--- Log opened Sun Feb 18 00:00:56 2018
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05:25 < kanzure> 20:54 < sipa> small writeup on communicating random ec points as bytes indistinguishable from random: https://gist.github.com/sipa/29118d3fcfac69f9930d57433316c039
05:25 < kanzure> http://icoboard.org/ "contains a Lattice FPGA with 8k LUT, 100MHz max clock, up to 8 MBit of SRAM and is programmable in Verilog by a complete open source FPGA toolchain."
05:39 < kanzure> some sort of anti-onetab tool (drag-and-drop bookmarks is somehow better?) https://chrome.google.com/webstore/detail/toby-for-chrome/hddnkoipeenegfoeaoibdmnaalmgkpip?hl=en
05:39 < kanzure> https://chrome.google.com/webstore/detail/the-great-suspender/klbibkeccnjlkjkiokjodocebajanakg?hl=en
05:40 < kanzure> https://addons.mozilla.org/en-US/firefox/addon/pile-lightweight-bookmarking/
05:54 < kanzure> .tw https://twitter.com/GATTAquant/status/964059678727720961
05:54 < yoleaux> Quantifying Expansion Microscopy with DNA Origami Expansion Nanorulers https://doi.org/10.1101/265405 #ExM #nanoruler https://pbs.twimg.com/media/DWEHADGX0AA_H40.png (@GATTAquant)
05:55 < kanzure> .tw https://twitter.com/neuroecology/status/964526195663605760
05:55 < yoleaux> Learning DEEP in the brain - what would a biological deep learning really look like? By @Pieters_Tweet (Spoiler alert: it gets pretty damn complicated) http://sci-hub.la/10.1038/nrn.2018.6 https://pbs.twimg.com/media/DWKvSHTXUAAW-ag.jpg https://pbs.twimg.com/media/DWKvSylW0AAIysz.jpg (@neuroecology)
05:55 < kanzure> .tw https://twitter.com/rbhar90/status/963971648050180096
05:55 < yoleaux> This is one of the coolest deep bio papers I've seen recently! Directly predicts protein structure from sequence using the trick that a sequence of torsional angles encodes the 3D geometry https://twitter.com/fischer_cr/status/963966254401732608 (@rbhar90)
06:20 < kanzure> .title https://www.youtube.com/watch?v=c4slzFdykpc
06:20 < yoleaux> Dev++ | Thaddeus Dryja - Lightning Network and Discreet Log Contracts - YouTube
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10:33 < emeraldgreen> https://doi.org/10.1101/265231
10:57 < kanzure> .title
10:57 < yoleaux> End-to-end differentiable learning of protein structure | bioRxiv
11:10 < fenn> it's all over teh interwebs
11:11 < fenn> is this paper as big of a deal as it looks at first glance?
11:14 < fenn> also, i can't remember the last time i saw a science paper with one author
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11:23 < kanzure> gp-write is doing nth rewrite of tech roadmap for dna design, synthesis, editing, assembly, packaging, delivery
11:24 < kanzure> this time they want the "unknown or impossible" things to be in their own list
11:24 < kanzure> so i'm trying to think of particularly impossible things
11:25 < fenn> infinite improbability drive...
11:26 < kanzure> someone else contributed "in vivo programmable dna synthesis" but all the others are mine so far :-|
11:26 < kanzure> "in vivo dna synthesis" is not particularly impossible; it's extremely difficult but i wouldn't say impossible.
11:32 < fenn> also it would be really useful
11:34 < kanzure> near the "impossible" category should be things more like..... gas phase.
11:34 < fenn> matter lazer
11:34 < kanzure> shoots out lased matter in the form of dna?
11:34 < fenn> yeah, also it's exactly the sequence you want
11:35 < fenn> also teleports through walls etc
11:35 < fenn> quantum tunneling dna superconductor
11:36 < fenn> mix and match buzzwords until satisfied
11:36 < fenn> i don't really see the point of this exercise
11:36 < kanzure> i think (fast) dna synthesis is mostly solved so as long as we don't need hyper low error rates
11:36 < kanzure> well, i think they want impossible things that aren't impossible. i mean that's the only thing i can think of.
11:36 < fenn> perhaps you should write a list of really awesome and desirable technologies that have no obvious critical path (yet)
11:36 < kanzure> just "impossible" according to 80 year-old biologists
11:40 < kanzure> to my horror i still get questions like "why would you need to write a completely new genome every single day?"
11:40 < kanzure> "nobody needs that"
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13:24 < kanzure> .title https://www.youtube.com/watch?v=HNjpsQorvco
13:24 < yoleaux> Reversing Aging - 2018 update - YouTube
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14:59 < kanzure> "Extended longevity in mice lacking the insulin receptor in adipose tissue" http://mcb.berkeley.edu/courses/mcb135k/Discussion/572.pdf
15:04 < kanzure> yashgaroth: i am trying to convince jrayhawk to propose some metabolism gene therapy things
15:04 < yashgaroth> that paper looks interesting
15:04 < yoleaux> 16 Feb 2018 00:22Z <kanzure> yashgaroth: we should do opiod receptor density downregulation
15:04 < kanzure> like an inducible switch to temporarily turn off insulin production, and another switch to make your liver to gobble glucose at a higher rate, or something
15:05 < kanzure> unfortunately i do not currently have the full human metabolism network in my memory
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15:07 < yashgaroth> why you wanna turn off insulin production
15:07 < kanzure> don't want cells using no blood glucose
15:07 < kanzure> *any
15:07 < yashgaroth> but glucose has got what cells crave, especially neurons
15:08 < kanzure> they can survive on ketone bodies
15:09 < kanzure> i should emphasize that i mean temporary (so either inducible on/off, or not long-term integration or don't target stem cells)
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15:10 < kanzure> welp nevermind "levels of ketone bodies are regulated mainly by insulin and glucagon"
15:11 < kanzure> tangled web. hmm.
15:11 < yashgaroth> yeah you start digging at it keeps going
15:12 < yashgaroth> most glycogen is stored in muscle, some in liver...luckily those are the two easiest targets for AAV
15:13 < streety> what's the objective?
15:14 < kanzure> propose a gene therapy for fat burning and/or adipose tissue destruction and/or i'm not creative enough to pose the objective correctly
15:15 < kanzure> like, if i say "fat burning", then that really constrains things but i don't want that.    it would be interesting to have fat storage only work under an inducible promoter. that would be interesting.
15:15 < kanzure> the objective is "fun gene therapy things related to human metabolism and nutrition"
15:17 < streety> related themes would be inhibiting glucose absorption or speeding elimination
15:17 < streety> such as the sglt2 inhibitors in the kidney
15:17 < kanzure> by elimination you mean into waste?
15:17 < streety> urine
15:17 < kanzure> are there any disorders where the kidney dumps too much glucose straight to urine?
15:18 < streety> not sure, presumably any loss of function in sglt2 would work
15:18 < streety> not something I have looked into
15:19 < kanzure> "The renal effects of SGLT2 inhibitors and a mini-review of the literature" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298360/
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15:21 < kanzure> makes sense if you're shooting up sugar basically "Their most frequent adverse events are minor: genital and urinal tract infections"
15:22 < streety> increasing tolerance for cold followed with cold exposure would also be an option, brown fat should develop without needing to be forced
15:22 < streety> yeah, plenty of food for bacteria so bacteria are more likely to grow
15:25 < kanzure> unclear the magnitude of effect here
15:25 < kanzure> instead of inhibitors you could also downregulate the expression of sglt2 which might have a stronger impact
15:27 < streety> yeah, I assumed you were looking to go in that direction
15:28 < streety> the disadvantage is that with the inhibitors being available a gene therapy is harder to justify
15:29 < kanzure> editing and screwing up a single kidney isn't the end of the world for a person, so this is an interesting target
15:30 < kanzure> i briefly looked up one of the inhibitors (tofogliflozin?) and over 8 weeks there was only like a 3 lbs measured difference on a cohort
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15:43 < mrdata> (tofogliflozin?)!?
15:43 < mrdata> that should not be allowed to be a real name
15:44 < kanzure> biology is awful like this
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16:04 < streety> pharmaceutical companies are awful like that
16:04 < streety> no biological basis that I know about
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17:06 < kanzure> also we could do regulation of fatty acid transporters
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17:12 < kanzure> (temporary) overexpression of lysosomal lipase, hormone-sensitive lipase (triglyceride lipase), adipose triglyceride lipase, diglyceride lipase, monoglyceride lipase
17:12 < kanzure> "Only the initial enzyme is affected by hormones, hence its hormone-sensitive lipase name. The diglyceride and monoglyceride enzymes are tens to hundreds of times faster, hence HSL is the rate-limiting step in cleaving fatty acids from the triglyceride molecule.[10][11]"
17:13 < kanzure> or the activation mechanism of hormone-sensitive lipase: "phosphorylated perilipin A causes it to move to the surface of the lipid droplet, where it may begin hydrolyzing the lipid droplet"
17:13 < kanzure> ugh "Other lipases include LIPH, LIPI, LIPJ, LIPK, LIPM, LIPN, MGLL, DAGLA, DAGLB, and CEL."
17:13 < kanzure> of course not "There also are a diverse array of phospholipases, but these are not always classified with the other lipases"
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17:22 < kanzure> this study found that hormone-sensitive lipase is not a required factor for hydrolysis of triacylglycerols http://www.pnas.org/content/97/2/787.short
17:24 < kanzure> "severe hypertriglyceridemia" and neonatal death in lipoprotein lipase knockout mice https://dm5migu4zj3pb.cloudfront.net/manuscripts/118000/118319/JCI95118319.pdf
17:26 < kanzure> oh, well that might just be due to dietary intake
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17:27 < kanzure> "Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance" http://www.pnas.org/content/98/13/7522.short
17:33 < kanzure> "Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity" http://www.jbc.org/content/279/9/7521.short
17:33 < kanzure> there we go.
17:36 < kanzure> something something glycyrrhizic acid from glycyrrhiza glabra shrubs https://lipidworld.biomedcentral.com/articles/10.1186/1476-511X-9-81 for lipoprotein lipase expression level improvement
17:37 < kanzure> "Gene therapy for lipoprotein lipase deficiency: working toward clinical application" (2005) http://umh3625.edu.umh.es/wp-content/uploads/sites/882/2015/03/5.-Gene-Therapy-for-lipoprotein-lipase-deficiency.pdf
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17:41 < kanzure> "Topical application of capsaicin reduces visceral adipose fat by affecting adipokine levels in high-fat diet-induced obese mice" http://onlinelibrary.wiley.com/doi/10.1002/oby.20246/full
17:41 < kanzure> haha capsaicin
17:44 < kanzure> wut "Capsaicin is commonly applied topically to reduce aches and burning feelings, the frequently reported symptoms of painful neuropathy (14). It is currently used in topical creams and high-dose dermal patches to relieve the pain of peripheral neuropathies such as postherpetic neuralgia caused by shingles, and can be directly applied to abdominal skin with no side effects in animal models ...
17:44 < kanzure> ...and humans (15,16)."
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17:57 < kanzure> "Maximum tolerable dose of red pepper decreases fat intake independently of spicy sensation in the mouth" https://www.ncbi.nlm.nih.gov/pubmed/15182402?dopt=Abstract
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18:04 < kanzure> bodybuilding.com users talking about chugging DMSO
18:10 < kanzure> "Increasing adipocyte lipoprotein lipase improves glucose metabolism in high fat diet-induced obesity" http://www.jbc.org/content/290/18/11547.short
18:12 < kanzure> "We made a transgenic mouse in which the adiponectin (Adipoq) promoter drives expression of lipoprotein lipase (LPL) in adipocytes to potentially increase adipose tissue lipid storage [....] Adipoq-LPL mice did not gain more fat mass on HFD than control mice"
18:12 < kanzure> why does it say increase and not decrease?
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18:18 < kanzure> "Overexpression of hormone-sensitive lipase prevents triglyceride accumulation in adipocytes" https://www.jci.org/articles/view/117967
18:23 < kanzure> "ATGL and HSL are not coordinately regulated in response to fuel partitioning in fasted rats" https://www.sciencedirect.com/science/article/pii/S0955286310000781
18:23 < kanzure> (adipose triglyceride lipase)
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18:26 < kanzure> adipose triglyceride lipase stuff https://www.tugraz.at/fileadmin/user_upload/Institute/IBC/Publications/Fatmobilizationinadiposetissueispromoted.pdf    and http://www.jlr.org/content/50/1/3.short
18:27 < kanzure> for some reason "CGI-58" is the name of this lipase's activator -_-
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18:30 < kanzure> here, a team overexpressed an inhibitor of this lipase http://www.jbc.org/content/289/4/1905.short   "these results indicate that fat-specific G0S2 overexpression uncouples adiposity from insulin sensitivity and overall metabolic health through inhibiting adipose lipolysis and decreasing circulating fatty acids"
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18:33 < kanzure> "Perilipin overexpression in mice protects against diet-induced obesity" http://www.jlr.org/content/51/5/975.short
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18:36 < kanzure> "Adipose-selective overexpression of ABHD5/CGI-58 does not increase lipolysis or protect against diet-induced obesity" http://www.jlr.org/content/52/11/2032.short
18:36 < kanzure> grr.
18:36 < kanzure> which one was the overexpression of lipid droplet marker protein things?
18:39 < kanzure> "Targeted inhibition of galectin 1 by thiodigalactoside dramatically reduces body weight gain in diet-induced obese rats" https://www.nature.com/articles/ijo201574
18:39 < kanzure> ".. Our animal experiment revealed that intraperitoneal injection of TDG (5 mg kg−1) once per week for 5 weeks in Sprague-Dawley (SD) rats resulted in dramatic inhibition of HFD-induced body weight gain (27.3% reduction compared with HFD-fed controls) by inhibiting adipogenesis and lipogensis as well as by increasing expression of the proteins associated with thermogenesis and energy ...
18:39 < kanzure> ...expenditure"
18:39 < kanzure> (that's not the one i was thinking of.)
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18:43 < kanzure> "Targeted deletion of adipocyte Abca1 (ATP-binding casette transporter a1) impairs diet-induced obesity" http://atvb.ahajournals.org/content/early/2018/01/17/ATVBAHA.117.309880.short
18:44 < kanzure> ok it was the perilipin paper that had the lipid droplet phosphoprotein marker overexpression trick
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19:00 < kanzure> page 4 of the perilipin paper is such crap. turns out it didn't work for male mice so their claims in the paper are about the female mice only -_-.
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19:04 < kanzure> oh well. and it was high fat diet only anyway, not particularly impressive.
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19:28 < kanzure> maybe something really simple, like adipocyte-only conditional expression of apoptosis
19:31 < kanzure> not sure where the fats go though in that context..
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20:24 < kanzure> hmm.
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20:51 < kanzure> "Regulation of Ketone Body Metabolism and the Role of PPARα" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187893/
20:55 < kanzure> "Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities" http://www.jbc.org/content/277/10/8635.short
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20:57 < kanzure> here is one that increases thermogenesis in brown adipose tissue for similar effect https://www.nature.com/articles/ng1225
20:59 < kanzure> "Paradoxical resistance to diet-induced obesity in UCP1-deficient mice" https://www.jci.org/articles/view/JCI15737
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21:02 < kanzure> Ren1c knockout https://www.sciencedirect.com/science/article/pii/S155041310700304X
21:04 < kanzure> "Mice lacking ghrelin receptors resist the development of diet-induced obesity" https://www.jci.org/articles/view/26002
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21:09 < kanzure> "Adipose overexpression of desnutrin promotes fatty acid use and attenuates diet-induced obesity" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661591/
21:09 < kanzure> does this conflict with the "ABHD5/CGI-58" result from earlier?
21:11 < kanzure> oh, "Abhydrolase domain 5 (ABHD5) increases ATGL activity by an unknown mechanism"
21:11 < kanzure> so they did not directly test overexpression of adipose triglyceride lipase
21:13 < kanzure> "We and others have recently identified a TAG lipase that belongs to the patatin-like domain-containing family of proteins (5–7). We named this enzyme desnutrin (also called PNPLA2, adipose triglyceride lipase, TTS2.2, and iPLA2ζ) because it is induced during a low nutritional state in mice (i.e., fasting) and it belongs to the same patatin-like domain-containing family as another ...
21:13 < kanzure> ...nutritionally regulated protein, adiponutrin."
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21:17 < kanzure> "The G0/G1 switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase" https://www.sciencedirect.com/science/article/pii/S1550413110000306
21:17 < kanzure> "Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for triacylglycerol (TAG) hydrolysis in adipocytes. The precise mechanisms whereby ATGL is regulated remain uncertain. Here, we demonstrate that a protein encoded by G0/G1 switch gene 2 (G0S2) is a selective regulator of ATGL. G0S2 is highly expressed in adipose tissue and differentiated adipocytes. When overexpressed in HeLa ...
21:17 < kanzure> ...cells, G0S2 localizes to lipid droplets and prevents their degradation mediated by ATGL. Moreover, G0S2 specifically interacts with ATGL through the hydrophobic domain of G0S2 and the patatin-like domain of ATGL. More importantly, interaction with G0S2 inhibits ATGL TAG hydrolase activity. Knockdown of endogenous G0S2 accelerates basal and stimulated lipolysis in adipocytes, whereas ...
21:17 < kanzure> ...overexpression of G0S2 diminishes the rate of lipolysis in both adipocytes and adipose tissue explants. Thus, G0S2 functions to attenuate ATGL action both in vitro and in vivo and by this mechanism regulates TAG hydrolysis."
21:19 < kanzure> more perilipin stuff (apparently there are different perilipins) http://www.jbc.org/content/286/18/15707.short
21:21 < kanzure> ah here is a good review,
21:21 < kanzure> "Adipocyte lipases and lipid droplet-associated proteins: insight from transgenic mouse models" https://www.nature.com/articles/ijo2011113
21:22 < kanzure> am i missing something obvious like "just do overexpression of something that will massively increase thermogenesis"?
21:23 < kanzure> wasn't there a drug on the market that caused that, and people died, and other people thought hmm let's not do that
21:23 < kanzure> some sort of melting drug
21:24 < kanzure> .wik 2,4-dinitrophenol
21:24 < yoleaux> "2,4-Dinitrophenol (2,4-DNP or simply DNP) is an organic compound with the formula HOC6H3(NO2)2. It is a yellow, crystalline solid that has a sweet, musty odor. It sublimes, is volatile with steam, and is soluble in most organic solvents as well as aqueous alkaline solutions." — https://en.wikipedia.org/wiki/2,4-dinitrophenol
21:27 < kanzure> https://www.theguardian.com/science/the-h-word/2014/feb/06/dnp-deadly-weight-loss-drug-science-history
21:31 < kanzure> "In the 1980s Bachynsky eventually set up a series of weight loss clinics that promoted DNP as a method of treatment for obesity. He treated 14,000 patients before the FDA issued an injunction preventing further use of DNP."
21:31 < kanzure> ~injunctioned~
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