--- Log opened Mon Dec 18 00:00:02 2023
00:41 < hprmbridge> kanzure> one should wish for a system of aligned wishes
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04:15 < Ludack> anyone tried ashwagandha?
05:05 < docl> Ashstar: of late I've been pondering more radical solutions -- great mental exercise / learning prompt if nothing else. one I've considered in recent weeks here is the artificial nucleus. the nanotech requirement is narrower than it might seem, as the cell is partly insulated from the contents of the nucleus, the double layered nuclear membrane preventing large molecules from crossing. that means most 
05:05 < docl> of the cell function doesn't affect the inside of the nucleus nor vice versa
05:05 < docl> there are many caveats, of course, as it is biology
05:08 < docl> one caveat that I uncovered was the heterogeneous nature of ribosomes. traditionally ribosomes are produced in the nucleolus, but there are multiple possible ones that are thought to regulate translation. to preserve the black box effect we need the nucleus simulacrum to emit these under similar stress conditions and so on. but there is some margin for error given how simlar the ribosomes tend to be
05:57 < docl> Anyway the exciting prospect is you'd control transcription (the mRNA coming out of the nuclear pores) entirely. The engineered cells would be indistinguishable from natural ones until you look at what's inside the nucleus. Every bit as good at expressing genes, but you control what mRNA they express.
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06:29 < hprmbridge> kanzure> much of the cytoplasm does effect the nucleus and expression, like transcription factors
06:31 < hprmbridge> Katylase> And don't forget the length of Poly 2's tail!🙂
06:33 < docl> true, it's not tightly blackboxed. just more so than most biology...
06:35 < docl> the idea to handle transcription factors is to rig sensors up so you know how many of those there are in the cytoplasm, feed that into the scripts to adjust the gene expression parameters. but you can make exceptions easily when you want to 
06:37 < docl> hello @Katylase :)
06:38 < docl> Polymerase II? https://pubmed.ncbi.nlm.nih.gov/2251729/
06:42 < docl> ah, it does posttranscription modification to RNA to make RNPs. the article is calling them mRNA and mRNP? hmm 
06:44 < hprmbridge> Katylase> Poly's tail serves both as a scaffold for RNA, and as regulation mechanism (by phosphorylation and binding of transcription factors)
06:44 < docl> splicing events that result in an mRNA strand can probably be handled by alternative means, but if we need specific RNPs to do specific things we do have to closely follow the natural route (to avoid needing to invent new mechanisms)
06:46 < docl> I wonder why regulation can be handled entirely at the transcription side? maybe some of these regulatory aren't fundamentally necessary?
06:46 < docl> regulatory events, I mean
06:48 < docl> I'll need to study this more to understand whether or not there's an important functional reason for it being handled at the polymerase level... the idea is ambitious but has been a great catalyst for study for me :)
06:51 < docl> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465734/ // The RNA polymerase II CTD coordinates transcription and RNA processing
06:52 < docl> (more recent paper, open access)
06:56 < docl> for research purposes, something like a yeast cell or other model microbial eukaryote with heavily engineered intranuclear mechanisms would be a good starting point. see what you can/can't get away with changing
07:03 < docl> a different direction from my main artificial nucleus concept (I think this is in the logs before Ashstar joined) is to engineer a symbiote that works as an auxiliary source for ribosomes. that could make humans more stress resistant by limiting the need for the cell's nucleolus to swell up as a stress response. you could use drugs or genes that keep it nice and small without the usual side effects. 
07:03 < docl> might be a way to slow down aging. (yeast aging apparently consists of 2 routes, nucleolar and mitochondrial. mammal is more complicated, but nucleolar stress mechanisms could be important.) of course, a symbiote is something kanzure has advocated for a while now
07:15 < hprmbridge> kanzure> andrew hessel talking genome synthesis in the valleydao discord https://discord.gg/ZthtYhjf?event=1186306357071192135
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09:12 < docl> looking at these old 90's era ICAN II designs, it looks like they calculated you can convert 140 nanograms (26 MJ with 140 ng matter) to about 300 GJ of energy by fission-fusion pulses
09:12 < docl> https://web.archive.org/web/20150320131945/http://www.engr.psu.edu/antimatter/Papers/ICAN.pdf
09:12 < docl> http://ffden-2.phys.uaf.edu/213.web.stuff/Scott%20Kircher/fissionfusion.html
09:40 < docl> around 1.2 x 10^4 times as much out. 250 micrograms (natural production per year of Saturn) should then be about 500 TJ. not super impressive by global annual standards, but arguably enough for a saturn mission to pay for itself. I still think artificial production from solar makes more sense
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10:31 < fenn> the RNA scaffold tail got me thinking
10:32 < fenn> metal catalysts for hydrocarbon oxidation work by constraining the hydrocarbon and oxygen to a 2d space
10:33 < fenn> first the reagents bind to a surface, then they translate around until they randomly collide. if you're doing a random walk in 2D space, it's much less search space than a 3D space of the same unit length
10:34 < fenn> does biology have anything similar? you could increase the effective cross sectional area by adding a net or dream catcher or even just a long string of binding sites that can transfer from one to the next, effectively feeding the substrate into the gaping maw of your enzyme or whatever
10:34 < fenn> jellyfish tentacles
10:35 < fenn> the substrate molecules would be free to move either direction along the tentacle, but now it's constrained to 1D instead of 3D
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10:53 < fenn> it seems like the tail on RNA Pol-II is for keeping track of where it is in the transcription sequence (initiation, elongation, splicing introns, capping, adding a poly-A tail)
10:54 < fenn> if cell-wide metabolic problems like a lack of phosphorus affect this process, that's not necessarily what we want to reproduce
11:12 < hprmbridge> kanzure> yes biology does nano confinement for reactions
11:12 < hprmbridge> kanzure> in a lot of different contexts.
11:12 < hprmbridge> kanzure> non-ribosomal peptide synthases do the hand off thing. there are also microcompartments and jig-rig proteins for reaction support.
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11:41 < hprmbridge> nmz787> I want enzymes that only attack dangling bonds (I'd probably want a variety of removal-lengths available). Something that could dissolve hangnails perfectly AND work for something like nanofab planarization.
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12:10 < fenn> isn't that all enzymes? they have to be able to get in there to cut the bond
12:25 < hprmbridge> nmz787> Enzymes can cut stuff that's not dangling
12:28 < hprmbridge> Katylase> HisIle!
12:28 < hprmbridge> Katylase> Someone said enzymes? I AM AN ENZYME🤭😆
12:37 < Ashstar> docl, as far as the way our cellular clock is regulated, the double layer membrane has critical protein ion gates that are part of the way the cellular clock operates
12:37 < docl> are we talking about the nuclear pores?
12:37 < Ashstar> yes
12:38 < Ashstar> also, ion channels
12:41 < Ashstar> most of us who worked in the field of Chronobiology, researched the genetics of gated ion channels, particulary Ca++
12:42 < Ashstar> at least where I went to grad school
12:45 < Ashstar> you know about the Hayflick Limit?
12:45 < docl> of course
12:46 < Ashstar> he is still alive, I spoke to him a while back
12:46 < Ashstar> he's in his 90's
12:49 < Ashstar> https://pubmed.ncbi.nlm.nih.gov/23387885/
12:51 < docl> the idea is to obsolete most of the processes internal to the nucleus, including telomere unwinding and methylation and so on. replace chromatin with an engineered, computerized lookup system that you can actually script like a reasonable engineer
12:53 < docl> you'd need good sensors for feedbacks, but if transport is going to be a problem maybe more of those should be located outside the membrane
12:57 < Ashstar> besides using all the known tools, such as supplmentation, low caloric intake, occasional fasts, execise- I am believer in having a high level of activity or engagement as vital to longevity
13:00 < docl> hmm. reading this article I am getting the impression the ion channels are serving as a kind of sensor
13:00 < Ashstar> yes'
13:04 < docl> ok, so my abstraction probably doesn't collapse due to that. I'm already assuming you need fairly good sensors. might keep using the calcium (and other ion) channels for this since we don't want to alter the nuclear membrane (as the idea is to keep the exterior more or less indistinduishable from the natural form)
13:13 < Ashstar> there is another key thing that is important to longevity. It is our gut biome. We are facultative omnivores as such, our gut is fairly long. Too long to do well with lots of hard to digest meat, like red meat with it's connective tissue. A lot of undigested protein ends up feeding protolitic bacteria. The amount of ammonia, nitrosamines and other biproducts tax our liver, cause small 
13:13 < Ashstar> point mutations, transcription errors. 
13:16 < Ashstar> I strongly believe in using lactic bacteria, unless there are milk issues, it not only has a very high surface area per protein, what goes through helps control these bacteria
13:18 < Ashstar> also, easily digested protein, like fish, fowl
13:22 < Ashstar> red meat, as I said, is tough to breack down with it's tough collagen connective tissue
13:25 < fenn> gentlemen, i present to you the most advanced breakthrough in life extension technology: the crock-pot
13:25 < docl> engineered gut bacteria could do a lot for us. it won't extend life past the normal limit, but it's a good low hanging target. (in part because it's microbial engineering instead of human.)
13:26 < Ashstar> yea
13:27 < Ashstar> having a super gut microbe
13:27 < Ashstar> might be a low hanging fruit
13:28 < docl> if you think about the limits of that, immune to vitamin deficiency, non glandular ways to preserve homeostasis in general (insulin, testosterone, etc.)
13:29 < Ashstar> and fenn your right, the advent of cooking meat well, helped us evolve
13:31 < Ashstar> a lot of possibilities there w engineered gut microbes, if it could pass FDA- 
13:34 < L29Ah> fenn: i don't see how a slow cooker extends life
13:34  * L29Ah bought his first pressure cooker recently and is happy af
13:34 < L29Ah> too bad it's not osfw and quite awkward
13:34 < docl> bypassing fda is part of the point, are they going to care if I eat some yeast I cooked up in my lab?
13:36 < docl> real life extension past is going to need changes to the actual human cells though, presumably
13:36 < docl> we have powers the alchemists of old would have dreamed of. how to best pursue the great work? that's the question. a bit of sound short term health advice isn't bad, but it's not our focus.
13:36 < Ashstar> one of my collegues has made a yeast that produces a precurser to morphine, so why not
13:40 < docl> how about a yeast that turns itself into special human stem-like cells that you can talk to with an LED via li-fi, turning them into a well regulated young version of whatever cell you should have at a given location
13:44 < Ashstar> sounds cool
14:07 < docl> sounds ambitious, maybe overly so :P
14:26 < hprmbridge> nmz787> L29Ah it certainly extends how long it takes for food to "get in my belly"
14:27 < hprmbridge> nmz787> (austin powers reference)
14:28 < hprmbridge> nmz787> My guess is he could mean something about reducing the risk of the maillard reaction
14:34 < L29Ah> my experience with boiling and pressure cooking doesn't demonstrate observable with a naked eye amounts of maillard reaction products
14:37 < fenn> collagen hydrolyzes, removing the immanent threat of viciously undercooked gristle
14:37 < fenn> blort
14:38 < L29Ah> nothing an hour of pressure cooking can't achieve afaiu
14:39 < fenn> right, that's all i meant
14:45 < hprmbridge> nmz787> InstaPot are definitely a great invention
15:38 < docl> in principle you could thrive on sawdust with the right gut bacteria. not that you'd want to (given any other option) but probably handy in famine situations
15:45 < fenn> bacteria aren't known to break down cellulose
15:47 < fenn> oh my information is out of date by a few hundred million years it seems
15:48 < fenn> if we're genetic engineering anyway, why not program the human to release cellulases instead?
15:51 < docl> generally easier to experiment genetically on microbes
15:51 < fenn> .wik Trichoderma reesei
15:51 < EmmyNoether> "Trichoderma reesei is a mesophilic and filamentous fungus. It is an anamorph of the fungus Hypocrea jecorina. / T. reesei can secrete large amounts of cellulolytic enzymes (cellulases and hemicellulases)." - https://en.wikipedia.org/wiki/Trichoderma_reesei
15:51 < docl> (weak reason, depends on tech grade and so on)
15:55 < fenn> but i haven't added a new wing to my palace since 1887
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17:42 < hprmbridge> nmz787> Fenn I didn't know you were /that/ old!
17:42 < hprmbridge> nmz787> (the hundred million years quote)
17:43 < hprmbridge> nmz787> Sawdust to something my diesel engines can run on seems like a really really smart idea
17:44 < L29Ah> you can also eat your homework!
17:44 < hprmbridge> nmz787> Especially after watching this a few days ago https://youtu.be/dr3mFzh0KSk
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17:54 < fenn> "the battery protection cover was scratched, so the insurance company had to write off the car for its entire value" doesn't seem like a problem with batteries
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20:42 < Ashstar> https://pubmed.ncbi.nlm.nih.gov/3130057/
20:43 < Ashstar> https://www.jbc.org/article/S0021-9258(17)50097-6/fulltext
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21:36 < jrayhawk> age-dependent if norming on pathology
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21:38 < jrayhawk> glutathione deficiency and unmanaged methylglyoxal or unmanaged aldehydes, 25-OHD deficiency, retinoid deficiency, zinc deficiency, glyphosate, etc.
21:48 < Ashstar> all this, if one doesn't exercise, levate heart rate to 200 minus age
21:48 < Ashstar> elevate
21:49 < Ashstar> is just so much excess 
--- Log closed Tue Dec 19 00:00:03 2023