--- Log opened Sat Aug 03 00:00:11 2024
01:18 < fenn> there should be a whole series of CAM cycle agricultural crops, to fill in all the niches usually provided by C3 and C4 crops
01:18 < fenn> not just pineapples and agave
01:19 < fenn> this breeding program should have started 75 years ago
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02:51 < fenn> "purified endotoxin from Escherichia coli can induce obesity and insulin-resistance when injected into germ-free mouse models" "liver, but not whole-body, insulin resistance was detected in LPS-infused mice" https://pubmed.ncbi.nlm.nih.gov/17456850/
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03:00 < jrayhawk> also increses endothelial adhesion, permeability, and upregulates LDL for cleanup
03:21 < fenn> LPS increases permeability? that sounds backwards
03:22 < fenn> yeah there's that whole floodgates flush-the-pathogen system, but like, reverse leakage had to have happened in nature too? if the sorta-pathogen which continuously stimulated the zonulin pathway were just some commensal microbe
03:27 < fenn> PCSK9 regulates uptake of LPS (small world)
03:27 < jrayhawk> you are thinking of epithelial permeability
03:29 < fenn> ok a lot of this diabetes stuff is about intestinal microbiome
03:29 < jrayhawk> epithelial tissues have a tissue-specific tolerance for LPS
03:30 < jrayhawk> intestines take a lot to piss off, most other mucous membranes take relatively little
03:31 < hprmbridge> kanzure> there was a C4 project in the backlogs
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03:32 < fenn> the theory is that LPS sensitivity was driven by an evolutionary arms race with lower respiratory tract bacteria Haemophilus influenzae, Klebsiella pneumoniae, Morazella catarhalis
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03:33 < jrayhawk> that seems unnecessarily specific
03:33 < fenn> these have hexa-acylated LPS which the human immune system is most sensitive to
03:33 < fenn> the explanation is that this modification makes the bacterial cell wall harder to grab on to with mucus, or something
03:34 < fenn> .t https://pubmed.ncbi.nlm.nih.gov/33689211
03:34 < saxo> Sepsis and the evolution of human increased sensitivity to lipopolysaccharide - PubMed
03:34 < jrayhawk> LPS has a lot of random binding affinities
03:35 < jrayhawk> this makes it structurally useful as well as causing chaos when let loose in biochemical systems
03:36 < jrayhawk> which also makes it easy to detect by the immune system, which makes it a useful signal of sepsis
03:36 < jrayhawk> so the body goes to defcon 2 in response
03:38 < fenn> why are humans 1000x more sensitive to it than other primates?
03:39 < jrayhawk> in what sense?
03:40 < fenn> hmm maybe not 1000? less than 10x the dose required to cause fever in macaques and babboons will cause septic shock in humans
03:41 < fenn> oh it is a log plot
03:42 < fenn> it's an apples to oranges comparison, but the difference seems vast
03:43 < fenn> 10 CFU/kg vs 10 million CFU/kg
03:47 < jrayhawk> modern humans always have low-grade endotoxemia due to grain (and similar) addiction; i wouldn't take challenge studies of LPS on modern humans seriously for the purposes of making evolutionary hypotheses
03:48 < fenn> this sounds eminently testable
03:48 < jrayhawk> for instance, humans have stronger stomach acid than obligate scavengers due to being the only predators of adult pachyderms
03:48 < jrayhawk> humans are actually evolved specifically to deal with fermenting meat other species would consider too dangerous
03:48 < jrayhawk> which includes huge LPS loads
03:51 < jrayhawk> you can see this in action with some of the more wacko raw meat dieters
03:56 < jrayhawk> humans can also afford more serum sensitivity due to having a less varied toxin load threatening epithelial barrier integrity
04:01 < fenn> i had trouble understanding PCSK9 inhibitors. i think this diagram is the least bad i've seen so far: https://www.biovendor.com/file/11362/pcsk9-vloha-doplnujici-obrazek.jpg?version=201811201458
04:05 < jrayhawk> https://www.goodrx.com/classes/pcsk9-inhibitors good luck affording them
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04:09 < jrayhawk> yeah, you can just think of it as increasing liver uptake of LDL. Most tissues just take bites out of LDL using LPL; the liver is the main thing taking up whole lipoproteins.
04:14 < jrayhawk> High LDL residence time due to genetic disorders or thyroid downregulation leads to fatty acid and ApoB100 oxidation; PCSK lowers residence time, allowing for recycling and replenishment with a fresh stash of tocopherols and tocotrienols.
04:14 < jrayhawk> as opposed to statins, which do jack shit about residence time and trash membrane repair capacity needed to deal with the aftermath
04:19 < jrayhawk> the "small, dense LDL" lipid profile cardiologists are trained to spot and treat is a product of remnant LDL with nothing left to give to LPS waiting for whole uptake by LDLR and friends, or LDL that's been produced by the liver with no contents in response to an immune insult such as LPS.
04:21 < jrayhawk> er, excuse me, pcsk9 inhibitors lower residence time
04:23 < fenn> mumble mumble LDLR gene therapy
04:24 < fenn> just take hep-C and slap a payload in it :D
04:26 < fenn> is the total surface area of all LDL particles greater than the exposed lipid surface area of cell membranes?
04:27 < jrayhawk> nope, but cells are metabolically active and self-repairing where lipoproteins are not.
04:27 < fenn> i'm just kind of astonished that these two seemingly random systems (fat delivery and bacterial cleanup) are interacting in this way
04:27 < fenn> why do the LDL particles help with LPS clearance in the first place?
04:28 < jrayhawk> an interesting question that's beyond my knowledge
04:28 < jrayhawk> let me know if you work out a good answer
04:28 < jrayhawk> my guess would be "accident of evolution"
04:30 < fenn> you said LPS has lots of binding affinities, so i assumed it's just a matter of the small fatty particle being more likely to interact with the LPS particle than the large particle, because there's more of them and the velocity is faster so more chances
04:30 < fenn> (the large particle being a cell)
04:30 < fenn> i know cells aren't spherical billiard balls bouncing around, but that's how we usually model chemical reaction kinetics
04:32 < fenn> presumably the lipid chain part of LPS is what sticks to LDL
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05:13 < fenn> "The proinflammatory activity of plasma LPS is increased by LBP (LPS-binding protein), which is higher in obesity."
05:16 < fenn> not clear which way the causality flows, but LBP might be a thing to poke at
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13:00 < hprmbridge> kanzure> https://archive.org/details/romhacking.net-20240801
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19:07 < fenn> "p0g0__> fenn, as a guy that studied plant breeding in the pre-GM era in California, Kentucky and New Zealand, there was a lot of ignorance and denial about global warming, the total population was much lower, Ehrlich's Limits To Growth wasn't getting the message across to the granters and universities, and most of the sentiment was to double down on existing food crops to increase their yields.
19:07 < fenn> CAM was an area of interest, but so was breeding for thicker leaves, fewer stomata, salt tolerance, and better heat stress tolerance.  The deserts weren't getting much attention except as a source of interesting species.  The GM folks were just getting into plant breeders rights and patenting life forms, public funding for research was shrinking, and the Monsantos of the world didn't see any big
19:07 < fenn> money in it."
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23:06 < docl> .t https://www.nature.com/articles/s41467-024-50767-2
23:06 < saxo> A frugal CRISPR kit for equitable and accessible education in gene editing and synthetic biology | Nature Communications
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23:14 < docl> .t https://www.crisprkit.org/
23:14 < saxo> CRISPRkit
23:15 < docl> doesn't seem especially useful in current form, but I like the mindset
23:17 < docl> apparently it's rna modification only in a cell free solution. so that's an advantage in a high school setting since you don't want to deal with a biohazard
23:28 < docl> actually I think it is dna not rna being modified
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--- Log closed Sun Aug 04 00:00:12 2024