--- Log opened Mon Oct 02 00:00:39 2023
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06:51 < muurkha> fenn: it's been a while, but I don't recall knowing about zeolite-based CO₂ scrubbers.  What would you recommend reading on the subject?
06:52 < muurkha> They did already exist, but soda-lime and *ethanolamine rebreathers still seem to be enormously more common
10:31 < hprmbridge> kanzure> "Phage-assisted evolution and protein engineering yield compact, efficient prime editors" https://www.sciencedirect.com/science/article/pii/S0092867423008541
10:31 < hprmbridge> kanzure> https://twitter.com/davidrliu/status/1697269310522065396
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12:45 < kanzure> plover has moved to https://www.openstenoproject.org/
14:01 < hprmbridge> kanzure> streamingLLM https://news.ycombinator.com/item?id=37740932
15:30 < sphertext_> you guys know that narrative trope where someone wakes up hungover and slowly starts piecing together wtf happened the night before? that is me right now, except i wasn't drunk or cognitively impaired; i had a terrifyingly productive day 
15:30 < sphertext_>  ike8 ^ 
15:33 < sphertext_> i cleaned my flat, i read some new maths for my book, started using a new diagramming tool and made a solid outline, did 90min of resistance training, ran errands 
15:34 < sphertext_> that's most of what i remember at least 
15:34 < kanzure> could you do more?
15:35 < fenn> sphertext_: corticosteroids?
15:35 < sphertext_> kanzure imma try. woke up a bit tired tbh, but fixing it with nutrients and a slow start 
15:36 < sphertext_> fenn no, i think the main effect comes from a synergy between selegiline and phenyl 
15:37 < fenn> oh, the pile everything on at once approach
15:39 < sphertext_> i didn't get much side effects from the steroid tbh. it just mainly obliterated my libido and gave me slight insomnia. that kinda tummy butterfly feeling similar to when you are in love. but apart from that it isn't doing much 
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15:40 < sphertext_> fenn i microdose selegiline btw. not using it at the normal dose where it completely inhibits MAOb. it's a 10/10 nootropic 
15:41 < sphertext_> but yeah, in combination with phenyl yesterday it was solid 
15:43 < L29Ah> i ate seligiline for a few months, didn't notice much effect
15:47 < sphertext_> oh yesterday i also used a dose of aGPC about half way through, because i was getting symptoms of insufficient choline (for me that feels like running out of "fuel", the intention is there, but it's not coming together yet; staring blank at the walls). 
15:49 < sphertext_> L29Ah interesting. i've generally been on top of my shit ever since i started taking it daily 6 weeks ago 
15:51 < sphertext_> selegiline feels like driving a car without breaks. every impulse of motivation just goes on. and on. and on. and on. 
15:52 < sphertext_> motivation maybe isn't really the right word. maybe like drive. or oompf 
15:52 < L29Ah> i took 5mg every morning
15:53 < L29Ah> maybe there was some minor stimulation (<50mg caffeine, <10mg amphetamine-level) but i don't remember it
15:53 < sphertext_> it makes cognitive impulses more expansive than they normally would be. so basically if you were driving a car, but you don't use the break anymore. so even if you lift your foot off the pedal, it keeps going for a while :D
15:53 < ike8> how did you get Selegiline? it's scheduled in most countries
15:54 < L29Ah> ike8: from some random internet shop
15:54 < L29Ah> it was from some indian brand
15:54 < ike8> no trouble at customs?
15:55 < L29Ah> dunno, i'm not the one who imported it
15:55 < L29Ah> i've checked the laws before that and figured that by .ru laws it would be a meth analogue 
15:55 < L29Ah> so decided to use a local reseller instead of ordering it myself from abroad
15:56 < L29Ah> curiously it is also registered in .ru as a legit drug
15:56 < sphertext_> L29Ah i take 1mg/day. this is the protocol recommended by Knoll for longevity. he invented selegiline, so he is biased, BUT he lived well into his 90s and was very lucid (n=1). however, there is no actual evidence for the 1mg/day protocol. he pulled it out of his ass. it was just his way of saying "microdose selegiline it's probably good for you"
15:57 < L29Ah> sphertext_: after reading more into research on selegiline's purported longevity benefits i decided not to pursue it further: it's unlikely to be effective at preventing neurodegenerative disease, i don't remember the details sadly
15:58 < L29Ah> generally something about MAO-B producing toxic byproducts
15:58 < sphertext_> ike8 i got it from an indian online pharmacy with good reputation. would you like the link? 
15:59 < ike8> absolutely
15:59 < sphertext_> and nah, customs were chill. they don't care about importing RX, as long as it's a personal amount 
16:00 < sphertext_> ike8 https://www.buy-pharma.md/Selegiline-p-253.html
16:00 < sphertext_> it's 5mg pills, so i break them into quarters 
16:01 < kanzure> you should try to do 30-50 things per day
16:01 < L29Ah> ah yes i ate a quarter every morning!
16:01 < ike8> nice, ty
16:01 < sphertext_> ah then you did the 1mg/day protocol L29Ah 
16:02 < sphertext_> ike8  note that sublingual bioavailbility is 7-10x. it's up to you what you want to do. at 10mg/day (or 1mg/day sublingual equivalent), it is a complete and irreversible inhibitor of MAOb. this is the normal therapeutic dose for neurological disorders. 
16:05 < sphertext_> however selegiline has broad effects that are independent of MAO inhibition. here is an interesting take: https://old.reddit.com/r/Nootropics/comments/158f63m/how_would_you_describe_the_effects_of_selegiline/jt9y9l0/ . and see this paper as well which corroborates: https://pubmed.ncbi.nlm.nih.gov/11813232/
16:08 < sphertext_> kanzure i'm pretty sure just my cell division exceeds that target. and it's mostly passive too 
16:08 < kanzure> hm? i mean 30-50 things on your todo list.
16:08 < L29Ah> [08.09.2020 16:26:00] L29Ah: i remember some words about relations with TAAR/phenylethylamine (but it's likely to occur through MAO-B inhibition), and also the prime developer of the theory seems to have died, and the developments aren't going much forward after that
16:10 < sphertext_> i think it was probably knoll you referred you 
16:12 < sphertext_> the "toxic byproducts of MAOb" theory was the leading hypothesis yes. but see the paper i linked above with tentative evidence that some of selegiline's benefits are in fact independent of MAOb inhibition 
16:14 < sphertext_> unfortunately it's true that after knoll died, experiments slowed down. patent for the drug expired, so yeah, as usual, our respectable researchers dedicated to scientific progress inexplicably lost interest.
16:15 < sphertext_> i think the salient thing is that it's safe, has modest evidence of broad health benefits and, for me at least, it has the tangible nootropic effect on drive, that i mentioned before 
16:18 < ike8> might add it to my black-friday list
16:21 < sphertext_> selegiline was the first serious dopaminergic i used. sulbutiamine was the closest i came to modulating dopamine before. i always got good results from cholinergic (racetams), so i just sticked to that. 
16:21 < sphertext_> ike8 you responded well to dopaminergics in the past, right? it was bromantane? 
16:24 < ike8> ooooh yes. Pretty much every dopamine re-uptake inhibitor I tried has worked wonders for me; except Sabroxy (Oroxylin-A).
16:35 < sphertext_> ike8 im watching that interview with sinclair.. it's so cringe. i already didn't like him, but this is exceedingly bad. his scientific papers are decent, but watching him in his spare time being so desperate for clout and ordinary in his speech, makes me really question his contribution, compared to the other authors. "my book selling a million copies is one thing; but publishing something in the world's leading scientific journals is
16:35 < sphertext_>  another". what kind of professional scientist says that with a straight face? he sounds like a news reporter. and then he started peddling his pill and lost his train of thought when he tried to give a technical answer: "what is it called.. like.. CRISPR.. molecular biology.. yeah"
16:36 < sphertext_> anyway, here is the situation - 
16:37 < ike8> yeah, the interview was not great
16:41 < sphertext_> sinclair used to be all in on NAD and sirtuins, because he started a company trying to manufacture a patented form of NMN. he kept peddling NMN over NR, because NR was owned by chromadex; even tho research on NMN was (and remains) far more scarce than NR and we also know for sure that their effects are not even 100% comparable. so this already showed a certain lack of integrity on his part, endorsing disproportionately something with
16:41 < sphertext_>  inferior evidence  
16:42 < sphertext_> then his lab suddenly pivoted to partial epigenetic reprogramming, with a paper published in december 2020 
16:42 < sphertext_> just out of the blue lmao 
16:43 < sphertext_> it was a good paper tho 
16:44 < sphertext_> in partial epi reprogramming, the idea is that you give cells a subset of the original yamanaka factors, to gently prod it back towards a more pluripotent state 
16:47 < L29Ah> everyone has a good opinion on dopaminergics until they build up tolerance ;)
16:48 < L29Ah> i guess i wasn't very excited by selegiline because of my extensive experience with substituted phenylethylamines
16:50 < sphertext_> the idea is that at some point during this process of de-differentiation -> pluripotency -> re-differentiation, there is some reset/rejuvenation being triggered (that clears up accumulated damage in the cell, for example)
16:50 < sphertext_> but when you over-do it and the cells start to actually lose their identity, then you end up with teratomas 
16:51 < sphertext_> so the challenge is to just gently prod them towards this process, so that the rejuvenation is triggered, but then stop before the more complex stages of cell identity change 
16:52 < sphertext_> the first experiments in reprogramming administered the factors indiscriminately, and the mice all got teratomas, so it was declared a failure.
16:53 < sphertext_> but then another group discovered that if you just administered the factors in small, short bursts, then you could trigger rejuvenation, without the teratomas 
16:53 < sphertext_> note that none of this was sinclair's work. this was already being done back in 2016 
16:54 < sphertext_> what sinclair did in 2020 was just to use the same idea of _partial_ epigenetic reprogramming and apply it to damaged nerve cells in the eye 
16:57 < sphertext_> now the problem with partial epi reprogramming is that we have no idea how to effectively determine the correct intensity, so that it triggers enough rejuvenation, but without identity loss and subsequent risk of teratomas 
16:57 < sphertext_> the threshold could be on a cell-by-cell basis, it could be tissue-by-tissue, etc. 
16:58 < sphertext_> and we also have no effective way of administering the factors in a targeted way, for example to a specific tissue in the body. so if different tissues turn out to have different threshold (which is highly likely), and you administer the factors systemically, then you have no control
17:02 < fenn> you defined "partial" in two different ways, first as a subset of yamanaka factors, then as a short burst (of the complete set presumably)
17:02 < sphertext_> so without a mechanism to control and limit the intensity + a way to target the intervention, there is no way to use this in humans, because the cancer risks are too high. these are both very complicated problems to solve, so partial epi reprogramming is nowhere near to being available in the clinic. and this is very different from the impression sinclair is trying to give in that interview. 
17:06 < sphertext_> fenn no sorry, partial reprogramming means to prod the cell towards the very early stages of induced pluripotency, stopping before it actually starts to reverse its identity, because that's presumably when you get the risk of teratomas. the fact that the factors are a subset of the original yamanaka ones is just somethign i mentioned incidentally for historical context  
17:07 < sphertext_> originally it was assumed you needed all of the yamanaka transcription factors to induce pluripotency, but later it was discovered that fewer factors can also be sufficient. 
17:08 < sphertext_> you can use the OSK subset to induce total, or partial reprogramming 
17:08 < sphertext_> the difference is in how long you administer the transcription factors for
17:09 < sphertext_> if you spam the cell, it will de-differentiate and go back to an earlier pluripotent phenotype 
17:09 < fenn> the spam phenotype
17:10 < sphertext_>  if you just do a short burst, it will do start doing some preliminary clean up, but remain what it is 
17:10 < fenn> maybe there is some gene that is needed to go further down that route, and it can be temporarily or permanently blocked
17:12 < sphertext_> yeah, or maybe some kind of signal or marker, that can be used to know when to stop. but achieving this kinda of logic at the molecular level... very hard problem. the fact that sinclair claims he has a "pill for it" makes him sound like an idiot 
17:13 < fenn> i mean it's not possible, but that's several tech generations away, and we aren't even at generation 1
17:13 < sphertext_> a pill is systemic, it is completely indiscriminate. and its halflife is determined entirely by metabolism. it is comically nowhere near the time-sensitive precision required for this 
17:13 < fenn> not impossible*
17:14 < sphertext_> yeah, for sure. im just saying this in the context of sinclair talking about his new pill 
17:14 < fenn> what's in the pill? what does it do?
17:14 < sphertext_> it's a very interesting problem to solve 
17:14 < sphertext_> he can't say :D 
17:14 < fenn> does he have any bridges for sale
17:15 < sphertext_> his answer was "what is it called.. gene.. like CRISPR.. molecular biology.. yeah" 
17:15 < sphertext_> "but i can't tell you more without an NDA" 
17:15 < sphertext_> wdym bridge
17:15 < fenn> like the brooklyn bridge in new york city
17:15 < fenn> if you didn't get it, nevermind
17:16 < fenn> "the usual confidence trick"
17:16 < fenn> can you hire an actor to pretend to be you and go around acting confident about your ideas
17:17 < fenn> i mean, who would know it's really you or not
17:17 < fenn> "i got a haircut"
17:17 < kanzure> "maybe you're just bad at recognizing faces. how offensive!"
17:17 < fenn> "i've been exercising more lately"
17:27 < sphertext_> also another thing that annoys me in that interview is that he's drawing some completely irrelevant parallel between autophagy and partial reprogramming.. like wtf lol. literally 0 connection. he says that partial reprogramming is a universally conserved biological mechanism on earth that life triggers in response to stress, adversity and nutrient restriction, but it's literally an artificial intervention, unrelated to autophagy and hormesis
17:28 < sphertext_> he's insane 
17:30 < sphertext_> it's kinda terrifying to watch him so cold blooded while orchestrating this elaborate confusion for the general public, under the pretence of being a science communicator 
17:36 < L29Ah> hahaha science communication go brrrr
17:37 < fenn> the connection is that both processes are able to digest big piles of molecular junk
17:43 < sphertext_> yeah but.. imagine there's someone with no background and this is the first exposure he gets to the field. maybe he then decides to dive in. but he's gonna end up having to spend extra effort, just to undo his intuitive knowledge caused by this vague connection, before he can actually have a rigorous baseline from which to engage with the actual research directly.
17:45 < sphertext_> do you see my point? why treat people as if they're hopeless idiots and don't deserve the dignity of an imidiate, accurate understanding? 
17:47 < sphertext_> well i know the answer. because he needs people to exist outside of his professional peers, so that there is someone to buy his shitty book and shitty supplement and sponsor his shitty interviews 
17:49 < sphertext_> bro i can't believe he started with partial epigenetic programming and ended up with resveratrol lmao
17:49 < sphertext_> in the same train of thought 
17:50 < sphertext_> this is actually making me laugh 
18:14 < ike8> enlightening
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19:11 < jrayhawk> autophagy and yamanaka upregulation are both induced by protein fasting
19:26 < sphertext_> jrayhawk i am not aware that protein fasting activates the yamanaka genes. do you have a source for that please? 
19:29 < sphertext_> if it's true, i guess the parallel makes a bit more sense. although it's still a stretch, since protein fasting doesn't take you anywhere near a molecular trigger for cellular reprogramming 
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21:09 < sphertext_> literally can't find any source that links dietary restriction to activation of yamanaka genes 
21:10 < sphertext_> and instead i even found the opposite: "The most prominent result observed was a downregulation in the expression levels of the stem cell marker, Sox2, in CR [caloric restriction]-fed animals" 
21:14 < sphertext_>  ppl out there be trying to diet their way back to an embryonic stage 
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--- Log closed Tue Oct 03 00:00:44 2023