--- Log opened Tue Jun 25 00:00:34 2024
00:28 < docl> hmm, I don't see why transgenic mice that express trehalose for cryo survival purposes wouldn't be doable. it's not like trehalose is toxic to mammals...
00:29 < docl> https://www.sciencedirect.com/science/article/pii/S1074552102002922 // Insights into Trehalose Synthesis Provided by the Structure of the Retaining Glucosyltransferase OtsA
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01:06 < docl> a mouse that survives the process might still need some selective breeding, but this would probably be way faster than trying to breed cryo survival into normal mice
01:32 < fenn> at the very least it would reveal other problems that occur during the freeze/thaw process that can be worked on in parallel to the critical path
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06:16 < kanzure> https://x.com/Agalmicist/status/1805459566349762976
06:27 < kanzure> "transformers explained from the atom up" https://www.youtube.com/watch?v=Ys4rFt8XbMM https://x.com/jacobrintamaki/status/1805548164860330441
06:28 < kanzure> https://www.evolutionaryscale.ai/blog/esm3-release
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07:46 < kanzure> "Effective cryopreservation of human brain tissue and neural organoids" https://www.cell.com/cell-reports-methods/fulltext/S2667-2375(24)00121-8
07:46 < kanzure> why not cryopreservation and vitrification of human brain slices? yes the connectivity gets funked up but we know how to preserve small biological samples.
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08:35 < docl> yes, slice and dice was my initial reaction to the problems back in the day. still think it has promise, the main drawback is that low damage slicing is tricky in something as soft as unfixed brain tissue
08:40 < docl> I think you would want to start by inducing hypothermia, to limit the cascading damage events. ideally you'd fix it using a resin that can be removed during rewarming before making the small slices, limiting the mechanical damage and osmotic damage as you immerse and diffuse the colligative cryoprotectants
08:43 < docl> cradle.xyz is working on robotic stuff for their high throughput screening, so they might end up with the expertise to do this
08:51 < docl> not the most marketable approach, but you gotta follow the science... "we wanted cryopods so we built this fancy blender, think you can talk grandma into stepping in?"
08:54 < hprmbridge> kanzure> blender can work if you use the DNA barcoding stuff and synapse barcoding thingies
09:01 < docl> yeah that would be the way to keep track of them. demonstrating that you can put the pieces together and get a functioning brain might be hard still. but you probably do get a stronger case that future science can handle it
09:02 < docl> and it's a kind of repair that current science might be more amenable to at least seriously researching
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11:17 < hprmbridge> Eli> Definitely not me. Im not an expert in the area. I pretty much defer to Peter Attia on prevention because he talks to the people who write the papers on atherosclerosis and I recall he has higher risk of CVD so he has a personal stake in investigating most recent research.
12:30 < hprmbridge> Eli> Just read the lesswrong post. A lot of it seems to be basically saying things Peter Attia says. apob and lpa seem to be the biomarkers we should care about the most. If you are genetically predisposed to having issues with lpa/apob, your lifestyle doesn't necessarily make up for it. This is why this guy can have a heart attack at age 51 (https://www.phillyburbs.com/story/news/2010/07/15/biggest-
12:30 < hprmbridge> Eli> loser-trainer-bob/17925408007/). I'm not sure why the guy in the lesswrong post is recommending berberine. I'm not sure if berberine's MOA is any different than Metformin. They both activate AMPK. And the evidence is that Metformin for healthy people is considered harmful. I'm not knowledgeable about Red yeast rice. We already have statins, PCSK9 Inhibitors, and Bempedoic acid. So, we can
12:30 < hprmbridge> Eli> significantly lower lpa/apob.
12:30 < hprmbridge> Eli>
12:30 < hprmbridge> Eli> I'll ask my tenant who is a heart doctor if there's been any progress on using lpa/apob as a biomarker in hospitals. It is generally not even tested for at this point. And you have to ask for it to be tested or just order it yourself.
12:57 < hprmbridge> Eli> These prices are extraordinary. How do they get them so cheap? Are they a charity that uses the data for data mining or something? How do we know they do proper testing and are legit?
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14:36 < hprmbridge> kanzure> "Extended supercooled storage of red blood cells" https://www.nature.com/articles/s42003-024-06463-4
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16:35 < docl> note that they were only doing -5°C
17:41 < jrayhawk> uh... isn't that freezing-point-depression rather than supercooling?
17:49 < jrayhawk> eli: peter attia makes his money selling diagnostics and prescriptions; while he gets the hepatically generated apoliprotein-B100-containing lipoprotein story correct, he does not talk about expression of adhesive protoglycans on endothelial cells, permeability of tight barrier junctions between endothelial cells, peroxidation of ApoB100, phospholipids and other fatty acids in lipoproteins, 
17:50 < jrayhawk> endothelial cells, and macrophages, or macrophage deficiency or dysfunction.
17:50 < jrayhawk> Those other things he does not have tests for and cannot build prescriptions around without risking his medical license.
17:51 < jrayhawk> But they're actually vastly less stupid as intervention targets than ApoB100-containing lipoproteins themselves
17:52 < jrayhawk> https://en.wikipedia.org/wiki/Streetlight_effect
17:54 < jrayhawk> At least, for the majority of people that do not have frank lipoprotein processing disorders such as familial hypercholesterolemia or ApoE4
18:00 < jrayhawk> ApoB100-containing lipoproteins are critical parts of the immune system and cellular resource trafficing sytems; if standard of care weren't colosally boneheaded, we would work out *why* they're elevated and *if* that elevation is a problem on an individual basis.
18:00 < docl> there's some freezing point depression in anything that isn't pure water, but it sounds like they aren't depressing it a full 5 degrees (otherwise what would be the point of sealing it with mineral oil)
18:01 < jrayhawk> i only skimmed through it; did they actually discuss what the freezing point of their solutions is?
18:01 < jrayhawk> s/point of their solutions is/points of their solutions are/
18:03 < docl> it's entirely plausible they are mistaken about why their RBC solution isn't freezing, if the details aren't buried in there somewhere
18:05 < jrayhawk> Attia's promotion of PCSK9 inhibitors (speeding clearance and recycling) over traditional statins (slowing production) is at least a step in the right direction for minority of cases with lipoprotein processing disorders, but this remains intellectual baby steps for an epistemically broken industry
18:07 < docl> ah, at least there are some measurements for the additive solutions: "The osmolarity levels for E-Sol 5, AS-7, CPDA-1, and SAGM were measured as 270, 203, 498, and 350 mOsm/kg, respectively."
18:20 < jrayhawk> jesus christ i forgot how bullshitty attia's website is
18:25 < hprmbridge> Eli> I’m not sure I’m tracking. If someone has high apob/lpa due to genetics, and evidence seems to suggest getting those levels down is likely to reduce CVD, wouldn’t standard of care be to prescribe statins if they don’t cause statin toxicity? Is your argument that apob/lpa are worse biomarkers than ldlc? Or that it’s ok to have high apob/lpa? If we don’t have tests for other biomarkers, then what is
18:25 < hprmbridge> Eli> a licensed dr supposed to do here? If a fitness instructor can have a heart attack at 51, what do we tell them when they first come into the office? Genuinely curious on your thoughts
18:25 < jrayhawk> er, s/protoglycans/proteoglycans/
18:27 < jrayhawk> Elevated circulating ApoB100 is neither necessary nor sufficient for CVD, and its treatment is more expensive and less effective than other interventions.
18:28 < jrayhawk> And usually antithetical to QALYs.
18:29 < jrayhawk> It is just one factor among the five classes I mentioned, and it is the least safe to modify.
18:29 < jrayhawk> It is used by doctors because it is the easiest to measure.
18:29 < jrayhawk> Or, rather, used by Peter Attia. Most doctors do something way, way dumber (LDL-C, as you mention).
18:33 < hprmbridge> Eli> Ok, so let’s say someone comes into your office and wants to prevent heart disease. Ldlc is dumber than apob/lpa. You’ve already maxed out diet, sleep, and exercise (and apparently sugar alcohol based on recent research). But their family has a history of heart disease. What biomarkers are readily available to test from quest labs and what is my first line treatment? And at what age do we start
18:33 < hprmbridge> Eli> them at?
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18:44 < docl> jrayhawk: the paper doesn't mention how much freezing point depression to expect, nor is it called out in the peer review document, so I looked it up and 1 mol/L would depress by 1.86 °C, so that can be ruled out. annoying they didn't mention it specifically
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19:13 < jrayhawk> Eli: Biomarkers are a waste of money at the outset. The initial intervention is to remove universal sources of oxidative stress, inflammation, and micronutrient deficiency. Remove addictive epithelial and endothelial chemokine receptor agonists ( https://pubmed.ncbi.nlm.nih.gov/21248165/ ), membrane sterol disruptors ( https://www.mdpi.com/2227-9717/7/8/513 ) and other endothelial immunogens ( 
19:13 < jrayhawk> https://pubmed.ncbi.nlm.nih.gov/34223877/ ) that induce chronic endotoxemia and membrane damage for which hepatically-generated lipoproteins are the body's primary defense. get them off of systemically dangerous levels of oxidatively unstable linoleic acid ( 
19:13 < jrayhawk> https://diyhpl.us/~jrayhawk/the_metabolic_syndrome/10.1056-NEJM196205172662001-a-controlled-clinical-trial-of-a-diet-high-in-unsaturated-fat-in-preventing-complications-of-atherosclerosis-figure_8.png , 
19:13 < jrayhawk> https://diyhpl.us/~jrayhawk/the_metabolic_syndrome/10.1056-NEJM196205172662001-a-controlled-clinical-trial-of-a-diet-high-in-unsaturated-fat-in-preventing-complications-of-atherosclerosis-figure_14.png ), add physilogically appropriate levels of docosahexaenoic acid and arachidonic acid for use in immunology (this is partially entering standard of care now), provide myeloid differentiation factors 
19:13 < jrayhawk> and calcium management molecules (menatetrenone, retinoids, vitamin D).
19:13 < jrayhawk> THEN you can start to look at biomarkers.
19:31 < jrayhawk> intuition-building resources: https://vimeo.com/152402052 https://youtube.com/watch?v=aDmDVOH9U-U https://youtube.com/watch?v=N0XnXWM-92M http://youtube.com/watch?v=8uQuF9isqFo
19:33 < jrayhawk> The general epistemic principle in play is that you can get any result in any human single-variable randomized controled trial IF you norm on pathology.
19:35 < jrayhawk> You come to very, very different conclusions if you norm on human health and reverse-engineer disease from there.
19:36 < hprmbridge> Eli> I don't think any doctor would disagree with reducing unnecessary inflammation. Before I get too deep into the papers, couldn't I test for this? We have inflammation biomarkers like CRP, IL6, etc ...
19:36 < jrayhawk> Most of the time, LDL-P is a marker for inflammation.
19:37 < jrayhawk> or, rather, elevated LDL-P
19:37 < jrayhawk> (non-linear)
19:42 < hprmbridge> Eli> I agree that Vitamin D3/K2 is super cheap and easy. I can test for micronutrient deficiences (which I've done). And I take astaxanthin which is extremely powerful in reducing inflammation and oxidative stress (but I wish it had more data and I only am on 4mg). You're definitely taking more of a holistic view, which I think is great. But, you're also using biomarkers here. A patient would have to
19:42 < hprmbridge> Eli> go to a cash based doctor who does this stuff, and even then there would likely be tests on different biomarkers. Most of our standard medical system doesn't care to do this. And the patient would have to know enough to seek this out. And then they might be paying quite a bit, so I think that's why the Western medical system doesn't do this. I think yuo are dealing with the good, fast, cheap
19:42 < hprmbridge> Eli> triangle.
19:43 < hprmbridge> Eli> I mean, I guess you could order all these tests yourself if you know what you're doing. But, then you are probably in the medical field already or have friends in it. So, you're still dealing with the reality of good, fast, cheap
19:48 < jrayhawk> There are no testing involved. The majority of western adults have the metabolic syndrome. These are big, obvious universal causes. What manifestations they get, be it atherosclerosis, hypertension, insulin resistance, autoimmunity, etc. are determined by genetic and environmental tradeoffs. If you go into it without dealing with the universals, you are just allopathically fiddling with numbers 
19:48 < jrayhawk> without having an effect on mortality (as seen with statin and PUFA interventions).
19:53 < jrayhawk> And, quite often, *with* disastrous effects on QALYs, which are more inconvenient to characterize and measure.
20:01 < hprmbridge> Eli> Yes, I agree. But, I'm not referring to the average American. I'm talking about the biohacker (not the ones buying snake oil), who want to use evidence to maximize their phenotype. They want to get out in front of a developed nations top killers instead of treating them in the ER where western medicine has few solutions.
20:01 < hprmbridge> Eli>
20:01 < hprmbridge> Eli> I do blood tests every year. I work on the big three (diet, sleep, exercise). I can test for heavy metals and inflammation markers. What's next? Eventually we will have more large-n CVD trials we can comb for data. Unfortunately, we are still probing in the dark and updating biases based on every study that comes out. Our advances have been incremental, sometimes wrong, sometimes right.
20:19 < jrayhawk> Dave Feldman et al's work on "Lean-Mass Hyperresponders" may invalidate my claim that PSCK9 inhibitors are an okay intervention for lipoprotein processing disorders. I am interested to see how that pans out.
20:20 < jrayhawk> er, PCSK9
20:44 < jrayhawk> Reminder: Just because it is more measurable doesn't mean it is more actionable. Science has been littering the past 60 years with the skulls of people who thought using biomarkers to determine treatment for CVD was a good concept. Hand-to-mouth hunter-gatherers, on the other hand, have been mostly fine (exceptions, such as ancient arctic people with arterial plaques, do exist. Get your vitamin D.).
20:54 < jrayhawk> If I were to make a medical test for "Do you express CXCR3 receptors?" which reduces to "Are you a human?" at over 99% specificity and sensitivity, and used said test to determine whether or not to use CXCR3 agonist restriction as a treatment for manifestatoins of the metabolic syndrome, how much do you suppose I could charge you for it?
20:54 < jrayhawk> I... uh... mean... these theoretically biohackers you speak of
20:56 < jrayhawk> asking for a friend
21:30 < jrayhawk> If your answer is "I would not pay for it, that is stupid", then think *real hard* about what incentives you're setting up for the medical industry to pursue.
21:42 < hprmbridge> Eli> Depends on if you put it in a minicircle…
21:43 < jrayhawk> haha
21:45 < hprmbridge> Eli> Their diet, exercise, and genetics are different. Eskimo and masai are genetically different than you so they don’t necessarily have the issues with saturated fat. Hunter gatherers got very little saturated fat. They are obsessed with food.
21:48 < jrayhawk> Yes, the interesting thing is seeing those cultures acquire diseases of civilization as they stop being hand-to-mouth hunter-gatherers.
21:49 < jrayhawk> *That* is where productive hypothesis generation for the metabolic syndrome emerges.
21:50 < jrayhawk> (Mind you we now know in detail how atherosclerosis works, it just took us six decades of nonsense hypotheses to get there.)
21:53 < hprmbridge> Eli> Are there no mysteries about atherosclerosis left? I feel like I could pull up a systematic review of how seed oils cause CVD from a few years ago. But most nutrition people are not anti-seed oil now as far as I can tell
21:55 < jrayhawk> Yeah, the mechanism for lipid plaques is well-understood. ApoB100-the-protein-itself oxidizes and, as a result, the lipoprotein gets trapped below the vascular intima at rates faster than macrophages can manage and clean up.
21:57 < jrayhawk> there should be another comma after "intima"
21:57 < hprmbridge> Eli> I asked my tenant cardiologist about using apob as a biomarker in medical practice. He said he didn’t know doctors were doing that now
21:58 < jrayhawk> oh my god
21:58 < jrayhawk> NMR has been commonly available since 2005
21:59 < hprmbridge> Eli> It’s not like they include apob or lpa in most lipid panels. I can sympathize
22:01 < jrayhawk> when i say "well understood" i mean "by researchers" not "by doctors, who are perpetually 60 years behind the science because standard of care is a political epistemology enforced with seniority protectionism and vicious hazing"
22:02 < jrayhawk> "along with shared-knowledge coordination problems"
22:09 < jrayhawk> the awkward thing is that getting trapped below the vascular intima is actually one of the safer places for a lipoprotein to oxidize and break down
22:09 < jrayhawk> people typically do that for *decades* before it becomes a real problem
22:10 < hprmbridge> Eli> So in your opinion, are there any legit biomarkers to measure and use as a target for a pharmaceutical medication (with the exception of a genetic mutation like familial hypercholesterolemia) for CVD? Or do you think these can only be allopathic and downstream of the source of the problem?
22:12 < hprmbridge> Eli> Like, is your theory that the most highly correlated CVD markers are not measured at quest labs and so pharma is aiming at the wrong target?
22:13 < hprmbridge> Eli> Or is it simply all lifestyle choices?
22:18 < jrayhawk> There are discriminating tests that can productively result in discriminating treatments (weird metabolic disorders arising from genetic polymorphisms, messed up thyroid ratios, messed up th1/th2 ratios), but those tests will almost always be nonsense until the universal treatments for which nobody will pay for tests (i.e. reducible to "are you human?"), and will almost always have worse 
22:18 < jrayhawk> cost/benefit ratios
22:32 < hprmbridge> Eli> Ok, that’s definitely an interesting perspective and one I hadn’t considered before. I’m sure we will have many more large studies coming down the pipeline to dissect and for people smarter than me to make sense of.
22:37 < jrayhawk> Don't hold your breath. We had three[1;5C very good RCTs that disprovind the lipid hypothesis prior to 1980 (LA VA, Minnesota, Sydney), all of which were politically silenced. Nobody's going to shell out money for that sort of thing as long as the USDA is in charge of food policy. The structural incentives have not changed.
22:39 < hprmbridge> Eli> The famous Minnesota study. I need to brush up on these and all the controversies.
22:43 < jrayhawk> (The images I linked earlier were from LA VA)
22:43 < hprmbridge> Eli> Ah ok. I’ve got too many papers to read and it only gets worse every day. I think I’m just going to hire chatgpt for everything now.
23:20 < jrayhawk> The LessWrong-mega-autism-accessible framework here is something like "the more kinds of mesa-optimizer misalignment, the harder it is to debug. move towards the training distribution to simplify debugging."
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--- Log closed Wed Jun 26 00:00:35 2024