increases my belief in whole body transplantation.
17:35 < hprmbridge> kanzure> https://www.biorxiv.org/content/10.1101/2025.09.13.674972v1
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18:10 < pasky> damn, Pantheon is very good
18:11 < hprmbridge> kanzure> yes.
18:11 < hprmbridge> kanzure> pantheon is great.
18:13 < pasky> before the last episode i was wondering if it was going NGE or what... but no! it went permutation city(-esque) instead :)
18:13 < hprmbridge> kanzure> two lab mouse anti-pain anti-suffering initiatives:  https://www.invinciblewellbeing.com/mercy-for-lab-mice and https://www.media.mit.edu/projects/reducing-suffering-in-laboratory-animals/overview/
18:14 < hprmbridge> kanzure> pasky, someone of talent must have been involved in making the show.
18:14 < hprmbridge> kanzure> what i am also impressed by is that audiences online seem to really engage with the questions of brain emulation and mind uploading.
18:15 < hprmbridge> kanzure> and they seem to discuss the subject with non-zero coherency which is unusual.
18:17 < hprmbridge> kanzure> another anti-pain group https://farout.bio/ probably all just fronts for david pearce
18:17 < pasky> i think that's because the show really sets it up well! i disliked bits of the technobabble in the early episodes that were semi-coherent enough to be in an uncanny valley, but that's just cosmetics
18:18 < pasky> somehow that must've been mostly outside my bubble, i didn't learn about the show until @sama tweeted about it a month ago
18:22 < hprmbridge> kanzure> ah, i was late to the party because it was geographically unavailable to me at first, and my heart has been broken too many times.
18:37 < hprmbridge> kanzure> "Potent and selective repression of SCN9A by engineered zinc finger repressors for the treatment of neuropathic pain"  https://www.biorxiv.org/content/10.1101/2024.09.06.609976v1.abstract
18:38 < hprmbridge> kanzure> they should just do that.
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23:00 < fenn> what's the problem with twins born several years apart?
23:02 < fenn> all of these objections sound completely insane
23:03 < fenn> what if a twin got on a spaceship traveling at the speed of light for four years before returning to earth? oh no!
23:03 < fenn> the philosophical and psychological implications would be too much!
23:16 < fenn> MuaddibLLM: what happened to the GDF11 youthening hype
23:16 < MuaddibLLM> diving into the GDF11 aging hype graveyard...
23:17 < fenn> wow that was 11 years ago
23:17 < MuaddibLLM> The GDF11 youthening hype largely collapsed due to assay cross-reactivity - the original "breakthrough" studies used antibodies that detected both GDF11 and GDF8 (myostatin), so when they claimed GDF11 levels decline with age, they were actually measuring mostly GDF8 decline. When proper assays were developed, GDF8 (not GDF11) was the age-declining factor. While exogenous GDF11 still shows some beneficial effects in 
23:17 < MuaddibLLM> specific disease models, the original aging reversal claims were fundamentally flawed. https://pmc.ncbi.nlm.nih.gov/articles/PMC10793994/
23:19 < fenn> "GDF11 is similar to GDF8 (also called Myostatin), differing only by 11 amino acids in their mature signaling domains."
23:42 < fenn> alzheimers by education level https://media.market.us/wp-content/uploads/2023/07/prevalence-of-alzheimer-s-disease.png
23:43 < fenn> nevermind. that's a fraction of all alzheimers patients so it just reflects the rarity of getting a doctorate degree
23:44 < fenn> mislabeled graph
23:55 < hprmbridge> kanzure> "Neuralink hopes to put its device in a healthy person (i.e., nonmedical use) by 2030, with the eventual goal of creating consumer technology." you and your 600 employees can't figure out how to put it into a healthy person before 2030? fire them all.
--- Log closed Mon Sep 22 00:00:47 2025