--- Log opened Wed Aug 20 00:00:15 2025
00:09 < hprmbridge> .monokhrome> yeah, the allotopic expression aubrey de grey used to talk about
00:11 < hprmbridge> .monokhrome> still being carried out: https://pubmed.ncbi.nlm.nih.gov/39659757/
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05:18 < hprmbridge> kanzure> "DNA nanoscopy" (now "DNA microscopy" in the literature?) seems to be progressing well enough, with some example figures of the molecular proximity decoding technique here: https://www.nature.com/articles/s41587-025-02613-z
05:21 < hprmbridge> kanzure> for spatial proteomics purposes, i wonder if the RNA or DNA interferes too much with protein-protein localization. seems like a more relevant technique for organelles or large structural (cytoskeleton? membrane?) features.
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06:30 < hprmbridge> kanzure> "Baudrillard gave a retelling of Borges’ fable... in which cartographers of a powerful Empire created a map of its territories so intricately detailed that it became indistinguishable from the Empire itself. As the actual Empire collapsed, its citizens unwittingly began to inhabit the symbolic abstraction that they themselves had forged. The map became so vividly real to them that they entirely
06:30 < hprmbridge> kanzure> forgot the crumbling Empire beyond its boundaries. They exchanged the real for mere symbols of the real, yet all of their actions remained constrained to the map, rather than the real territory it once represented."
07:01 < hprmbridge> kanzure> from https://bewaterltd.com/p/the-rise-of-skynet-the-algorithmization-abd (not very well written, be warned)
07:16 < jrayhawk> i sometiems wonder if getting seduced by the reification fallacy is just a natural phase of intellectual development that happens at some point in people's lives
07:19 < jrayhawk> the "put everything in git" phase, the "psychadelics let me commune with the universe" phase, or the "every word and concept is a social construct" phase
07:20 < jrayhawk> or "put everything on a blockchain" i guess is the more modern version of the git thing
07:24 < L29Ah> isn't a "natural phase of intellectual development" a reification fallacy?
07:26 < jrayhawk> i don't see how
07:28 < L29Ah> it doesn't offer improved world predictability over the existing "fallacy" notion
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07:55 < jrayhawk> 1) that would make it either redundant or false (fallacious), not specifically a failure to separate the properties of the abstraction from the properties of the underlying thing. 2) the unique predictions arise from it being A) intrinsic or nearly-intrinsic to intellectual development (which most fallacies are not) and B) restricted in time (phasic) in a way that most fallacies are not (although 
07:55 < jrayhawk> arrested development can occur)
08:13 < jrayhawk> for instance, i predict that doing LSD or reading Derrida/Lacan *during* that phase much more strongly risks *inducing* arrested development ("treating the properties of the abstraction as being more consequential than the underling thing they represent is good, actually")
08:16 < jrayhawk> er, underlying
08:41 < hprmbridge> kanzure> there is a startup doing ex vivo uterus as a semi-artificial womb. very glad to be told about this, as none of the other artificial womb startups have interested me.
08:42 < hprmbridge> kanzure> obviously the other thing to do is egenesis pig blastocyst complementation of human uterus, would scale better than harvesting underutilized adult uteri
09:01 < hprmbridge> nmz787> Jrayhawk's nutrition list could be a wishlist for genetic fixes so we don't need to watch what we eat so much
09:03 < kanzure> yeah... a few years ago i said something similar, there was at least one major genetic alteration proposed in the logs.
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09:10 < jrayhawk> there's a million of those. some of them are common and severe enough to pop out from GWAS, such as adult lactase persistance, ApoE4, familial hypercholesterolemia, beta-carotene monoxygenase, histamine intolerance/mcas/mastocytosis, various mitochondrial ECT complex disorders, biotin processing, methylation, VDR...
09:11 < jrayhawk> methylation gets into "what is appropriate natural human diversity" territory
09:12 < kanzure> what are the most common pathological dietary inputs that large quantities of humans are consuming but are not metabolically capable of processing or digesting correctly -> are any of these something that can be "trivially" fixed with some genetic engineering (not just single nucleotide change necessarily) and also are not opportunities discoverable by GWAS?
09:16 < jrayhawk> we've discussed GLO before as an interesting case: https://pmc.ncbi.nlm.nih.gov/articles/PMC3145266/
09:17 < jrayhawk> we don't really know what the metabolic costs are of bringing it back or what other misalignments might occur
09:17 < kanzure> l-gulonolactone oxidase knock-in would grant human synthesis of vitamin C
09:18 < kanzure> some of the local metabolic/kinetic costs can be analyzed in cell culture or tissue culture. as for adults, who knows if it would translate. *shrug*
09:19 < kanzure> was more thinking things like... linoleic acid metabolism. 
09:21 < jrayhawk> do you mean fatty acid elongase and desaturase? that opens up a can of worms. humans have a bunch of problems with the intermediate-size omega-6s.
09:21 < L29Ah> jrayhawk: what are your current recommendations re omega-6 intake?
09:22 < kanzure> for example, maybe delta-6 desaturase processivity needs to be increased
09:23 < kanzure> what if you could eat all the seed oils you want but you gotta pop up a pill that grants you some extra digestion (or, for whatever reason, a probiotic with this is unable to colonize your gut and i guess you need a pill to deliver the enzyme?)
09:24 < kanzure> wait why is this not fully solvable via (possibly engineered) probiotics?
09:24 < kanzure> possibly the energy requirements for this kind of processing cannot be supported inside of these microbes?
09:33 < jrayhawk> L29Ah: avoid industrial PUFA isolates, get your 1g of essential EFAs from a mixture of arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid (humans suck at elongase/desaturase and dealing with intermediates, but are okay at DHA->EPA conversion, at least), conceptualize PUFA-rich oil quality in terms of mixed {alpha,gamma}-{tocopherol,trienol}-to-PUFA ratio, avoid eating so much that it 
09:33 < jrayhawk> overwhelms metabolic pathways and has to be managed in storage
09:36 < jrayhawk> kanzure: you are, in essence, asking for a pill that magically reverses entropy
09:36 < jrayhawk> "why can't we just make a fire engine that reverses structural fires"
09:37 < jrayhawk> "then we can just set stuff on fire all the time for fun!"
09:38 < jrayhawk> find some other form of fun
09:38 < jrayhawk> there are plenty
09:43 < kanzure> the thing about an enzyme that is slightly more active, like has better binding kinetics or is more efficient per ATP or something, for digesting a certain molecule?
09:51 < jrayhawk> PUFAs slowly auto-oxidize in proportion to light and temperature, and quickly recursively oxidize eachother and other molecules. They are intrinsically metabolically costly in terms of firefighting. There are around 1g/d worth of contexts in humans, at human body temperatures, in which they are necessary.
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09:59 < jrayhawk> more during phases of rapid encephalization, such as pregnancy
10:00 < jrayhawk> we can typically manage to stabilize them with enough {α,γ}-toco{pher,trien}ols long enough to burn them in appropriate places (oxphos) up to something like 100g/d, although people with high lipoprotein residence time (FH) can't even do that
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10:06 < kanzure> wtf:
10:06 < kanzure> "Donor chimera model for tolerance induction in transplantation" https://www.sciencedirect.com/science/article/abs/pii/S0198885913000141
10:07 < kanzure> "This paper introduces the ‘donor chimera model’ (DCM) (Fig. 2) and the concept of ‘closed transplantation loop’ (CTL) approach for tolerance induction whereby, the recipient genotype is introduced to an animal fetus body via the blastocyst injection. Then the fetal organ of interest is recovered for transplantation into recipient. It is assumed that in this way, using the ...
10:07 < kanzure> ...immunotolerant capacity of the fetus body [8], [9], the fetus tissues are educated to become tolerogenic for the recipient immune system after transplantation. This happens following growth of the recipient cells in the fetus organ and expression of the recipient antigens on the rest of the fetus cells as it is shown by Geiger et al. [10], [11]. Consequently, immunosuppression therapy may be ...
10:07 < kanzure> ...limited to the minimum dose required for immunological balance."
10:07 < kanzure> and:
10:07 < kanzure> "According to the study on Freemartin chimeric cattle performed by Owen, dizygotic twins which share a common circulation during gestation can accept allografts from each other (lymphohematopoietic chimeras) without the need for immunosuppression [32]. Also, Billingham et al. extrapolated this observation by demonstrating that graft tolerance could be induced by exposure of neonatal animals to ...
10:07 < kanzure> ...allogeneic cells [12]. Their work led to the observation that hematopoietic chimerism can be associated with a state of donor-specific tolerance [28,33,34]."
10:08 < kanzure> and:
10:08 < kanzure> "In general, fetuses provide miniature replicas of body organs that are highly tolerogenic, clean, healthy and purified of memory cells and more importantly, antigen presenting cells (APCs) that mediate ‘direct’ host recognition of alloantigens or xenoantigens [20]. Therefore, the immature fetal immune system is relatively more permissive of transplantation with HLA-mismatched donor cells, ...
10:08 < kanzure> ...as they may be recognized as ‘self’. Administration of the recipient['s other otherwise available] cells in different stages of the [donor's embryonic] developmental process, using techniques such as blastocyst injection or in utero transplantation (IUT) [19,35], can make a chimeric animal whose organ is tolerogenic to the recipient immune system [10,11]. Organ transplantation from the ...
10:08 < kanzure> ...fetal chimera into a non-immunosuppressed host induces a state of peripheral immune tolerance secondary to T cell ‘ignorance’ in the non-histocompatible host and permits survival of the chimeric transplanted organ [20,36]. Fetal cells also have high capacity for proliferation, differentiation and development that permit the organ to grow and differentiate in the recipient body in a short ...
10:08 < kanzure> ...period. Limitation of the immunosuppressive therapy in this model prepares a safer methodology than the current mix chimerism induction protocol."
10:11 < jrayhawk> being unable to proteolyze proline for lack of prolase expression would be another out-of-left-field genetic target that would massively enable direct plant consumption, but i have to think there are some immense tradeoffs given that i don't think i have seen any vertebrate genoems that encode it
10:11 < kanzure> separately: "'Acquired tolerance' refers to the antigen-specific unresponsiveness to foreign antigens that have been deliberately introduced to manipulate the immune system. Following introduction of cells from one mouse strain into a neonatal mouse of another strain, some of these cells survive for most of the recipient animal’s life and the recipient will then accept a graft from the ...
10:11 < kanzure> ...original donor even though it rejects a ‘third-party’ graft. This concept was already introduced by, Billingham, Brent, and Medawar as 'actively acquired immunologic tolerance' [8,12]."
10:12 < kanzure> okay well that might be mouse-only mouse magic because all sorts of weird things work in mice.......
10:14 < jrayhawk> i suspect most of the first 1000 or so severity-indexed list of snpedia entries involve diet-dependent pathology, but i haven't tried to classify that
10:46 < kanzure> GWAS and SNPs are sufficiently studied that i feel reasonably likely to be able to consult the literature to pull out useful mutations, plus many are already in genetic-modifications.mdwn on the wiki
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10:47 < kanzure> but there is no active contingent of biologists thinking about "hey what if we do some simple genetic engineering techniques to improve [this pathway | this enzyme] which would substantially improve the state of human nutrition and diet"
10:48 < kanzure> i suppose one candidate approach is to look at SNPs and then extrapolate that maybe additional kinetic behavior would be more-good, and see if that looks true for any of the SNP nutrition improvement candidates.
10:53 < jrayhawk> phytase would be another one
10:54 < jrayhawk> oh, and cellulase, of course
10:55 < L29Ah> went to the largest supermarket in my village, took a look at sporty food shelf, the only amino acid isolate they have is glutamine:taurine 20:1, i wonder why
10:55 < jrayhawk> cobalamin production would be interesting
10:56 < L29Ah> but B12 is dirt cheap
10:58 < jrayhawk> cyanocobalamin is dirt cheap, but i don't see why anyone would want to try to reverse cyanide detox
10:59 < L29Ah> .t https://www.lifespan.io/news/low-dose-lithium-reverses-features-of-alzheimers-in-mice/
10:59 < saxo> Low-Dose Lithium Reverses Features of Alzheimer’s in Mice
11:00 < L29Ah> jrayhawk: there is tiny amount of cyanide in there, i don't think it is clinically relevant, and perhaps your better bet to reduce cyanide would be completely eliminating almonds
11:02 < jrayhawk> the way to reduce cyanide is to bind it to cobalamin and excrete it
11:03 < jrayhawk> https://scholar.google.com/scholar?q=lithium+AND+%28+arachidonic+acid+OR+docosahexaenoic+acid+OR+eicosapentaenoic+acid+%29 lithium seems to help stabilize arachidonic acid, but i haven't looked into it very hard
11:05 < L29Ah> i doubt it is the only good way to dispose of cyanide
11:07 < jrayhawk> if anyone can find a paper that makes mechanistic sense of why lithium's arachidonic acid results are so good and frequent where docosahexaenoic acid results are a lot more mixed, i would be curious to read it
11:09 < L29Ah> MuaddibLLM: how much of dietary linoleic acid gets converted into arachidonic acid?
11:09 < MuaddibLLM> gimme a sec, checking tracer studies for actual % conversion numbers
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11:09 < MuaddibLLM> Short answer: usually under 1% of dietary linoleic acid gets converted to arachidonic acid in adults - often ~0.2-0.7% and strongly modulated by FADS1/2 genotype, sex, and competing n-3 intake - so tissue AA tracks diet and remodeling more than de novo conversion (refs: https://pmc.ncbi.nlm.nih.gov/articles/PMC3494092/ , https://pmc.ncbi.nlm.nih.gov/articles/PMC4139254/).
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11:14 < L29Ah> https://pmc.ncbi.nlm.nih.gov/articles/PMC3494092/ black master race
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11:27 < kanzure> evidence for the xenotransplantation proposal above  seems to be flakey; the article relies on twin transplantation tolerance which is not very surprising or interesting, and a sheep-goat chimeric embryo surviving to term where sheep embryo implanted in goat (and vice versa) did not survive.
11:29 < kanzure> idea of transplanting animal fetal organs (before birth) seems like a reasonably good idea to try
11:32 < kanzure> the 1953 citation for "actively acquired tolerance" "describes how animals may acquire tolerance to skin grafts derived from genetically unrelated stocks following prenatal exposure to the donor's tissues", which is different because it requires the recipient to be prenatally exposed to the donor's tissues, instead of prenatally exposing the donor to the recipient's cells per his article.
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12:48 < kanzure> well, even if that article is bunk, i wonder if it would be a good idea to introduce xenogenic hematopoietic cells into human embryos or blastocysts under the theory that the human would later be tolerant to future xenogenic organ transplants from the same xenogenic source (well, the animal would be cloned a bunch, but you get the idea)
12:55 < kanzure> in utero transplantation of xenogenic hematopoietic cells may also be able to achieve the same effect without earlier blastocyst modification?
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17:07 < hprmbridge> kanzure> in-browser 15 MiB vision model using transformers.js https://huggingface.co/spaces/webml-community/dinov3-web
17:10 < hprmbridge> kanzure> text-to-speech demo https://huggingface.co/spaces/webml-community/KittenTTS-web
17:24 < hprmbridge> kanzure> 10 tokens/second from a phone in the browser isn't so bad https://huggingface.co/spaces/HuggingFaceTB/SmolLM2-1.7B-Instruct-WebGPU
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19:59 < hprmbridge> kanzure> jrayhawk, the slop machine says "Lithium consistently shows strong effects on the arachidonic acid (AA) pathway because it directly downregulates AA-specific enzymes like cPLA₂ and COX-2 at the transcriptional and protein level, which reduces AA turnover and signaling. This upstream targeting makes the results reproducible across studies. By contrast, docosahexaenoic acid (DHA) mainly acts within
19:59 < hprmbridge> kanzure> its own separate cascade and through altering membrane composition, where its influence on AA signaling is indirect and context-dependent. Because its effects depend heavily on factors like baseline n-6/n-3 balance and enzyme expression, DHA outcomes appear more variable and mixed compared to lithium."
20:34 < hprmbridge> Eli> Alzheimers research hasn't really produced anything other than a graveyard of pharma meds. So, I try to remain skeptical. But, I'm starting to wonder if we are going to start making progress. Seems like there are a number of interesting meds coming down the pipeline. https://youtu.be/DipVwic6pPI
20:37 < hprmbridge> Eli> Some data came out on the association between glp1 receptor agonists and dementia. It is strong enough to tell my relatives with dementia and metabolic disorder to get on it. https://www.youtube.com/watch?v=i9Nm84nqeWA
20:44 < hprmbridge> Eli> If glp1 ras and sglt2is have this kind of effect, it makes you wonder if you can go the other direction. Like, not having diabetes results in less dementia. Cool. What if I take it to the next level? What if I do lifestylemaxxing? How much could that delay alzheimers? If we could sell lifestylemaxxing in a pill, would that basically be the ultimate alzheimers treatment/prevention? Is dementia just
20:44 < hprmbridge> Eli> cognitive frailty that we can avoid by exercising our brain in the same way that we can avoid sarcopenia by exercising our muscles when we are young?
21:10 < jrayhawk> kanzure: why are you spamming useless AI garbage atme
21:14 < jrayhawk> what the hell do you mean Alzheimer's research hasn't produced anything? the most obvious stuff in the world that's been actively proposed going back to the 1960s is working fine. https://www.mdpi.com/2227-9059/12/8/1776
21:17 < jrayhawk> stuff like "if you want to reduce symptoms of a neuroinflammatory disease, maybe you should stop eating epithelial and endothelial chemokine receptor agonists three times a day"
21:24 < jrayhawk> and "maybe you should provide basic substrates for neuron construction and immunological signalling using preformed retinoids, docosahexaenoic acid, eicosapentaenoic acid, and choline instead of operating under the economically and politically convenient pretense that humans are herbivores like the USDA does"
21:45 < hprmbridge> Eli> I mean It hasn't produced much in terms of pharma medication. The success rate of clinical trials for alzheimers is particularly abysmal when compared to the success rate of trials for other diseases (100 failures in phase 2/3).
21:45 < hprmbridge> Eli>
21:45 < hprmbridge> Eli> The paper you are showing where they discuss "precision medicine" is probably a more scientific description than "lifestylemaxxing". But, I think they are basically the same. The paper describes the issues with pharma meds and basically talks about biohacking to reduce dementia: fix nocturnal hypoxia, metabolic fixing, etc ... That's pretty much in line with what I would expect. Basically, if we
21:45 < hprmbridge> Eli> can put lifestyle modification into a pill it would be the best selling pharma med of all time. Obciously, if you have a UTI, mycotoxin issue, heavy metal, etc ... I'm guessing those would not be super fun cognitively and you would need to address those in other ways. But yeah, I'm in agreement with you.
21:48 < jrayhawk> bredesen's and wahls' neuroinflammatory disease trials avoid straightforward branding in order to secure NIH funding
21:48 < jrayhawk> "personalized medicine" and MD-branded name protocols are infinitely less embarassing to the entire establishment than "paleo diet"
21:56 < jrayhawk> alzheimers pharmaceutical paradigms are largely taxonomically doomed from the start; amyloid and tau pathologies are just one specific manifestation of an underlying problem with neuroinflammation that's going to 90% disease substitute into something else when naively treated
21:59 < hprmbridge> Eli> Yeah, I think some people are starting to come around to that. The fraudulent/retracted amyloid papers probably were not great for society.
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22:01 < jrayhawk> i dunno, that's one place where two wrongs might make a right.
22:06 < jrayhawk> distrust that "alzheimers as taxonomically defined by amyloid plaques and tau tangles" is not actually useful (due to disease substitution) might be true and good; distrust that "alzheimers as taxonomically defined by amyloid plaques and tau tangles" is entirely epistemically false is probably wrong, but might produce the same set of implications as it merely being useless 
22:07 < jrayhawk> in that laymen can't understand the difference, but demand more holistic solutions cognitive decline either way
22:08 < hprmbridge> Eli> It would have been good for society to spend money on 100 medications that didnt fail phase 2/3. From that perspective, it wasn't great.
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--- Log closed Thu Aug 21 00:00:16 2025