--- Log opened Wed Apr 05 00:00:18 2017
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06:20 < superkuh> http://science.sciencemag.org/content/355/6331/eaaj1497 - guy figures out a way to record the potentials from tiny dendrites in live animals. Basically, four electrodes and the slipping the dendrite in between them then an immune responses of the glia closes off the entire setup.
06:22 < superkuh> "The dendrites generated several-fold more spikes than the soma. The large dendritic spike rates could be responsible for the seemingly weak correlations between the somatic spikes across neurons. This requires a revision of many prevailing beliefs, for example, the dendrites are largely passive in vivo, and the somatic spike is the fundamental unit of neural computation."
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06:34 < kanzure> .title
06:34 < yoleaux> Dynamics of cortical dendritic membrane potential and spikes in freely behaving rats | Science
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06:37 < superkuh> If it's not just some weirdness caused by the glia sealing things off (maybe changing internal ion concentrations, or anything really) then it'd be a big news paper.
06:38 < superkuh> I'm not done reading the full text yet.
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07:37 < kanzure> "Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity" http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2000698 https://twitter.com/KFSHRC_Research/status/849471717063917568
07:37 < kanzure> ".. we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts"
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07:39 < kanzure> http://pdbe.org/latest
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09:15 < nmz787_i> dnascript.co never loads for me
09:18 < kanzure> there's really nothing on there except something about "divide error rate by 500, divide synthesis time by 50, divide synthesis cost by 10,000"
09:19 < kanzure> and then some peoplefaces
09:21 < kanzure> nmz787_i: http://www.google.us/patents/WO2015159023A1?cl=en
09:23 < kanzure> musics https://www.youtube.com/watch?v=Zy7V5DXUhCM
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09:53 < nmz787_i1> hi chris_99
09:55 < chris_99> hey, manage to get anywhere with your electroporator?
09:55 < yoleaux> 02:46Z <nmz787_> chris_99: : you may see this by the time you get this message: http://hackaday.com/2017/04/04/edm-for-the-cheap-and-adventurous/
09:56 < chris_99> oh cool let me check
09:56 < chris_99> neat
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10:13 < nmz787_i1> chris_99: nah I haven't even ordered the new components... I was waiting to hear back from the EE who built the board, and just got lazy about ordering
10:13 < nmz787_i1> been playing with SAT solvers again since last Friday, for PCB board routing (or other routing)
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10:17 < chris_99> ooh neat
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10:25 < cevi_> so, how "doable" is protein design? I have a specific thing I want to make a protein to do, but I'm getting the impression this might be harder than I originally anticipated
10:28 < cevi_> my goal is to make a protein that takes three strands of DNA, and makes a new strand of DNA where each nucleotide of the output is determined by a majority vote of the three input strands
10:29 < nmz787_i> cevi_: totally doable, I'd pencil out at least 10-20 years of research
10:29 < kanzure> you can make a protein that can bind to three strands of dna, or at least has three different dna recognition sites or pores that strongly bind to dna, but the poylmerization part and consensus vote part is currently impossible for the most part
10:30 < kanzure> as for ratcheting along three strands, that's probably not known, other than the typical polymerase ratcheting mechanisms, which sort of involve an entire movement of the whole enzyme during its normal polymerization activity
10:30 < nmz787_i> maybe 20-40 years.... actually, depending on if you are working alone or not
10:31  * nmz787_i just realized I've almost been at this stuff for 10 years
10:32 < kanzure> cevi_: here's a bunch of papers about polymerase, read them all: http://diyhpl.us/~bryan/papers2/polymerase/
10:33 < cevi_> sweet
10:34 < cevi_> also - would this need a ton of special software? I have a hard time imagining that "standard" protein simulation software would also simulate interactions with DNA
10:34 < kanzure> protein simulation software is extremely slow, and only simulates what we already know, if you're inventing something new then you need to do it with actual biology
10:35 < kanzure> dna binding pockets on proteins can be simulated to some extent, but dna (especially dna that we're interested in) tends to be a really huge molecule
10:35 < kanzure> why do you want a vote?
10:36 < cevi_> the cover story is to eliminate rare genetic diseases
10:36 < cevi_> or to do error correction
10:36 < kanzure> error correction mechanisms exist already, by looking at template strands, these are really high fidelity actually
10:36 < kanzure> and can be further optimized if you'd like, using highly conventional laboratory techniques
10:37 < cevi_> the real reason is that I was intrigued by the mathematical model for genetic effect on intelligence described here: https://arxiv.org/abs/1408.3421
10:37 < kanzure> some polymerases literally have error correction modules on their butts, and they go back over the same segment if they make an error
10:37 < kanzure> .title
10:37 < yoleaux> [1408.3421] On the genetic architecture of intelligence and other quantitative traits
10:38 < kanzure> cevi_: here we document a bunch of intelligence/memory-related mutations that you'll be interested in, http://diyhpl.us/wiki/genetic-modifications/
10:38 < cevi_> the short version is that apparently for most genes related to intelligence, 90% of humans have the good version and 10% have the bad version
10:38 < kanzure> cevi_: however, these will at most confer only a standard deviation or two in memory capacity, whereas i think we have an alternative (non-genetic) method that might do 10-100x
10:39 < kanzure> (well it's not fair to call it non-genetic.... i should call it non-genomic.)
10:39 < cevi_> intriguing
10:39 < kanzure> cevi_: page 15 http://diyhpl.us/~bryan/irc/2017-02-03-beacon.pdf#page=15
10:40 < kanzure> we can also do the same technique for hippocampus size
10:40 < kanzure> also this does not require 40 years of molecular biology research....
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10:42 < cevi_> ooh, and this ties back into the ultimate goal of making superinteligent mice
10:42 < cevi_> *intelligent
10:43 < kanzure> well we have to do it in mice because people get angry when you do it in people, during development
10:43 < kanzure> later you apply it to chimpanzees and then eventually to people
10:44 < cevi_> why bother with the last two steps? are superintelligent humans preferable to superintelligent mice?
10:44 < kanzure> unknown
10:45 < nmz787_i> unless the chimps take over before we can apply it to ourselves
10:45 < nmz787_i> https://frinkiac.com/caption/S05E15/451016
10:45 < kanzure> we really should have never let you find out about frinkiac
10:46 < nmz787_i> "I'LL FIELD THIS ONE. THE ONLY DANGER IS... IF THEY SEND US TO THAT TERRIBLE PLANET OF THE APES. WAIT A MINUTE. STATUE OF LIBERTY. THAT WAS OURPLANET!"
10:46 < nmz787_i> haha
10:46 < nmz787_i> it is great
10:46 < nmz787_i> basically my version of 'OK Google' or Siri
10:47 < nmz787_i> have you seen the movies about the super smart rats that kill for the owner?
10:47 < cevi_> nope
10:47 < nmz787_i> the title was a guy's name
10:47 < kanzure> cevi_: do you have additions for this page? http://diyhpl.us/wiki/genetic-modifications/
10:47 < nmz787_i> willard
10:47 < nmz787_i> 1971 and 2003
10:47 < nmz787_i> I seem to recall the 70s version was better
10:47 < kanzure> cevi_: i think you'll like WWC1/rs17070145
10:48 < cevi_> I don't have any modifications - the whole point of the majority vote idea is to consolidate all the good genetic mutations without needing to figure out what they are
10:49 < nmz787_i> unless you apply it to someone with a bunch of double-copies of shit genes
10:49 < kanzure> cevi_: so why not just do that in silico, then manufacture the genome using chemical dna synthesis? you know, other than cost...
10:49 < cevi_> the cost was the reason
10:49 < kanzure> also, genomes are not mutually aligned
10:49 < kanzure> you can't get a consensus vote like that
10:50 < cevi_> yeah, there would need to be some sort of slignment correction of something
10:50 < cevi_> *alignment
10:51 < cevi_> hypothetically, if we knew how to make such a protein, the cost would be trivial
10:51 < cevi_> so I was hoping the design could all be done on a computer
10:51 < kanzure> so, the real problem is dna synthesis cost
10:52 < cevi_> yeah
10:52 < kanzure> we need cheap genome synthesis, at less than $1/genome
10:52 < kanzure> this would give us direct access to molecular nanotechnology
10:52 < cevi_> or dna modification cost - if we could start with a human genome and then modify it in a million places cheaply that would be nice
10:52 < nmz787_i> cevi_: simulations are really slow
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10:53 < kanzure> cevi_: we've been thinking about a dna synthesis machine, we could do 100 million drops/second of reactions http://diyhpl.us/wiki/dna/synthesis/notes/
10:53 < nmz787_i> cevi_: ideally you would come up with a new way to simulate bio models, which was immensely faster but also correct (or correct enough)
10:54 < nmz787_i> cevi_: which could be using real cells, and some clever DNA tricks
10:54 < nmz787_i> cevi_: ideally though, you would recombine existing knowledge into something new... rather than engineering a new protein
10:55 < nmz787_i> there is a lot of solution space that hasn't been explored, as far as all the existing technology we have available (bio and non-bio tech)
10:55 < kanzure> dna synthesis is the bottleneck for this and many, many other projects.
10:56 < nmz787_i> hmm: https://www.infona.pl/resource/bwmeta1.element.ieee-art-000005361301
10:56 < nmz787_i> .title
10:56 < yoleaux> SAT-based protein design
10:56 < nmz787_i> http://ieeexplore.ieee.org/document/5361301/
10:57 < nmz787_i> same I guess, but with text
10:58 < nmz787_i> cevi_: personally I want to play with SAT solvers for some protein design ideas
10:59 < nmz787_i> there was a big push yesterday to MonoSAT... adding a simple planar PCB routing demo
10:59 < kanzure> btw here's some stuff on protein design http://diyhpl.us/~bryan/papers2/bio/protein-engineering/
11:00 < nmz787_i> I've got a 3D example that does pretty well at this point, want to add diff-pairs and length-matching next... as well as a mode for pin-breakout (i.e. a source can terminate at any edge-location around the border/edge of the PCB)
11:01 < nmz787_i> https://gist.github.com/nmz787/10c60e76941a8e5de624454666ea65b3
11:01 < cevi_> I hadn't heard of MonoSAT before
11:01 < cevi_> just glucose and lingeling
11:02 < kanzure> cevi_: how did you find us?
11:02 < cevi_> r/rational linked to your page
11:02 < kanzure> oh the lesswrong people?
11:02 < cevi_> it's mostly a reddit for fiction
11:02 < cevi_> that claims to be rational
11:03 < cevi_> I was also in the process of searching for biohacking groups
11:03 < kanzure> in other words this is all very unlikely
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11:05 < cevi_> oh, I see - MonoSAT is one of those solvability modulo theories things
11:05 < nmz787_i> cevi_: I've used pycoSAT, miniSAT, cryptoMiniSat... and maybe tried a few others
11:06 < nmz787_i> well they all offer plain-jane boolean SAT too... just add a bunch of helpers so you don't have to generate commonly-used complex-clauses yourself
11:06 < nmz787_i> and also MonoSAT has some graph reasoning added
11:06 < nmz787_i> cryptoMiniSat has XOR added, for better performance
11:09 < cevi_> this SAT-solver approach seems to assume that you've already got the general protein design laid out
11:09 < nmz787_i> I'd want to use it for reverse-design, I guess it might be called
11:09 < kanzure> basically the only way you are going to get a consensus polymerase to work is if you put three polymerases next to each other so that their active sites are basically touching
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11:10 < kanzure> and then you would need to treat them as coenzymes or as a dimer or whatever it's called
11:10 < nmz787_i> i.e. in your case, set the positions of the DNA binding pockets, set the position for the 'backbone' you want all the appendage motifs to attach to... then solve for everything in-between, within some constraints (like balancing acid and base side-chains)
11:11 < kanzure> if you use a dimer or trimer (grr what's the word), then you are reducing your problem to merely modifying a single polymerase to interact with two counterparts, you keep most of the existing protein as best you can
11:11 < cevi_> I like the name "consensus polymerase"
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11:12 < cevi_> reusing existing proteins does seem to be the way to go here
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11:14 < jcorgan> oligomer
11:14 < nmz787_i> what is the IRC message char limit?
11:15 < kanzure> 500ish?
11:15 < kanzure> 512
11:15 < nmz787_i> that seems to match what I see
11:15 < nmz787_i> "Recall, each rotamer rk?{r1,...rm} corresponds to an assignment of an amino acid and its dihedrals to a particular position. For the basic SAT encoding of our protein optimization approach, we simply use Boolean variables rk to reflect the inclusion of the rotamer in the protein design. The assignment rk= true indicates that rotamer rk has been selected for its position, whereas rk= false means it has not been selected."
11:16 < nmz787_i> basically what I had been thinking
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11:29 < cevi_> how do dna error-correction mechanisms work? that seems like a rather similar function to consensus voting
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11:34 < cevi_> I'm imagining using two strands of dna to decide when to "repair" the third to agree with them whenever they agree with each other
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11:50 < kanzure> cevi_: some error correction mechanisms have been well-characterized, to the point that there are animations in youtube videos that will explain this
11:50 < kanzure> there are even more exotic implementations too, see "dna repair" stuff
11:51 < kanzure> btw not all poylmerases have error correction tails
11:52 < kanzure> cevi_: maybe this one https://www.youtube.com/watch?v=v8gH404a3Gg
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12:24 < nmz787_i> "The source code of our tool ProtSAT and all data used for the experiments have been released for research purposes and can be downloaded at https:llsourceJorge.netlprojectslprotsat. This work was supported by an NSF CAREER award (MCB-0744541) to T.K."
12:25 < nmz787_i> I never liked the quality of code over on sourceJorge... source
12:25 < nmz787_i> https://sourceforge.net/projects/protsat
12:25 < kanzure> you pronounce it source jorge?
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12:26 < nmz787_i> haha, nah I was joking about the paper having that typo in it
12:26 < nmz787_i> wtf, that repo seems empty
12:27 < nmz787_i> that has to be a violation of NSF or something
12:28 < kanzure> nsf.gov armed agents will be descending from helicopter any minute now
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12:38 < nmz787_i> well, just emailed what I think might be that author's email address
12:40 < nmz787_i> well, that failed quickly
12:40 < cevi_> email bounced?
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12:55 < nmz787_i> yeah
12:55 < nmz787_i> tried a pattern I found for cadence.com
12:59 < kanzure> cevi_: what is your background skillset?
13:00 < cevi_> cs and math
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15:12 < kanzure> "BIP proposal: Inhibiting a covert attack on the Bitcoin PoW function" https://lists.linuxfoundation.org/pipermail/bitcoin-dev/2017-April/013996.html
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15:45 < kanzure> and https://www.reddit.com/r/Bitcoin/comments/63otrp/gregory_maxwell_major_asic_manufacturer_is/
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16:04 < kanzure> cevi_: you could probably split dsDNA into ssDNA and then do error correction and repair based purely on one of the strands, then you do it a second time against another ssDNA from another genome.   you repeat for however many times you want, at the end you should have a statistically averaged genome i think.
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16:09 < cevi_> so, if we just focus on one particular nucleotide, let's say two of the genomes have the good choice and one has the bad choice - I think at the end of your procedure, you will have a 1/3 chance of having the bad choice there
16:10 < cevi_> which is not better than just picking one of the three original strands at random
16:11 < cevi_> I want to make an argument along the lines of "there is no way to achieve the desired effect by doing stuff with only two pieces of dna at a time", but in fact that is clearly false
16:11 < cevi_> since you can build any circuit out of gates which each take two inputs
16:13 < kanzure> yea you need them to be weighted or something
16:13 < kanzure> maybe add a methyl group to nucleotides that had consensus the last pass, and then see if the nucleotide matches the next strand, and check whether it is methylated
16:14 < kanzure> on a related fun note, "Epigenetic editing of Ascl1 gene in neural stem cells by optogenetics" http://www.nature.com/articles/srep42047
16:15 < cevi_> oh, I like that idea
16:18 < kanzure> we have a draft paper in here that we've been working on, for an electronically and optically controlled polymerase enzyme, a "digital polymerase" as it were. it's not what you're looking for, but hyper-cheap genome synthesis solves a bunch of your problems.
16:19 < cevi_> genome synthesis would be a better solution
16:20 < kanzure> basically the method for an optically controlled polymerase would involve lots of azobenzene molecules and friends, which are optically switchable and can change protein conformation... but the exact conformational changes required for 5-bit control aren't known yet (2 bits for nucleotide choice, then a few other bits probably required for stop/go/move/forwards/backwards/etc).
16:23 < cevi_> how close is this to being a real thing people can build/use?
16:23 < kanzure> haha
16:23 < kanzure> well, if you want real shit, that's more the direction of inkjet genome synthesis like http://diyhpl.us/wiki/dna/synthesis/notes/
16:24 < kanzure> as for digital polymerase, we have a professor at georgia university and a phd student looking at the problem (for electronic control, not optical control)
16:24 < kanzure> i would expect electronic/optical control of polymerase to take a number of years
16:24 < kanzure> like.. more than five.
16:25 < cevi_> shucks
16:25 < kanzure> inkjet oligonucleotide synthesis is much more near-term practical, the problem with inkjetting is DNA assembly (combining the molecules into a final genome)
16:26 < kanzure> my other problem has been finding and hiring a damn chemist to debug the machine!
16:26 < kanzure> apparently "work for shady irc channel" is just not an appealing job description to most chemists, *shrug*
16:27 < cevi_> no mad scientists in chemistry?
16:27 < cevi_> weird
16:27 < kanzure> well this place is sort of next level mad, i guess.
16:27 < kanzure> logarithmically mad science
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18:08 < kanzure> .tw https://twitter.com/ferdousbhai/status/849760500456054784
18:08 < yoleaux> This guy reverse engineered a mining chip to discover ASICBOOST while trolling people 24/7 on reddit and contributing to Bitcoin Core. (@ferdousbhai, in reply to tw:849760389147525124)
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18:55 < kanzure> yashgaroth: yo
18:55 < yashgaroth> hey
18:55 < kanzure> check backlog re: consensus polymerase? cevi_ wants to make a consensus genome by using a polymerase enzyme (or something) rather than doing de novo synthesis.
19:00 < yashgaroth> I don't get how it would allow one to "consolidate all the good genetic mutations"...if you wanted to do it without solving the protein folding problem, there's plenty of mismatch endonucleases that'll cleave incorrect bases
19:00 < yashgaroth> then you theoretically just mix them all together until the minority nucleotides at that position are degraded
19:01 < kanzure> yes so it should work in vitro in bulk, i think..
19:01 < kanzure> but as far as i can tell, it would jus tmake the popular alleles float to the top
19:01 < kanzure> (metaphorically)
19:01 < yashgaroth> isn't that their goal anyway?
19:01 < yashgaroth> I don't know how it leads to hyperintelligent mice or w/e
19:02 < kanzure> i dunno... chromosomes are not aligned like this, between two members of same species the same chromosome is not guaranteed to have similar dna junk at similar positions.
19:02 < yashgaroth> oh no it'd be a massive clusterfuck, kinda breaks down at the genome scale
19:02 < kanzure> lotta random chunks of chromosomes copied everywhere, right?
19:03 < yashgaroth> I mean maybe chop them into manageable pieces with restriction enzymes, then separate and merge later
19:04 < kanzure> ok, sure, you could restrict it to genomes where you know everything looks mostly the same, like families
19:05 < yashgaroth> mhm, but if you want some sort of cage match between the genomes of the smartest people until you get some magic result, I suppose that's out
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19:08 < yashgaroth> using a triplex polymerase & genome for error correction is a pipe dream of mine, since right now a mutation can't really be corrected; but it doesn't exist in nature since evolution would move super slowly for the organism
19:09 < kanzure> do you know about error correction codes, like FEC etc?
19:10 < yashgaroth> not really, but after reading about it for 30 seconds it'd be similar in principle
19:12 < kanzure> yashgaroth: so, in error correcting codes, the idea would be to use an encoding that is self-correcting.. it's where checksums come from. proooobably wouldn't work biologically without a lot of fiddling.
19:12 < kanzure> instead of 64 amino acid alphabet, you would have something .. er.. different.
19:13 < yashgaroth> possibly with a diploid genome you could have a polymerase that scans both strands simultaneously, and if one of the four bases is wrong it gets ID'd and replaced
19:13 < yashgaroth> checksums in biology is beyond my imagination, but you never know
19:14 < kanzure> strangely enough, i had a dream about error correction codes in the genome a few nights ago, mentioned it in the logs.
19:14 < kanzure> i guess the dream was because of https://github.com/sipa/bech32/blob/master/bip-witaddr.mediawiki
19:14 < kanzure> basically the dream story was that his employer (blockstream) decided to go into biology :P
19:17 < yashgaroth> somehow we can convince a bitcoin company to encode the blockchain into DNA, and reap the benefits of whatever gene synthesis tech they have to invent to make it happen
19:18 < kanzure> actually a bunch of the bitcoin people are transhumanists
19:18 < yashgaroth> shocking
19:19 < yashgaroth> true for diybio people too, I suppose
19:24 < kanzure> yes but the diybio people have no money :P
19:25 < yashgaroth> I...yeah
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20:33 < kanzure> nmz787_: could you show Taek your electron microscope? plzkthx
20:34 < nmz787_> Taek: whatcha want to see
20:34 < Taek> a picture of it :)
20:34 < Taek> just how it fits in your bedroom lol
20:35 < kanzure> .title https://github.com/nitram2342/degate
20:35 < yoleaux> GitHub - nitram2342/degate: Open source software for chip reverse engineering.
20:35 < nmz787_> here are a few https://www.takeitapart.com/guide/136
20:39 < nmz787_> here it is in-situ http://imgur.com/S2iSqDG
20:39 < Taek> that's pretty sweet
20:39 < Taek> is it noisy?
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20:39 < nmz787_> nah
20:41 < kanzure> Taek: btw it's another person that's been doing decapping
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20:51 < kanzure> from taek https://lists.linuxfoundation.org/pipermail/bitcoin-dev/2017-April/014012.html
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22:14 < kanzure> blort.
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--- Log closed Thu Apr 06 00:00:18 2017