sarahconstantin's Shortform

• Psychotic “delusions” are more about holding certain genres of idea with a socially inappropriate amount of intensity and obsession than holding a false idea. Lots of non-psychotic people hold false beliefs (eg religious people). And, interestingly, it is absolutely possible to hold a true belief in a psychotic way.
• I have observed people during psychotic episodes get obsessed with the idea that social media was sending them personalized messages (quite true; targeted ads are real) or the idea that the nurses on the psych ward were lying to them (they were).
• Preoccupation with the revelation of secret knowledge, with one’s own importance, with mistrust of others’ motives, and with influencing others' thoughts or being influenced by other's thoughts, are classic psychotic themes.
  • And it can be a symptom of schizophrenia when someone’s mind gets disproportionately drawn to those themes. This is called being “paranoid” or “grandiose.”
  • But sometimes (and I suspect more often with more intelligent/self-aware people) the literal content of their paranoid or grandiose beliefs is true!
    • sometimes the truth really has been hidden!
    • sometimes people really are lying to you or trying to manipulate you!
    • sometimes you really are, in some ways, important! sometimes influential people really are paying attention to you!
    • of course people influence each others' thoughts -- not through telepathy but through communication!
  • a false psychotic-flavored thought is "they put a chip in my brain that controls my thoughts." a true psychotic-flavored thought is "Hollywood moviemakers are trying to promote progressive values in the public by implanting messages in their movies."
    • These thoughts can come from the same emotional drive, they are drawn from dwelling on the same theme of "anxiety that one's own thoughts are externally influenced", they are in a deep sense mere arbitrary verbal representations of a single mental phenomenon...
    • but if you take the content literally, then clearly one claim is true and one is false.
    • and a sufficiently smart/self-aware person will feel the "anxiety-about-mental-influence" experience, will search around for a thought that fits that vibe but is also true, and will come up with something a lot more credible than "they put a mind-control chip in my brain", but is fundamentally coming from the same motive.  
• There’s an analogous but easier to recognize thing with depression.
  • A depressed person’s mind is unusually drawn to obsessing over bad things. But this obviously doesn’t mean that no bad things are real or that no depressive’s depressing claims are true.
  • When a depressive literally believes they are already dead, we call that Cotard's Delusion, a severe form of psychotic depression. When they say "everybody hates me" we call it a mere "distorted thought". When they talk accurately about the heat death of the universe we call it "thermodynamics." But it's all coming from the same emotional place.
• In general, mental illnesses, and mental states generally, provide a "tropism" towards thoughts that fit with certain emotional/aesthetic vibes.
  • Depression makes you dwell on thoughts of futility and despair
  • Anxiety makes you dwell on thoughts of things that can go wrong
  • Mania makes you dwell on thoughts of yourself as powerful or on the extreme importance of whatever you're currently doing
  • Paranoid psychosis makes you dwell on thoughts of mistrust, secrets, and influencing/being influenced
• You can, to some extent, "filter" your thoughts (or the ones you publicly express) by insisting that they make sense. You still have a bias towards the emotional "vibe" you're disposed to gravitate towards; but maybe you don't let absurd claims through your filter even if they fit the vibe. Maybe you grudgingly admit the truth of things that don't fit the vibe but technically seem correct.
  • this does not mean that the underlying "tropism" or "bias" does not exist!!!
  • this does not mean that you believe things "only because they are true"!
  • in a certain sense, you are doing the exact same thing as the more overtly irrational person, just hiding it better!
    • the "bottom line" in terms of vibe has already been written, so it conveys no "updates" about the world
    • the "bottom line" in terms of details may still be informative because you're checking that part and it's flexible
• "He's not wrong but he's still crazy" is a valid reaction to someone who seems to have a mental-illness-shaped tropism to their preoccupations.
  • eg if every post he writes, on a variety of topics, is negative and gloomy, then maybe his conclusions say more about him than about the truth concerning the topic;
    • he might still be right about some details but you shouldn't update too far in the direction of "maybe I should be gloomy about this too"
  • Conversely, "this sounds like a classic crazy-person thought, but I still separately have to check whether it's true" is also a valid and important move to make (when the issue is important enough to you that the extra effort is worth it). 
    • Just because someone has a mental illness doesn't mean every word out of their mouth is false!
    • (and of course this assumption -- that "crazy" people never tell the truth -- drives a lot of psychiatric abuse.)

link: https://roamresearch.com/#/app/srcpublic/page/71kfTFGmK

• “we” can’t steer the future.
• it’s wrong to try to control people or stop them from doing locally self-interested & non-violent things in the interest of “humanity’s future”, in part because this is so futile.
  • if the only way we survive is if we coerce people to make a costly and painful investment in a speculative idea that might not even work, then we don’t survive! you do not put people through real pain today for a “someday maybe!” This applies to climate change,  AI x-risk, and socially-conservative cultural reform.
• most cultures and societies in human history have been so bad, by my present values, that I’m not sure they’re not worse than extinction, and we should expect that most possible future states are similarly bad;
• history clearly teaches us that civilizations and states collapse (on timescales of centuries) and the way to bet is that ours will as well, but it’s kind of insane hubris to think that this can be prevented;
• the literal species Homo sapiens is pretty resilient and might avoid extinction for a very long time, but have you MET Homo sapiens? this is cold fucking comfort! (see e.g. C. J. Cherryh’s vision in 40,000 in Gehenna for a fictional representation not far from my true beliefs — we are excellent at adaptation and survival but when we “survive” this often involves unimaginable harshness and cruelty, and changing into something that our ancestors would not have liked at all.)
• identifying with species-survival instead of with the stuff we value now is popular among the thoughtful but doesn’t make any sense to me;
• in general it does not make sense, to me, to compromise on personal values in order to have more power/influence. you will be able to cause stuff to happen, but who cares if it’s not the stuff you want?
• similarly, it does not make sense to consciously optimize for having lots of long-term descendants. I love my children; I expect they’ll love their children; but go too many generations out and it’s straight-up fantasyland. My great-grandparents would have hated me.  And that’s still a lot of shared culture and values! Do you really have that much in common with anyone from five thousand years ago?
• Evolution is not your friend. God is not your friend. Everything worth loving will almost certainly perish. Did you expect it to last forever?
• “I love whatever is best at surviving” or “I love whatever is strongest” means you don’t actually care what it’s like. It means you have no loyalty and no standards. It means you don’t care so much if the way things turn out is hideous, brutal, miserable, abusive… so long as it technically “is alive” or “wins”. Fuck that.
• I despise sour grapes. If the thing I want isn’t available, I’m not going to pretend that what is available is what I want.
• I am not going to embrace the “realistic” plan of allying with something detestable but potent. There is always an alternative, even if the only alternative is “stay true to your dreams and then get clobbered.”

Link to this on my Roam

"weak benevolence isn't fake": https://roamresearch.com/#/app/srcpublic/page/ic5Xitb70

• there's a class of statements that go like:
  • "fair-weather friends" who are only nice to you when it's easy for them, are not true friends at all
  • if you don't have the courage/determination to do the right thing when it's difficult, you never cared about doing the right thing at all
  • if you sometimes engage in motivated cognition or are sometimes intellectually lazy/sloppy, then you don't really care about truth at all
  • if you "mean well" but don't put in the work to ensure that you're actually making a positive difference, then your supposed "well-meaning" intentions were fake all along
• I can see why people have these views.
  • if you actually need help when you're in trouble, then "fair-weather friends" are no use to you
  • if you're relying on someone to accomplish something, it's not enough for them to "mean well", they have to deliver effectively, and they have to do so consistently. otherwise you can't count on them.
  • if you are in an environment where people constantly declare good intentions or "well-meaning" attitudes, but most of these people are not people you can count on, you will find yourself caring a lot about how to filter out the "posers" and "virtue signalers" and find out who's true-blue, high-integrity, and reliable.
• but I think it's literally false and sometimes harmful to treat "weak"/unreliable good intentions as absolutely worthless.
  • not all failures are failures to care enough/try hard enough/be brave enough/etc.
    • sometimes people legitimately lack needed skills, knowledge, or resources!
    • "either I can count on you to successfully achieve the desired outcome, or you never really cared at all" is a long way from true.
    • even the more reasonable, "either you take what I consider to be due/appropriate measures to make sure you deliver, or you never really cared at all" isn't always true either!
      • some people don't know how to do what you consider to be due/appropriate measures
      • some people care some, but not enough to do everything you consider necessary
      • sometimes you have your own biases about what's important, and you really want to see people demonstrate a certain form of "showing they care" otherwise you'll consider them negligent, but that's not actually the most effective way to increase their success rate
  • almost everyone has a finite amount of effort they're willing to put into things, and a finite amount of cost they're willing to pay. that doesn't mean you need to dismiss the help they are willing and able to provide.
    • as an extreme example, do you dismiss everybody as "insufficiently committed" if they're not willing to die for the cause? or do you accept graciously if all they do is donate $50?
    • "they only help if it's fun/trendy/easy/etc" -- ok, that can be disappointing, but is it possible you should just make it fun/trendy/easy/etc? or just keep their name on file in case a situation ever comes up where it is fun/trendy/easy and they'll be helpful then?
  • it's harmful to apply this attitude to yourself, saying "oh I failed at this, or I didn't put enough effort in to ensure a good outcome, so I must literally not care about ideals/ethics/truth/other people."
    • like...you do care any amount. you did, in fact, mean well.
      • you may have lacked skill;
      • you may have not been putting in enough effort;
      • or maybe you care somewhat but not as much as you care about something else
      • but it's probably not accurate or healthy to take a maximally-cynical view of yourself where you have no "noble" motives at all, just because you also have "ignoble" motives (like laziness, cowardice, vanity, hedonism, spite, etc).
        • if you have a flicker of a "good intention" to help people, make the world a better place, accomplish something cool, etc, you want to nurture it, not stomp it out as "probably fake".
        • your "good intentions" are real and genuinely good, even if you haven't always followed through on them, even if you haven't always succeeded in pursuing them.
        • you don't deserve "credit" for good intentions equal to the "credit" for actually doing a good thing, but you do deserve any credit at all.
        • basic behavioral "shaping" -- to get from zero to a complex behavior, you have to reward very incremental simple steps in the right direction.
          • e.g. if you wish you were "nicer to people", you may have to pat yourself on the back for doing any small acts of kindness, even really "easy" and "trivial" ones, and notice & make part of your self-concept any inclinations you have to be warm or helpful.
          • "I mean well and I'm trying" has to become a sentence you can say with a straight face. and your good intentions will outpace your skills so you have to give yourself some credit for them.
  • it may be net-harmful to create a social environment where people believe their "good intentions" will be met with intense suspicion.
    • it's legitimately hard to prove that you have done a good thing, particularly if what you're doing is ambitious and long-term.
    • if people have the experience of meaning well and trying to do good but constantly being suspected of insincerity (or nefarious motives), this can actually shift their self-concept from "would-be hero" to "self-identified villain"
      • which is bad, generally
        • at best, identifying as a villain doesn't make you actually do anything unethical, but it makes you less effective, because you preemptively "brace" for hostility from others instead of confidently attracting allies
        • at worst, it makes you lean into legitimately villainous behavior
    • OTOH, skepticism is valuable, including skepticism of people's motives.
    • but it can be undesirable when someone is placed in a "no-win situation", where from their perspective "no matter what I do, nobody will believe that I mean well, or give me any credit for my good intentions."
    • if you appreciate people for their good intentions, sometimes that can be a means to encourage them to do more. it's not a guarantee, but it can be a starting point for building rapport and starting to persuade. people often want to live up to your good opinion of them.

links 10/25/24: https://roamresearch.com/#/app/srcpublic/page/10-25-2024

• https://theoryandpractice.org/2024/10/Yes,%20we%20did%20discover%20the%20Higgs!/  CERN's statistical methods are good actually. compare this to any other stats-heavy area of natural or social science and they come out impressively rigorous. blinded data analyses? whoa.
• https://en.m.wikipedia.org/wiki/Siege_engine  a siege engine is any machine you use against the city you're besieging -- from towers to catapults to flamethrowers to artillery.
• there's a new field of "pan-cancer" where you make (mostly molbio) comparisons across cancers, including vulnerability screens where you use CRISPR or RNAi to knock down each gene and see which ones kill the cancer cells when absent.
  • https://aacrjournals.org/clincancerres/article/24/9/2182/81290/Pan-Cancer-Molecular-Classes-Transcending-Tumor representative paper
  • https://www.nature.com/articles/s41467-019-13528-0 you can also do it with the proteome
  • https://www.nature.com/articles/s41422-020-0355-0 you can single-cell it
  • https://www.science.org/doi/10.1126/science.abe6474 you can profile the TILs cell by cell
  • https://link.springer.com/content/pdf/10.1186/s13059-023-03020-w.pdf CRISPR and RNAi both have their strengths and weaknesses but if you look at the overlap there are still a bunch of "pan-essential" genes that all cancers need to survive. (do healthy cells also need those, or are they good therapeutic targets? we just don't know.)
  • https://www.researchgate.net/profile/Yize-Li/publication/354641293_Moving_pan-cancer_studies_from_basic_research_toward_the_clinic/links/615f5d570bf51d4817512465/Moving-pan-cancer-studies-from-basic-research-toward-the-clinic.pdf?_sg%5B0%5D=started_experiment_milestone&_sg%5B1%5D=started_experiment_milestone&origin=journalDetail by "towards the clinic" we mean "very gingerly", apparently
  • https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30656-5 when you target pan-essential genes you are in the chemo zone, where by default the therapeutic index is low (kills cancer AND healthy cells) and you need to put more work in to handling toxicity.
• tumors -- most tumors -- get coated with IgG, much more than other tissues. is this a systemic defense against cancer or a tumor-secreted IgG? hard to say.
  • https://www.cell.com/cell/pdf/S0092-8674(22)00192-1.pdf mostly ovarian carcinoma but they also compare to a bunch of other tumor types
  • https://www.mdpi.com/1422-0067/22/21/11597 could be tumor-derived
  • https://www.nature.com/articles/srep05088.pdf this is Sanford Simon -- endogenous IgG concentrates around mouse tumors of many types
• James Watson's vision for cancer research -- this is what he originally became a "controversial figure" for, before the race thing. https://royalsocietypublishing.org/doi/full/10.1098/rsob.120144
  • basically, this is a few things:
    • a call to work harder dammit and treat it like a true war on cancer, not a sedate and bureaucratic academic field
    • a call for more pan-cancer RNAi vulnerability screens
    • a call to focus on transcription factors as targets, particularly things like Myc and BRD4 that are particularly involved in the transition to metastasis -- we don't yet have any good drug therapies that work well on metastatic cancers
      • transcription factors are obviously causally upstream of what makes cancer cancer -- its invasiveness, its metastatic potential, its evasion of immune surveillance, etc
      • they are hard to drug though, because they're in the nucleus, not on the cell surface. but we can start to do hard things now!
      • cell surface growth factors (think EGFR) are the easiest to target but the associated drugs have unimpressive clinical effects in most patients because targeting growth factors only slows growth, it doesn't kill cancer cells. usually just slightly delays the inevitable.
    • a statement of his redox hobbyhorse -- ROS is good, ROS is how the body fights cancer, etc.
      • not sure how to operationalize this as a strategy. it might, as it turns out, be redundant with immunotherapy.
    • a couple specific targets/mechanisms he thinks deserve more attention -- apparently the circadian regulator PER2 is a tumor suppressor. i'm always down for more attention to circadian stuff.
• the Halifax Project researched the hypothesis that low-dose combinations of environmental carcinogens might synergistically increase cancer risk:
  • https://www.ewg.org/research/rethinking-carcinogens
  • https://www.degruyter.com/document/doi/10.1515/reveh-2020-0033/html
• https://en.wikipedia.org/wiki/CpG_oligodeoxynucleotide this is the inflammatory molecule on bacteria that's the reason bacterial infections sometimes cause complete regressions of very difficult tumors (like sarcoma -- we have no drugs for sarcoma! it's either surgery or death!). fortunately the immunooncology people are On It and researching this as an immunostimulant.
  • if you've heard of "Coley Toxins", they're kind of an alt-med thing with a tantalizing grain of truth -- but we don't need to inject bacteria into tumors any more, we know how they work, we can replicate the effect with well-defined compounds now.
• https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(23)00221-0?rss=yes#mmc1 this is AOH1996, the mindblowingly selective new pan-cancer drug candidate.
  • basically this is using the same principle as old-fashioned chemo -- hit it in the DNA replication -- but with a new target, and with modern structural-biology-based rational drug design to hit the cancer version of the target rather than the healthy-cell type.
    • would I have guessed there was room for optimism here a priori? no way.
    • but apparently we have not explored this space sufficiently. now try it with AlphaFold.
    • https://www.science.org/content/blog-post/new-mode-cancer-treatment and Derek Lowe is impressed.
    •  
• https://www.nature.com/articles/s41419-021-04468-z inducible caspase 9 allows conditional apoptosis. it's incredibly powerful. unfortunately it doesn't always work and this raises drug resistance concerns.
  • I haven't yet seen many examples of "put the iCasp9 in the cell if-and-only-if the cell has some molecular marker" but that's the obvious place to go.
  • you can kinda reduce the drug resistance thing by putting a promotor to increase iCasp9 expression. buddy if this is where we are in 2022 i'm going to predict there is a LOT of potential value in continuing to work out the kinks in this system. get in on the ground floor!
• https://en.wikipedia.org/wiki/Proteolysis_targeting_chimera a PROTAC is "this protein? kill it." uses the ubiquitin system.
• sadly, the Warburg Effect is not as cool as I once thought.
  • glucose deprivation is just not that deadly across tumor lines: https://www.sciencedirect.com/science/article/abs/pii/S0899900720300319
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC3237863/ i mean, 2DG + metformin might do a thing?
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC5095922/#BST-2016-0094C20 yeah...it's not what you think.
  • https://www.sciencedirect.com/science/article/abs/pii/S0006291X0302504X if you actually measure what % of ATP comes from glycolysis, cancers cover a wide range, and the distribution overlaps substantially with the distribution of healthy cells. glycolysis dominance is not a distinguishing characteristic of all or even most cancers.
  • https://journals.sagepub.com/doi/pdf/10.2310/7290.2015.00021 heavy glucose uptake is enough of a thing for PET imaging to be used clinically though
  •  
• are cancer cells selectively vulnerable to mechanical stress? kinda, but also it sometimes stimulates them to go metastatic so beware.
  • https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/full/10.1002/elsc.201900154 vibrate em and they apoptose
  • https://www.sciencedirect.com/science/article/abs/pii/S0168365915302819 just mcfuckin spin some tiny magnets around in your brain tumor. apparently it works in rodents but aaaaaah
  • https://www.sciencedirect.com/science/article/pii/S0167488913003224 laminar but not oscillatory shear stress kills em? no non-cancer comparison
  • https://www.sciencedirect.com/science/article/pii/S2949907024000585 vibrations to kill prostate cancer? no non-cancer comparison
  • https://pubs.rsc.org/en/content/articlelanding/2015/nr/c5nr03518j/unauth magnetic particle vibration against renal cancer? no non-cancer comparison
  • https://www.nature.com/articles/s41557-023-01383-y.epdf?sharing_token=jICYt2mKBMQ0GsetiWodv9RgN0jAjWel9jnR3ZoTv0PPtLuduvirY9e9lvJJx5Q_iJTfP9UCvLlXVOkNBly5J-gi3DlHLxMYWqsmEJBOrH0s7RbtQm1UREc3FbrfF2vDNLzTfS250KEAwBdVsczhxamax0pSp4TP23jM_ehG703560use7dJ6hnsaVLpnXsWU1n14UplHLGvaXHsJ444z96C3IEcjmnjMZvijAgkKsQ%3D&tracking_referrer=www.genengnews.com "vibronic molecular jackhammers"? still no non-cancer comparison, but at least they tried some mice
  • https://www.nature.com/articles/s41413-020-00111-3 vibration to reduce metastatic potential of breast cancer cells. no non-cancer comparison.
  • https://www.science.org/doi/10.1126/science.adp7206 gently ultrasound the tumor to sensitize it to chemo or induce an immune anti-tumor response.
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC10068349/ Piezo1 might be involved in an apoptotic response to mechanical stress?
  • https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/full/10.1002/elsc.201900154 vibrate some cancer cells and they go apoptotic but not necrotic. no non-cancer comparison.
  • https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4703126 more ultrasound, including in vivo, Piezo1 mediated.
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC8274378/ mechanical stress is also a natural feature of cancer -- tumors get more rigid and experience pressure. in fact this stress can be a trigger for increased proliferation or metastasis, so watch out!
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC5992512/ oops shear stress can promote metastasis
  • https://www.cell.com/biophysj/fulltext/S0006-3495(22)00367-8 substrate stiffness promotes invasion and metastasis
  • https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.955595/full "mechanoptosis" (mechanical pressure causing cancer apoptosis)
  • https://elifesciences.org/for-the-press/12916d1e/migrating-through-small-spaces-makes-cancer-cells-more-aggressive squish cancer cells through tight spaces (eg on a microfluidic chip) and you get more invasive/metastatic potential
  •  
• are cancer cells selectively vulnerable to electrical stress? also kinda yeah
  • https://www.mdpi.com/2072-6694/13/9/2283 "tumor treating fields", just an oscillating electric field, are actually an approved therapy in glioblastoma that extends life a few months. (not saying much though...glioblastoma is so deadly that it's easy mode from an FDA standpoint)
  • of course you can just kill *cells* with pulsed electric fields, cancer or not: https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.02-0859fje
  • https://jamanetwork.com/journals/jama/article-abstract/2475446 more electrical fields for glioblastoma
  • https://aacrjournals.org/cancerres/article/64/9/3288/517864/Disruption-of-cancer-Cell-Replication-by ah this actually IS a differential effect in tumor vs. non cancer cell lines. plus in vivo, in mice.
• i don't even know man. somebody who knows physics explain this. little nanoelectrodes with some chemical functionalization kill cancer cells? "quantum biological tunneling?" https://www.nature.com/articles/s41565-023-01496-y
• https://nyulangone.org/news/coping-mechanism-suggests-new-way-make-cancer-cells-more-vulnerable-chemotherapies "stress granules" as a form of chemo resistance, driven by KRAS?
• https://www.nature.com/articles/s41420-022-01202-2 cancer can be selectively vulnerable to proteotoxic stress. they're worse at expressing heat shock proteins.
  • https://www.researchgate.net/profile/Pietro-Taverna-2/publication/221748736_The_Novel_Oral_Hsp90_Inhibitor_NVP-HSP990_Exhibits_Potent_and_Broad-spectrum_Antitumor_Activities_In_Vitro_and_In_Vivo/links/56d0a18708ae059e375d4920/The-Novel-Oral-Hsp90-Inhibitor-NVP-HSP990-Exhibits-Potent-and-Broad-spectrum-Antitumor-Activities-In-Vitro-and-In-Vivo.pdf heat shock protein inhibitor reduces tumor growth in many cell lines
• cancer cells have depolarized membranes -- you can literally distinguish them from healthy cells by voltage alone.
  • this is a Michael Levin thing. https://pmc.ncbi.nlm.nih.gov/articles/PMC3528107/ you can give a frog a tumor -- or make the tumor go away -- through manipulating voltage alone! it does not matter what ion channel you use, it's about the voltage.
    • more Michael Levin https://pmc.ncbi.nlm.nih.gov/articles/PMC4267524/#R250
  • apparently Wnt signaling is involved. https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP278661 in general you get alterations in membrane voltage potential by changing the behavior of ion channels
  • https://jamanetwork.com/journals/jamasurgery/article-abstract/591620#google_vignette depolarization occurs early in the development of colon cancer in mice exposed to a carcinogen.
  • https://www.medigraphic.com/pdfs/hepato/ah-2017/ah172s.pdf cancer stem cells are depolarized relative to normal stem cells
  • https://www.nature.com/articles/s41598-021-92951-0.pdf here's math modeling if you care.
  • https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2013.00185/full a lot of ion channels are involved
  • https://karger.com/tbi/article-abstract/15/3/147/299607/Electrical-Potential-Measurements-in-Human-Breast breast cancers vs non-cancer tumors show up differently on an external volt meter!!!!
    • literally, you can try this at home! stick a voltmeter across your boob!
  • https://aacrjournals.org/cancerres/article/40/6/1830/484668/Cellular-Potentials-of-Normal-and-cancerous cancerous cells have lower membrane potential than their healthy counterparts
  • https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.1974.tb26808.x even in non-cancer cells membrane potential correlates negatively with proliferation
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC9652252/ cancer membrane potentials also fluctuate more than healthy cell membrane potentials
  • https://aacrjournals.org/amjcancer/article/32/2/240/679553/Bio-Electric-Properties-of-Cancer-Resistant-and going back to 1938, if you put a volt meter across a mouse's body you can tell the ones with tumors from the ones without. it is literally that simple and has been known that long.
• something in (some of?) the neutrophils in (some) humans and a cancer-resistant strain of mice can kill cancer, including when transferred. a Zheng Cui research program.
  • my take is, he's not an immunologist and modern methods could elucidate the specific clonal population a LOT better than this, but I like the thought process.
  • https://www.cell.com/heliyon/fulltext/S2405-8440(17)31693-6 they did some infusions from young blood donors into 3 patients with advanced metastatic cancer got a bunch of tumor necrosis and a cytokine release syndrome. all died within 3 months though.
  • https://link.springer.com/article/10.1186/1475-2867-11-26 healthy controls' leukocytes are better at killing cancer in vitro than cancer patients'. this is as expected.
  • https://link.springer.com/article/10.1186/1471-2407-10-179 SR/CR cancer resistant mice seem to need the leukocytes to physically home to the cancer cells. again, not news; neutrophils infiltrate tumors.
    • Cui has been beating this drum since before immunotherapy was cool, so let's not blame him too much, but we do very much know this bit independently
    • eg https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01710/full -- sometimes neutrophils promote cancer actually!
    • eg https://www.cell.com/cell-reports/pdfExtended/S2211-1247(22)00984-6 we can determine the "good guy" neutrophil subpopulation that infiltrates tumors and promotes an anti-tumor immune response: it's HLA-DR+CD80+CD86+ICAM1+PD-L1-. in metastasis these guys become PD-L1+ and immunosuppressive.
    • so like...the secret to replicating Zheng Cui's miracle mice...might be nivolumab?? don't get me wrong it's a good drug but this is anticlimactic.
      • a great example of the mundanity of success
  • https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0059995&type=printable the Danes do not replicate quite as much cancer resistance from SR/CR mice as Cui's lab
  • https://www.pnas.org/doi/pdf/10.1073/pnas.0602382103 whatever the SR/CR mice are doing, you can transfer it to other mice and get cancer resistance. Lloyd J. Old is a coauthor!!!
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC4544930/ independent description of anti-tumor neutrophils extracted from mice
  • https://www.sciencedirect.com/science/article/abs/pii/S0171298510000033 more evidence of anti-tumor granulocytes(which include neutrophils)
  • https://www.tandfonline.com/doi/abs/10.4161/cbt.7.9.6417 cancer patients' granulocytes are less active
• more Zheng Cui: cancer cells are negatively charged, such that positively charged nanoparticles can detect them VERY specifically. this is legit IMO.
  • https://link.springer.com/article/10.1007/s41048-018-0080-0 works on 22 different cancer cell lines. absolutely no affinity for healthy cells, quite a bit for all cancer cells.
  • https://www.thno.org/v06p1887.htm
    • can't do it in vivo though
  • https://link.springer.com/article/10.1186/s12951-019-0491-1?fromPaywallRec=false detects four CTCs per 1 mL blood!!!!
  • https://www.science.org/doi/10.1126/science.abm5551#supplementary-materials sadly these guys think positive nanoparticles are too toxic to use as treatments -- the entire paper is about negative nanoparticles, which do sometimes add to the tumor uptake of chemotherapies
• https://www.sciencedirect.com/science/article/abs/pii/S1879625715000413 oncolytic virus BHV1 kills cancer cells in a variety of tumor types?
• https://www.nature.com/articles/s41598-023-47478-x.pdf broad-spectrum metastasis suppressing compounds targeting a lncRNA. scary-big chemical structures though.
• https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2010.01834.x broad spectrum effectiveness of a survivin inhibitor + tumor regressions in vivo.
  • survivin is pan-essential, i got a good feeling about this
• https://aacrjournals.org/cancerimmunolres/article/2/6/510/467367/VISTA-Is-a-Novel-Broad-Spectrum-Negative VISTA is another negative checkpoint regulator like PD1 and CTLA4 (which are both major successful drug targets)
• https://www.science.org/doi/abs/10.1126/scitranslmed.3007646 alkylphosphocholine is a type of lipid especially present in cancer cells, across cancer types, via lipid rafts. a synthetic analog has preferential uptake in basically all rodent & human tumors. usable for imaging and radiotherapy.
• https://www.nature.com/articles/s41568-023-00554-w Sanford Simon's personal journey against fibrolamellar hepatocellular carcinoma
  • they found a fusion transcript and a corresponding fusion protein -- the root cause
  • they did the reasonable thing: screen a compound library against tumor samples.
    • one hit is napabucasin, usually known as a STAT3 inhibitor (but that's not the mechanism here) but somebody owns it
    • another was irinotecan. and navitoclax...but navitoclax has platelet toxicity
      • irinotecan + a BcrX PROTAC is being investigated though
    • or you can just. shRNA the fusion transcript. that's a thing you can do now.
      • apparently Elana wanted to do that in 2013 but her dad said "pshaw RNA breaks down in the body." now Spinraza is a thing (antisense oligonucleotide.) not to mention the mRNA world. truly these are the days of miracle and wonder.
• https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00126/full redox balance is tricky, since cancers are both more prone to ROS and prone to develop coping mechanisms to regain redox balance.
• https://www.nature.com/articles/cdd2017180 there's nothing like TP53. mutated in 50-60% of cancers. the tumor suppressor gene par excellence.
• https://nousresearch.com/wp-content/uploads/2024/08/Hermes-3-Technical-Report.pdf the Hermes 3 model is fine-tuned to be more responsive to prompts, such that prompt engineering suffices for "in-character" writing style (which IME does not work on most Instruct models)
•  

neutrality (notes towards a blog post): https://roamresearch.com/#/app/srcpublic/page/Ql9YwmLas

• "neutrality is impossible" is sort-of-true, actually, but not a reason to give up.
  • even a "neutral" college class (let's say a standard algorithms & data structures CS class) is non-neutral relative to certain beliefs
    • some people object to the structure of universities and their classes to begin with;
    • some people may object on philosophical grounds to concepts that are unquestionably "standard" within a field like computer science.
    • some people may think "apolitical" education is itself unacceptable.
      • to consider a certain set of topics "political" and not mention them in the classroom is, implicitly, to believe that it is not urgent to resolve or act on those issues (at least in a classroom context), and therefore it implies some degree of acceptance of the default state of those issues.
    • our "neutral" CS class is implicitly taking a stand on certain things and in conflict with certain conceivable views. but, there's a wide range of views, including (I think) the vast majority of the actual views of relevant parties like students and faculty, that will find nothing to object to in the class.
  • we need to think about neutrality in more relative terms:
    • what rule are you using, and what things are you claiming it will be neutral between?
• what is neutrality anyway and when/why do you want it?
  • neutrality is a type of tactic for establishing cooperation between different entities.
    • one way (not the only way) to get all parties to cooperate willingly is to promise they will be treated equally.
    • this is most important when there is actual uncertainty about the balance of power.
      • eg the Dutch Republic was the first European polity to establish laws of religious tolerance, because it happened to be roughly evenly divided between multiple religions and needed to unite to win its independence.
  • a system is neutral towards things when it treats them the same.
    • there lots of ways to treat things the same:
      • "none of these things belong here"
        • eg no religion in "public" or "secular" spaces
          • is the "public secular space" the street? no-hijab rules?
          • or is it the government? no 10 Commandments in the courthouse?
      • "each of these things should get equal treatment"
        • eg Fairness Doctrine
      • "we will take no sides between these things; how they succeed or fail is up to you"
        • e.g. "marketplace of ideas", "colorblindness"
  • one can always ask, about any attempt at procedural neutrality:
    • what things does it promise to be neutral between?
      • are those the right or relevant things to be neutral on?
    • to what degree, and with what certainty, does this procedure produce neutrality?
      • is it robust to being intentionally subverted?
  • here and now, what kind of neutrality do we want?
    • thanks to the Internet, we can read and see all sorts of opinions from all over the world. a wider array of worldviews are plausible/relevant/worth-considering than ever before. it's harder to get "on the same page" with people because they may have come from very different informational backgrounds.
    • even tribes are fragmented. even people very similar to one another can struggle to synch up and collaborate, except in lowest-common-denominator ways that aren't very productive.
    • narrowing things down to US politics, no political tribe or ideology is anywhere close to a secure monopoly. nor are "tribes" united internally.
    • we have relied, until now, on a deep reserve of "normality" -- apolitical, even apathetic, Just The Way Things Are. In the US that means, people go to work at their jobs and get paid for it and have fun in their free time. 90's sitcom style.
      • there's still more "normality" out there than culture warriors tend to believe, but it's fragile. As soon as somebody asks "why is this the way things are?" unexamined normality vanishes.
        • to the extent that the "normal" of the recent past was functional, this is a troubling development...but in general the operation of the mind is a good thing!
        • we just have more rapid and broader idea propagation now.
          • why did "open borders" and "abolish the police" and "UBI" take off recently? because these are simple ideas with intuitive appeal. some % of people will think "that makes sense, that sounds good" once they hear of them. and now, way more people are hearing those kinds of ideas.
    • when unexamined normality declines, conscious neutrality may become more important.
      • conscious neutrality for the present day needs to be aware of the wide range of what people actually believe today, and avoid the naive Panglossianism of early web 2.0.
        • many people believe things you think are "crazy".
        • "democratization" may lead to the most popular ideas being hateful, trashy, or utterly bonkers.
        • on the other hand, depending on what you're trying to get done, you may very well need to collaborate with allies, or serve populations, whose views are well outside your comfort zone.
      • neutrality has things to offer:
        • a way to build trust with people very different from yourself, without compromising your own convictions;
          • "I don't agree with you on A, but you and I both value B, so I promise to do my best at B and we'll leave A out of it altogether"
        • a way to reconstruct some of the best things about our "unexamined normality" and place them on a firmer foundation so they won't disappear as soon as someone asks "why?"
• a "system of the world" is the framework of your neutrality: aka it's what you're not neutral about.
  • eg:
    • "melting pot" multiculturalism is neutral between cultures, but does believe that they should mostly be cosmetic forms of diversity (national costumes and ethnic foods) while more important things are "universal" and shared.
    • democratic norms are neutral about who will win, but not that majority vote should determine the winner.
    • scientific norms are neutral about which disputed claims will turn out to be true, but not on what sorts of processes and properties make claims credible, and not about certain well-established beliefs
  • right now our system-of-the-world is weak.
    • a lot of it is literally decided by software affordances. what the app lets you do is what there is.
      • there's a lot that's healthy and praiseworthy about software companies and their culture, especially 10-20 years ago. but they were never prepared for that responsibility!
  • a stronger system-of-the-world isn't dogmatism or naivety.
    • were intellectuals of the 20th, the 19th, or the 18th centuries childish because they had more explicit shared assumptions than we do? I don't think so.
      • we may no longer consider some of their frameworks to be true
      • but having a substantive framework at all clearly isn't incompatible with thinking independently, recognizing that people are flawed, or being open to changing your mind.
      • "hedgehogs" or "eternalists" are just people who consider some things definitely true.
        • it doesn't mean they came to those beliefs through "blind faith" or have never questioned them.
        • it also doesn't mean they can't recognize uncertainty about things that aren't foundational beliefs.
      • operating within a strongly-held, assumed-shared worldview can be functional for making collaborative progress, at least when that worldview isn't too incompatible with reality.
    • mathematics was "non-rigorous", by modern standards, until the early 20th century; and much of today's mathematics will be considered "non-rigorous" if machine-verified proofs ever become the norm. but people were still able to do mathematics in centuries past, most of which we still consider true.
      • the fact that you can generate a more general framework, within which the old framework was a special case; or in which the old framework was an unprincipled assumption of the world being "nicely behaved" in some sense; does not mean that the old framework was not fruitful for learning true things.
        • sometimes, taking for granted an assumption that's not literally always true (but is true mostly, more-or-less, or in the practically relevant cases) can even be more fruitful than a more radically skeptical and general view.
  • an *intellectual* system-of-the-world is the framework we want to use for the "republic of letters", the sub-community of people who communicate with each other in a single conversational web and value learning and truth.
    • that community expanded with the printing press and again with the internet.
    • it is radically diverse in opinion.
    • it is not literally universal. not everybody likes to read and write; not everybody is curious or creative. a lot of the "most interesting people in the world" influence each other.
      • everybody in the old "blogosphere" was, fundamentally, the same sort of person, despite our constant arguments with each other; and not a common sort of person in the broader population; and we have turned out to be more influential than we have ever been willing to admit.
    • but I do think of it as a pretty big and growing tent, not confined to 300 geniuses or anything like that.
      • "The" conversation -- the world's symbolic information and its technological infrastructure -- is something anybody can contribute to, but of course some contribute more than others.
      • I think the right boundary to draw is around "power users" -- people who participate in that network heavily rather than occasionally.
        • e.g. not all academics are great innovators, but pretty much all of them are "power users" and "active contributors" to the world's informational web.
        • I'm definitely a power user; I expect a lot of my readers are as well.
    • what do we need to not be neutral about in this context? what belongs in an intellectual system-of-the-world?
      • another way of asking this question: about what premises are you willing to say, not just for yourself but for the whole world and for your children's children, "if you don't accept this premise then I don't care to speak to you or hear from you, forever?"
        • clearly that's a high standard!
        • I have many values differences with, say, the author of the Epic of Gilgamesh, but I still want to read it. And I want lots of other people to be able to read it! I do not want the mind that created it to be blotted out of memory.
        • that's the level of minimal shared values we're talking about here. What do we have in common with everyone who has an interest in maintaining and extending humanity's collective record of thought?
      • lack of barriers to entry is not enough.
        • the old Web 2.0 idea was "allow everyone to communicate with everyone else, with equal affordances." This is a kind of "neutrality" -- every user account starts out exactly the same, and anybody can make an account.
          • I think that's still an underrated principle. "literally anybody can speak to anybody else who wants to listen" was an invention that created a lot of valuable affordances. we forget how painfully scarce information was when that wasn't true!
        • the problem is that an information system only works when a user can find the information they seek. And in many cases, what the user is seeking is true information.
        • mechanisms intended to make high quality information (reliable, accurate, credible, complete, etc) preferentially discoverable, are also necessary
          • but they shouldn't just recapitulate potentially-biased gatekeeping.
            • we want evaluative systems that, at least a priori, an ancient Sumerian could look at and say "yep, sounds fair", even if the Sumerian wouldn't like the "truths" that come out on top in those systems.
            • we really can't be parochial here. social media companies "patched" the problem of misinformation with opaque, partisan side-taking, and they suffered for it.
            • how "meta" do we have to get about determining what counts as reliable or valid? well, more meta than just picking a winning side in an ongoing political dispute, that's for sure.
              • probably also more "meta" than handpicking certain sources as trustworthy, the way Wikipedia does.
  • if we want to preserve and extend knowledge, the "republic of letters" needs intentional stewardship of the world's information, including serious attempts at neutrality.
    • perceived bias, of course, turns people away from information sources.
    • nostalgia for unexamined normality -- "just be neutral, y'know, like we were when I was young" -- is not a credible offer to people who have already found your nostalgic "normal" wanting.
    • rigorous neutrality tactics -- "we have so structured this system so that it is impossible for anyone to tamper with it in a biased fashion" -- are better.
      • this points towards protocols.
        • h/t Venkatesh Rao
        • think: zero-knowledge proofs, formal verification, prediction markets, mechanism design, crypto-flavored governance schemes, LLM-enabled argument mapping, AI mechanistic-interpretability and "showing its work", etc
      • getting fancy with the technology here often seems premature when the "public" doesn't even want neutrality; but I don't think it actually is.
        • people don't know they want the things that don't yet exist.
        • the people interested in developing "provably", "rigorously", "demonstrably" impartial systems are exactly the people you want to attract first, because they care the most.
        • getting it right matters.
          • a poorly executed attempt either fizzles instantly; or it catches on but its underlying flaws start to make it actively harmful once it's widely culturally influential.
      • OTOH, premature disputes on technology and methods are undesirable.
        • remember there aren't very many of you/us. that is:
          • pretty much everybody who wants to build rigorous neutrality, no matter why they want it or how they want to implement it, is a potential ally here.
            • the simple fact of wanting to build a "better" world that doesn't yet exist is a commonality, not to be taken for granted. most people don't do this at all.
            • the "softer" side, mutual support and collegiality, are especially important to people whose dreams are very far from fruition. people in this situation are unusually prone to both burnout and schism. be warm and encouraging; it helps keep dreams alive.
            • also, the whole "neutrality" thing is a sham if we can't even engage with collaborators with different views and cultural styles.
          • also, "there aren't very many of us" in the sense that none of these envisioned new products/tools/institutions are really off the ground yet, and the default outcome is that none of them get there.
            • you are playing in a sandbox. the goal is to eventually get out of the sandbox.
            • you will need to accumulate talent, ideas, resources, and vibe-momentum. right now these are scarce, or scattered; they need to be assembled.
            • be realistic about influence.
              • count how many people are at the conference or whatever. how many readers. how many users. how many dollars. in absolute terms it probably isn't much. don't get pretentious about a "movement", "community", or "industry" before it's shown appreciable results.
              • the "adjacent possible" people to get involved aren't the general public, they're the closest people in your social/communication graph who aren't yet participating. why aren't they part of the thing? (or why don't you feel comfortable going to them?) what would you need to change to satisfy the people you actually know?
                • this is a better framing than speculating about mass appeal.

links, 10/14/2024

• https://milton.host.dartmouth.edu/reading_room/pl/book_1/text.shtml [[John Milton]]'s Paradise Lost, annotated online [[poetry]]
• https://darioamodei.com/machines-of-loving-grace [[AI]] [[biotech]] [[Dario Amodei]] spends about half of this document talking about AI for bio, and I think it's the most credible "bull case" yet written for AI being radically transformative in the biomedical sphere.
  • one caveat is that I think if we're imagining a future with brain mapping, regeneration of macroscopic brain tissue loss, and understanding what brains are doing well enough to know why neurological abnormalities at the cell level produce the psychiatric or cognitive symptoms they do...then we probably can do brain uploading! it's really weird to single out this one piece as pie-in-the-sky science fiction when you're already imagining a lot of similarly ambitious things as achievable.
• https://venture.angellist.com/eli-dourado/syndicate [[tech industry]] when [[Eli Dourado]] picks startups, they're at least not boring! i haven't vetted the technical viability of any of these, but he claims to do a lot of that sort of numbers-in-spreadsheets work.
• https://forum.effectivealtruism.org/topics/shapley-values [? · GW] [[EA]] [[economics]] how do you assign credit (in a principled fashion) to an outcome that multiple people contributed to? Shapley values! It seems extremely hard to calculate in practice, and subject to contentious judgment calls about the assumptions you make, but maybe it's an improvement over raw handwaving.
• https://gwern.net/maze [[Gwern Branwen]] digs up the "Mr. Young" studying maze-running techniques in [[Richard Feynman]]'s "Cargo Cult Science" speech. His name wasn't Young but Quin Fischer Curtis, and he was part of a psychology research program at UMich that published little and had little influence on the outside world, and so was "rebooted" and forgotten. Impressive detective work, though not a story with a very satisfying "moral".
• https://en.m.wikipedia.org/wiki/Cary_Elwes [[celebrities]] [[Cary Elwes]] had an ancestor who was [[Charles Dickens]]' inspiration for Ebenezer Scrooge!
• https://feministkilljoys.com/2015/06/25/against-students/ [[politics]] an old essay by [[Sara Ahmed]] in defense of trigger warnings in the classroom and in general against the accusations that "students these days" are oversensitive and illiberal.
  • She's doing an interesting thing here that I haven't wrapped my head around. She's not making the positive case "students today are NOT oversensitive or illiberal" or "trigger warnings are beneficial," even though she seems to believe both those things. she's more calling into question "why has this complaint become a common talking point? what unstated assumptions does it perpetuate?" I am not sure whether this is a valid approach that's alternate to the forms of argument I'm more used to, or a sign of weakness (a thing she's doing only because she cannot make the positive case for the opposite of what her opponents claim.)
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080017/ [[cancer]][[medicine]] [[biology]] cancer preventatives are an emerging field
  • NSAIDS and omega-3 fatty acids prevent 95% of tumors in a tumor-prone mouse strain?!
  • also we're targeting [[STAT3]] now?! that's a thing we're doing.
    • ([[STAT3]] is a major oncogene but it's a transcription factor, it lives in the cytoplasm and the nucleus, this is not easy to target with small molecules like a cell surface protein.)
• https://en.m.wikipedia.org/wiki/CLARITY [[biotech]] make a tissue sample transparent so you can make 3D microscopic imaging, with contrast from immunostaining or DNA/RNA labels
• https://distill.pub/2020/circuits/frequency-edges/ [[AI]] [[neuroscience]] a type of neuron in vision neural nets, the "high-low frequency detector", has recently also been found to be a thing in literal mouse brain neurons (h/t [[Dario Amodei]]) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055119/
• https://mosaicmagazine.com/essay/israel-zionism/2024/10/the-failed-concepts-that-brought-israel-to-october-7/ [[politics]][[Israel]][[war]] an informative and sober view on "what went wrong" leading up to Oct 7
  • tl;dr: Hamas consistently wants to destroy Israel and commit violence against Israelis, they say so repeatedly, and there was never going to be a long-term possibility of living peacefully side-by-side with them; Netanyahu is a tough talker but kind of a procrastinator who's kicked the can down the road on national security issues for his entire career; catering to settlers is not in the best interests of Israel as a whole (they provoke violence) but they are an unduly powerful voting bloc; Palestinian misery is real but has been institutionalized by the structure of the Gazan state and the UN which prevents any investment into a real local economy; the "peace process" is doomed because Israel keeps offering peace and the Palestinians say no to any peace that isn't the abolition of the State of Israel.
  • it's pretty common for reasonable casual observers (eg in America) to see Israel/Palestine as a tragic conflict in which probably both parties are somewhat in the wrong, because that's a reasonable prior on all conflicts. The more you dig into the details, though, the more you realize that "let's live together in peace and make concessions to Palestinians as necessary" has been the mainstream Israeli position since before 1948. It's not a symmetric situation.
• [[von Economo neurons]] are spooky [[neuroscience]] https://en.wikipedia.org/wiki/Von_Economo_neuron
  • only found in great apes, cetaceans, and humans
  • concentrated in the [[anterior cingulate cortex]] and [[insular cortex]] which are closely related to the "sense of self" (i.e. interoception, emotional salience, and the perception that your e.g. hand is "yours" and it was "you" who moved it)
  • the first to go in [[frontotemporal dementia]]
  • https://www.nature.com/articles/s41467-020-14952-3 we don't know where they project to! they are so big that we haven't tracked them fully!
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953677/
• https://www.wired.com/story/lee-holloway-devastating-decline-brilliant-young-coder/ the founder of Cloudflare had [[frontotemporal dementia]] [[neurology]]
• [[frontotemporal dementia]] is maybe caused by misfolded proteins being passed around neuron-to-neuron, like prion disease! [[neurology]]
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838634/
  • https://www.nature.com/articles/s41467-018-06548-9.pdf inject the bad protein into a mouse and it really does spread!
  • https://researchfeatures.com/cell-cell-transmission-proteins-core-neurodegenerative-disease/ something similar might be happening in [[Alzheimer's]] as well
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943211/ the spread of [[ALS]] through the brain is consistent with cell-to-cell transmission of misfolded proteins
  •  

links 11/08/2024: https://roamresearch.com/#/app/srcpublic/page/11-08-2024

• https://agingbiotech.info/about/ a database of aging biotech companies compiled by Karl Pfleger
• https://longevitylist.com/longevity-industry-database/ a database of aging biotech companies compiled by Nathan Cheng, includes somewhat different picks
• GLP-1 receptor agonist drugs reduce all-cause mortality -- so what diseases or causes of death do they prevent?
  • https://www.nature.com/articles/s41467-024-50199-y kidney disease (in type-2 diabetes patients with kidney disease)
  • https://www.ajmc.com/view/glp-1s-reduce-cardiovascular-risk-equally-in-patients-with-overweight-obesity-regardless-of-diabetes cardiovascular disease (in overweight or obese patients)
    • https://journals.sagepub.com/doi/pdf/10.1177/17562864241281903
  • https://www.science.org/doi/10.1126/science.adn4128 (sadly I couldn't find the full article)
  • https://www.ingentaconnect.com/content/ben/cdr/2018/00000014/00000003/art00008 cardiovascular disease (in diabetics)
• https://wonder.cdc.gov/controller/datarequest/D176;jsessionid=C53D7110417D14C262ECD70F0091 what are the leading causes of death in 2023?
  • heart disease, cancer, accidents, stroke, COPD, Alzheimer's, diabetes, kidney disease, liver disease, COVID-19, suicide, influenza & pneumonia, hypertension, septicemia, Parkinson's
  • surprised suicide was so high and that COVID-19 was still so deadly (I assume mostly in the elderly)
• https://www.fiercebiotech.com/biotech/bioage-brings-almost-200m-ipo-obesity-biotech-joins-nasdaq BioAge IPO
• I forgot that Sam Altman invested in Retro Bio
  • https://www.technologyreview.com/2023/03/08/1069523/sam-altman-investment-180-million-retro-biosciences-longevity-death/
  • the man has good taste. like, it's not blindingly original to appreciate Retro, but it is eminently reasonable.
• there's a lot of moderate-Democrat post-election resignation to the effect of "this is what the country wanted; the median voter is in fact pretty OK with Trump" and "the progressive apparatus was more interested in staying in its comfort zone than winning elections"
  • https://substack.com/home/post/p-151278372 Jesse Singal
    • he was saying similar things all along: https://jessesingal.substack.com/p/democrats-should-acknowledge-reality
• I'm also seeing a fair number of women going "ok, sure, there are things to criticize about feminist dogma, but actually I have experienced traditionalist religious mores and they were Not Good", which I think is a needed corrective these days
  • https://substack.com/home/post/p-141175575 here's Audrey Horne
• https://backofmind.substack.com/p/incompetence-is-a-form-of-bias Dan Davies says incompetence is a form of bias -- the people who have the social skills and clout to get their problems fixed, will.
• Dan Davies on politics and populism...i'm not sure where he's going here but this is intriguing.
  • https://substack.com/home/post/p-151264334
• https://esmeralda.org/ Esmerelda, Devon Zeugel's Chautauqua-inspired village in California

links 11/6/2024: https://roamresearch.com/#/app/srcpublic/page/11-06-2024

• https://angrystaffofficer.com/2018/09/19/if-the-hoth-crash-was-an-air-force-investigation/
  • this taught me the phrase "mishap pilot"
• https://pmc.ncbi.nlm.nih.gov/articles/PMC5656536/ this is measles virus used against relapsed multiple myeloma; one complete response out of 32 patients.
  • https://www.nature.com/articles/s41375-020-0828-7.pdf the one patient with the CR had strong T-cell responses to measles virus proteins. suggests that when this works it's via immune response.
  • https://ajronline.org/doi/pdf/10.2214/AJR.09.3672 it works on mouse pancreatic cancer
  • https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.6_suppl.509 seems to be able to treat bladder cancer?
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC3018921/ blocks medulloblastoma growth in mice
  • https://en.wikipedia.org/wiki/CD46 the receptor for measles virus is also frequently expressed by cancer cells
  •  
• https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1095219/full targeting CDKs in sarcomas -- there are some clinical trials happening
  • https://ascopubs.org/doi/abs/10.1200/PO.24.00219 palcociclib: one partial response out of 42 sarcoma patients
  • https://aacrjournals.org/clincancerres/article/29/17/3484/728559 suggestive in-vitro/animal evidence
• targeting FGFRs in advanced solid tumors with FGFR mutations/overexpression:  https://dial.uclouvain.be/pr/boreal/object/boreal%3A285422/datastream/PDF_01/view
  • 3% complete response, 25% partial response with erdafitinib
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC8231807/ FGFR inhibitors are typically toxic
• MPNSTs cluster into two distinct types of genomic alteration with different drug vulnerabilities https://www.nature.com/articles/s41467-023-38432-6.pdf
• targeting MDM2 in advanced solid tumors: there's a trial.  https://clinicaltrials.gov/study/NCT03611868
  • https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.9517 2 complete responses in melanoma, 1 PR each in liposarcoma, urothelial, and NSCLC, but none in MPNST.
  • http://www.annclinlabsci.org/content/46/6/627.full it's being explored as a target in cancer
• https://www.sciencedirect.com/science/article/abs/pii/S0959804920313228 21% partial response in soft tissue sarcoma to a XPO1 inhibitor + chemo
  • review article on XPO1 inhibition https://www.nature.com/articles/s41571-020-00442-4
• https://www.centauri-dreams.org/2024/11/05/vegas-puzzling-disk/ the star Vega looks like it has a disc but no planets
• https://www.nature.com/articles/s41598-024-58899-7 CD74 in cancer is an indicator for M1 macrophage infiltration, across cancer types
• https://bibliome.ai/  is a resource for looking up specific genome variants and their references in the literature and open-access databases.
  • when i click through to references they're often inaccurate (they are claimed to reference a variant that they do not, in fact, contain) but tbh this is also true of Google Search and Google Scholar when it comes to rare variants.
•  

links 11/05/2024: https://roamresearch.com/#/app/srcpublic/page/11-05-2024

• https://en.wikipedia.org/wiki/IMM-101  a heat-killed bacterial preparation that might actually work (with chemo) for metastatic pancreatic cancer?
  • https://www.annalsofoncology.org/article/S0923-7534(19)64297-3/fulltext not bad in metastatic melanoma either
  • https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.9554 melanoma: 18% CR in treatment-naive patients when combined with nivolumab. (meh, nivolumab alone is comparable)
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC4731256/ this is one patient, but it's metastatic pancreatic cancer, this is super hard mode
  • made by these guys. https://www.immodulon.com/about-us/ they don't look crazypants
• https://en.wikipedia.org/wiki/Measles_virus_encoding_the_human_thyroidal_sodium_iodide_symporter  measles virus can be made oncolytic!
  • https://www.lymphomainfo.net/lifestyle/treatment/engineered-measles-virus-puts-myeloma-patient-into-remission
• https://www.nature.com/articles/s41591-021-01544-x peptide vaccines have a terrible track record overall but this one (on metastatic melanoma, combined with nivolumab) looks good
• https://www.nobelprize.org/prizes/medicine/2018/summary/ James Allison and Tasuku Honjo got the Nobel Prize for discovering the immune checkpoints CTLA4 and PD1 respectively
• https://www.nature.com/articles/s41562-017-0055 Carl Hart argues against viewing addiction as a "brain disease":
  • we have not found a physiological difference between the brains of addicts and non-addicts
  • people are more likely to get addicted to drugs when their lives are terrible; only focusing on biomedical angles on tackling drug addiction means that it's not considered "real" drug-addiction work to try to improve underlying social problems like poverty or injustice
    • in particular drug-war policies are often part of the problem, and biomedical addiction research can't critique laws
• https://www.science.org/doi/abs/10.1126/science.abb5920 this one didn't make the cutoff for my success-story post (only 1/10 patients had a CR) but it's astonishing that it does anything at all; a fecal matter transplant resulted in a complete response (and two partial responses) upon reintroduction of PD1 immunotherapy, in metastatic melanoma patients who had failed it before.
  • i am so disillusioned with FMTs that i might still chalk this up to a fluke, but who knows
• https://en.wikipedia.org/wiki/Imiquimod is a weird, weird drug, used for genital warts and cutaneous cancers.
  • it's a TLR7 activator.
    • (more innate immune stuff!!)
      • sarah do you just like the innate immune system because it's comprehensible? yes. yes i do. and you should too.
    • https://jamanetwork.com/journals/jamaoncology/fullarticle/2598488 works on cutaneous breast cancer metastatses.
      • note that it is TOPICAL.
      • really high complete response rates in metastatic cancers almost only occur when you have a topical/intratumoral/etc treatment physically localized to the tumor, frequently using an innate-immune mechanism.
        • that's also the literal majority of all historical cases of spontaneous tumor regressions -- they tend to happen when there's an infection at the tumor site, causing a powerful (innate! fever, inflammation, sepsis!) immune reaction.
        • the innate immune system is potent, and it is nasty, which is why you want to confine it.
• immune checkpoint inhibitors are real good for metastatic cancer:
  • https://www.tandfonline.com/doi/full/10.1080/2162402X.2016.1214788#abstract combined with radiotherapy, on melanoma brain metastases
  • https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.9537 on Merkel cell carcinoma, a skin cancer
  • https://www.nature.com/articles/npjgenmed201637 on liver and lung metastases of basal cell carcinoma
  • https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1078915/full in colon cancer
  • https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.615298/full in penile cancer
  • https://europepmc.org/article/med/36916116 in kidney cancer
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC11099454/ in pancreatic ductal adenocarcinoma (whoa)
• cell immunotherapies can also be amazing for metastatic cancer:
  • https://ar.iiarjournals.org/content/30/2/575.short this is a complete remission in metastatic renal cell carcinoma with adoptive gamma-delta T-cells (and IL-2; the innate immune system strikes again)
  • https://ascopubs.org/doi/full/10.1200/JCO.2014.58.9093 in cervical cancer, with tumor-infiltrating T cells
• https://www.nejm.org/doi/full/10.1056/NEJMoa2028485 here's an antibody-drug conjugate for metastatic breast cancer. not enough complete responses to make it into my post, but look at that sweet Kaplan-Meier curve.
• https://link.springer.com/article/10.1245/s10434-018-07143-4 isolated limb perfusion for melanoma: get higher doses of chemo into the tumor than the patient could survive otherwise, by cutting off circulation to the limb. when this sort of thing is possible, it really, really works.
  • https://link.springer.com/article/10.1245/s10434-011-2030-7 and more.
• https://link.springer.com/article/10.1186/s40425-018-0337-7 this is an oncolytic virus (intratumoral!) for metastatic melanoma.
• https://link.springer.com/article/10.1186/s40425-018-0337-7 more oncolytic viruses that work! (also metastatic melanoma, also intralesional).
• https://link.springer.com/article/10.1007/s10549-022-06678-1 I hate on growth factor-targeted therapies a lot, but there are exceptions. Herceptin is a real drug. Look at this. 69 HER2+ patients presenting with metastatic breast cancer and treated with trastuzumab as part of their initial treatment, 54% get a complete response. 41% survived 5+ years after diagnosis. This is really, really solid.
• electrochemotherapy is injecting tumors with cytotoxic drugs and electroporating the tumor so the drugs get in better.
  • It's only possible when you can physically access the tumor, i.e. when it's on the skin or when you're operating anyway (but can't surgically remove the tumor, because if you could, you would just do that).
  • it also, really, really works.  https://onlinelibrary.wiley.com/doi/full/10.1002/jso.23625
• https://cccblog.org/2018/06/13/the-surprising-security-benefits-of-end-to-end-formal-proofs/
  • if you can prove your computer program does what it's supposed to -- for almost any reasonable interpretation of "what it's supposed to" -- you will, as a side effect, also prove it doesn't have common security flaws like buffer overflows.
• people I looked up while reading Neal Stephenson's Baroque Cycle:
  • https://en.wikipedia.org/wiki/Caroline_of_Ansbach
  • https://en.wikipedia.org/wiki/Sophia_Charlotte_of_Hanover
  • https://en.wikipedia.org/wiki/Princess_Eleonore_Erdmuthe_of_Saxe-Eisenach
  • https://en.wikipedia.org/wiki/Sophia_of_Hanover

https://roamresearch.com/#/app/srcpublic/page/10-11-2024

• https://www.mindthefuture.info/p/why-im-not-a-bayesian [[Richard Ngo]] [[philosophy]] I think I agree with this, mostly.
  • I wouldn't say "not a Bayesian" because there's nothing wrong with Bayes' Rule and I don't like the tribal connotations, but lbr, we don't literally use Bayes' rule very often and when we do it often reveals just how much our conclusions depend on problem framing and prior assumptions. A lot of complexity/ambiguity necessarily "lives" in the part of the problem that Bayes' rule doesn't touch. To be fair, I think "just turn the crank on Bayes' rule and it'll solve all problems" is a bit of a strawman -- nobody literally believes that, do they? -- but yeah, sure, happy to admit that most of the "hard part" of figuring things out is not the part where you can mechanically apply probability.
• https://www.lesswrong.com/posts/YZvyQn2dAw4tL2xQY/rationalists-are-missing-a-core-piece-for-agent-like [LW · GW] [[tailcalled]] this one is actually interesting and novel; i'm not sure what to make of it. maybe literal physics, with like "forces", matters and needs to be treated differently than just a particular pattern of information that you could rederive statistically from sensory data? I kind of hate it but unlike tailcalled I don't know much about physics-based computational models...[[philosophy]]
• https://alignbio.org/ [[biology]] [[automation]] datasets generated by the Emerald Cloud Lab! [[Erika DeBenedectis]] project. Seems cool!
• https://www.sciencedirect.com/science/article/abs/pii/S0306453015009014?via%3Dihub [[psychology]] the forced swim test is a bad measure of depression.
  • when a mouse trapped in water stops struggling, that is not "despair" or "learned helplessness." these are anthropomorphisms. the mouse is in fact helpless, by design; struggling cannot save it; immobility is adaptive.
    • in fact, mice become immobile faster when they have more experience with the test. they learn that struggling is not useful and they retain that knowledge.
  • also, a mouse in an acute stress situation is not at all like a human's clinical depression, which develops gradually and persists chronically.
  • https://www.sciencedirect.com/science/article/abs/pii/S1359644621003615?via%3Dihub the forced swim test also doesn't predict clinical efficacy of antidepressants well. (admittedly this study was funded by PETA, which thinks the FST is cruel to mice)
• https://en.wikipedia.org/wiki/Copy_Exactly! [[semiconductors]] the Wiki doesn't mention that Copy Exactly was famously a failure. even when you try to document procedures perfectly and replicate them on the other side of the world, at unprecedented precision, it is really really hard to get the same results.
• https://neuroscience.stanford.edu/research/funded-research/optimization-african-killifish-platform-rapid-drug-screening-aggregate [[biology]] you know what's cool? building experimentation platforms for novel model organisms. Killifish are the shortest-lived vertebrate -- which is great if you want to study aging. they live in weird oxygen-poor freshwater zones that are hard to replicate in the lab. figuring out how to raise them in captivity and standardize experiments on them is the kind of unsung, underfunded accomplishment we need to celebrate and expand WAY more.
• https://www.nature.com/articles/513481a [[biology]] [[drug discovery]] ever heard of curcumin doing something for your health? resveratrol? EGCG? those are all natural compounds that light up a drug screen like a Christmas tree because they react with EVERYTHING. they are not going to work on your disease in real life.
  • they're called PAINs, pan-assay interference compounds, and if you're not a chemist (or don't consult one) your drug screen is probably full of 'em. false positives on academic drug screens (Big Pharma usually knows better) are a scourge. https://en.wikipedia.org/wiki/Pan-assay_interference_compounds
  • sadly, while they make automated PAINs alerts, they don't work for shit. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411023/ sorry, shut-ins and cheapskates; you might have to talk to an actual chemist.
• https://en.wikipedia.org/wiki/Fetal_bovine_serum [[biotech]] this cell culture medium is just...cow juice. it is not consistent batch to batch. this is a big problem.
• https://www.nature.com/articles/s42255-021-00372-0 [[biology]] mice housed at "room temperature" are too cold for their health; they are more disease-prone, which calls into question a lot of experimental results.
• https://calteches.library.caltech.edu/51/2/CargoCult.htm [[science]] the famous [[Richard Feynman]] "Cargo cult science" essay is about flawed experimental methods!
  • if your rat can smell the location of the cheese in the maze all along, then your maze isn't testing learning.
  • errybody want to test rats in mazes, ain't nobody want to test this janky-ass maze!
• https://fastgrants.org/ [[metascience]] [[COVID-19]] this was cool, we should bring it back for other stuff
• https://erikaaldendeb.substack.com/cp/147525831 [[biotech]] engineering biomanufacturing microbes for surviving on Mars?!
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278038/ [[prediction markets]] DARPA tried to use prediction markets to predict the success of projects. it didn't work! they couldn't get enough participants.
• https://www.citationfuture.com/ [[prediction markets]] these guys do prediction markets on science
• https://jamesclaims.substack.com/p/how-should-we-fund-scientific-error [[metascience]] [[James Heathers]] has a proposal for a science error detection (fraud, bad research, etc) nonprofit. We should fund him to do it!!
• https://en.wikipedia.org/wiki/Elisabeth_Bik [[metascience]] [[Elizabeth Bik]] is the queen of research fraud detection. pay her plz.
• https://substack.com/home/post/p-149791027 [[archaeology]] it was once thought that Gobekli Tepe was a "festival city" or religious sanctuary, where people visited but didn't live, because there wasn't a water source. Now, they've found something that looks like water cisterns, and they suspect people did live there.
  • I don't like the framing of "hunter-gatherer" = "nomadic" in this post.
    • We keep pushing the date of agriculture farther back in time. We keep discovering that "hunter-gatherers" picking plants in "wild" forests are actually doing some degree of forest management, planting seeds, or pulling undesirable weeds. Arguably there isn't a hard-and-fast distinction between "gathering" and "gardening". (Grain agriculture where you use a plow and completely clear a field for planting your crop is qualitatively different from the kind of kitchen-garden-like horticulture that can be done with hand tools and without clearing forests. My bet is that all so-called hunter-gatherers did some degree of horticulture until proven otherwise, excepting eg arctic environments)
    • what the water actually suggests is that people lived at Gobekli Tepe for at least part of the year. it doesn't say what they were eating.
    •  

links 11/15/2024: https://roamresearch.com/#/app/srcpublic/page/11-15-2024

• https://www.reddit.com/r/self/comments/1gleyhg/people_like_me_are_the_reason_trump_won/  a moderate/swing-voter (Obama, Trump, Biden) explains why he voted for Trump this time around:
  • he thinks Kamala Harris was an "empty shell" and unlikable and he felt the campaign was manipulative and deceptive.
  • he didn't like that she seemed to be a "DEI hire", but doesn't have a problem with black or female candidates generally, it's just that he resents cynical demographic box-checking.
    • this is a coherent POV -- he did vote for Obama, after all. and plenty of people are like "I want the best person regardless of demographics, not a person chosen for their demographics."
      • hm. why doesn't it seem natural to portray Obama as a "DEI hire"? his campaign made a bigger deal about race than Harris's, and he was criticized a lot for inexperience.
        • One guess: it's laughable to think Obama was chosen by anyone besides himself. He was not the Democratic Party's anointed -- that was Hillary. He's clearly an ambitious guy who wanted to be president on his own initiative and beat the odds to get the nomination. He can't be a "DEI hire" because he wasn't a hire at all.
        • another guess: Obama is clearly smart, speaks/writes in complete sentences, and welcomes lots of media attention and talks about his policies, while Harris has a tendency towards word salad, interviews poorly, avoids discussing issues, etc.
        • another guess: everyone seems to reject the idea that people prefer male to female candidates, but I'm still really not sure there isn't a gender effect! This is very vibes-based on my part, and apparently the data goes the other way, so very uncertain here.
• https://trevorklee.substack.com/p/if-langurs-can-drink-seawater-can  Trevor Klee on adaptations for drinking seawater

links 9/14/2024: https://roamresearch.com/#/app/srcpublic/page/11-14-2024

• https://archive.org/details/byte-magazine  retro magazines
• https://www.ribbonfarm.com/2019/09/17/weirding-diary-10/#more-6737 Venkatesh Rao on the fall of the MIT Media Lab
  • this stung a bit!
  • i have tended to think that the stuff with "intellectual-glamour" or "visionary" branding is actually pretty close to on-target. not always right, of course, often overhyped, but often still underinvested in even despite being highly hyped.
    • (a surprising number of famous scientists are starved for funding. a surprising number of inventions featured on TED, NYT, etc were never given resources to scale.)
  • I also am literally unconvinced that "Europe's kindergarten" was less sophisticated than our own time! but it seems like a fine debate to have at leisure, not totally sure how it would play out.
  • he's basically been proven right that energy has moved "underground" but that's not a mode i can work very effectively in. if you have to be invited to participate, well, it's probably not going to happen for me.
  • at the institutional level, he's probably right that it's wise to prepare for bad times and not get complacent. again, this was 2019; a lot of the bad times came later. i miss the good times; i want to believe they'll come again.

links 11/13/2024: https://roamresearch.com/#/app/srcpublic/page/11-13-2024

• https://amaranth.foundation/bottlenecks-of-aging the Amaranth Foundation's bottlenecks of aging
• https://www.celinehh.com/aging-field Celine Halioua on what the aging field needs -- notably, more biotech companies that are prepared to run their own clinical trials specifically for aging-related endpoints.
  • a typical new biotech company never runs its own clinical trials -- they license, partner, or get bought by pharma. but pharma's not that into aging (yet) and nobody really has expertise in running aging-focused clinical trials, so that may need to happen first in a startup context. which means some investors have to be willing to put up more cash than usual....
• https://en.wikipedia.org/wiki/Rapid_eye_movement_sleep_behavior_disorder is the rare sleep disorder that almost always progresses to Parkinson's about 20 years later
• https://pubmed.ncbi.nlm.nih.gov/12208347/ lipofuscin = cross-links.
  • it's a "brown-yellow" pigmented substance (first observed under the microscope in the 19th century) that accumulates in post-mitotic cells with age.
  • it's not one substance; it's a mixture of "garbage" (mostly protein and lipid) that accumulates around the lysosome but can't be disposed of through exocytosis.
  • it's "autofluorescent" -- it fluoresces in various wavelengths of light without being stained.
  • it accumulates more under conditions of oxidative stress like high-oxygen environments or in the presence of iron (which catalyzes oxidation reactions); it accumulates less in the presence of antioxidants and under caloric restriction.
  • evidence that lipofuscin accumulation causes disease or dysfunction seems a lot shakier in this paper.
• https://barnacles.substack.com/p/understanding-as-an-art Laura Deming on visualization and the spiritual side of science
  • I was a little self-conscious about her dissatisfaction with "San Francisco courtier culture" -- of course she's much better at the hustle than I ever was, but I actually love it. If anything, I've more often felt hurt that so many people I know got sick of the game before I ever really figured out how to play it.
• https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1824-y  some critiques of methylation clocks; the first one actually seems to have been an artifact of different distributions of cell types between old and young samples.
• https://www.science.org/content/article/scientific-showdown-seeks-biological-clock-best-tracks-aging  a contest for the best aging clock at predicting future mortality.
• https://www.exactsciences.com/ cancer prognostic/diagnostic biomarker company
• https://arxiv.org/abs/2411.04872  Epoch AI's new math benchmark of original, very hard problems
• https://arxiv.org/abs/2406.08467  a new benchmark for formal verification "hint" generation in the Dafny programming language
• https://dafny.org/ "Dafny is a verification-aware programming language that has native support for recording specifications and is equipped with a static program verifier."
  • Dafny's formal verification is based on automated SMT solvers; compared to proof assistants like Coq/Lean/etc it's less powerful
  • Dafny can be compiled to familiar languages such as such as C#, Java, JavaScript, Go and Python
  • https://www.reddit.com/r/rust/comments/1fs12l9/what_do_you_rustaceans_think_of_dafny_language/ Rust users don't think Dafny is practical for programming "real" things in.
• https://manifund.org/projects/hire-a-dev-to-finish-and-launch-our-dating-site Shreeda Segan's OKC-clone dating site needs $10,000 to build an MVP
• https://en.m.wikipedia.org/wiki/Eubulides the guy who brought you lists of paradoxes
• https://en.m.wikipedia.org/wiki/Epimenides_paradox  "Epimenides the Cretan says, all Cretans are liars"
  • as my 6-year-old son Simon pointed out, this is not actually a paradox; to be a "liar" doesn't mean every statement you utter is a lie.
  • Epimenides himself didn't intend it to be a paradox. Apparently he disagreed with his fellow Cretans about the immortality of the god Zeus.
    • They fashioned a tomb for thee, O holy and high one
    • The Cretans, always liars, evil beasts, idle bellies!
    • But thou art not dead: thou livest and abidest forever,
    • For in thee we live and move and have our being.
    • — Epimenides, Cretica
  • Wikipedia seems to trace the idea that this is a "paradox" to Bertrand Russell.
• https://en.m.wikipedia.org/wiki/Peter_the_Great
  • this is really badly written for a Wikipedia page. i suspect some kind of nationalist vandalism.
  • https://en.wikipedia.org/wiki/Russian_conquest_of_Siberia most of the conquest of Siberia actually happened before Peter the Great
    • https://en.wikipedia.org/wiki/Yermak_Timofeyevich the Cossack ataman who began the conquest of Siberia, under the reign of Ivan the Terrible in the 1500s.
      • why conquer Siberia? the fur trade.
      • why did it work? the khans didn't have firearms.
      • he was hired by a powerful merchant family, the Stroganovs
        • https://en.wikipedia.org/wiki/Stroganov_family
      • wow. this is a very close parallel (and historically contemporaneous) with the conquistadors and privateers of England, Spain, and Portugl in the Age of Exploration...except we don't make movies and novels about it in the West. But the swashbuckling potential is amazing.
        • i mean there was also genocide, to be fair.
• https://daviddfriedman.substack.com/p/libertarian-poems
  • I'll kind of give him Kipling and Cummings; those are genuine anti-communist, anti-monarchical-absolutism, and anti-war sentiments. Yeats is doing a different thing; I love him but he is Not Our Friend.
• https://www.pewresearch.org/short-reads/2024/10/24/majority-of-americans-arent-confident-in-the-safety-and-reliability-of-cryptocurrency/ wow -- a full 17% of Americans have ever owned crypto.

links 10/28/2024: https://roamresearch.com/#/app/srcpublic/page/10-28-2024

• Vincent deVita, chemotherapy pioneer, reflecting on how cancer research has changed (and become more bureaucratic) since the 1960s:
  • https://www.nature.com/articles/nrclinonc.2009.51
  • https://aacrjournals.org/cancerres/article/68/21/8643/541799/A-History-of-Cancer-Chemotherapy
  • https://cancerhistoryproject.com/article/vince-devita-on-the-history-of-chemotherapy/
  • https://www.yalemedicine.org/podcasts/cancer-answers-the-history-of-chemotherapy-july-6-2008
  • https://www.sciencefriday.com/articles/where-we-are-in-the-war-on-cancer/
  • https://vincenttdevitajrmdoncancer.blogspot.com/
• Michael Levin has his own team (of ~20) at Tufts working on morphogenetics: https://allencenter.tufts.edu/
  • with a $10M founding grant from the Allen Foundation, which I expect will not be enough to complete this research program. https://alleninstitute.org/news/the-paul-g-allen-frontiers-group-announces-allen-discovery-center-at-tufts-university/
•  

links 10/8/24 https://roamresearch.com/#/app/srcpublic/page/10-08-2024

links 11/01/2024: https://roamresearch.com/#/app/srcpublic/page/11-01-2024

• https://en.m.wikipedia.org/wiki/Neats_and_scruffies a typology of AI researchers
• https://notes.andymatuschak.org/About_these_notes Andy Matuschak's working notes, mostly about educational technology (but not educational games!)
  • https://notes.andymatuschak.org/zUVBJdPc4kBud5fsLmPFpbw
• https://notes.manjarinarayan.org/ Manjari Narayan's notes, mostly about statistics
• https://www.washingtonpost.com/health/2024/05/06/ultrasound-addiction-treatment/ ultrasound being used as an addiction treatment -- the full study results aren't published yet, but the anecdotes suggest very dramatic effects.
• all drugs for neuropathic pain have poor success rates.
  • https://jamanetwork.com/journals/jamaneurology/fullarticle/2769608#google_vignette
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC6452908/
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC10711341/
• https://pubmed.ncbi.nlm.nih.gov/24291734/ lots of people -- maybe 6-10% of the world population -- have neuropathic pain.
• https://pmc.ncbi.nlm.nih.gov/articles/PMC3201926/ chronic pain generally affects about 20% of adults worldwide.
  • https://www.ncbi.nlm.nih.gov/books/NBK553030/
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC3201926/
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC6676152/
• roughly half of opioid addicts treated with buprenorphine or methadone manage to abstain for 30 days after treatment: https://pubmed.ncbi.nlm.nih.gov/26599131/
• https://www.whitehouse.gov/ondcp/briefing-room/2021/05/28/biden-harris-administration-calls-for-historic-levels-of-funding-to-prevent-and-treat-addiction-and-overdose/ the Biden-Harris administration has allocated $41B to preventing and treating drug addiction; hard to extract from that exactly how much is spent on rehab/treatment vs. anti-drug campaigns or law enforcement
  • https://www.forbes.com/sites/danmunro/2015/04/27/inside-the-35-billion-addiction-treatment-industry/ US addiction treatment spending was estimated at $35B/year back in 2015
• Vampire Weekend's Ezra Koenig:
  • their latest album Only God Was Above Us is wrenching and it's kind of getting to me lately.
    • most of the commentary in interviews is about how Koening, now 40 with a 5-year-old kid, has matured and found peace (though if you listen to the lyrics it's an extremely nihilistic sort of being "at peace" with a terrible world and giving up on trying to change it)
    • nobody is remarking on what I see as pretty explicit themes like:
      • last album's "Harmony Hall" was about a sense of betrayal regarding Ivy-League antisemitism
      • this album is pretty clearly a rejection of the backlash, the Gen-X ("Gen X Cops"), ex-Eastern-Bloc ("Pravda"), or specifically Jewish (in the [[Bari Weiss]]/Tablet-mag vein) "vibe shift".
        • there's a lot of reflection on heritage and generation gaps, there's the sense that someone (his elders? his family?) is pushing him in a direction and he doesn't want to go that way, he thinks it doesn't make sense in his generation, in this era, but he does care enough to be conflicted and to yearn over the pain of people still (mistakenly, he thinks) struggling ("Capricorn").
  • https://en.wikipedia.org/wiki/Ezra_Koenig
  • https://people.com/vampire-weekend-ezra-koenig-finally-feels-adult-exclusive-8625179
  • https://www.theguardian.com/us-news/2016/jun/20/bernie-sanders-vampire-weekend-grizzly-bear-endorsements
  • https://www.theguardian.com/music/2024/mar/23/ezra-koenig-vampire-weekend-interview
  • https://www.thejc.com/life-and-culture/music/vampire-weekend-dont-call-us-white-c3xbezac

links 10/1/24

https://roamresearch.com/#/app/srcpublic/page/10-01-2024

links 11/18/2024: https://roamresearch.com/#/app/srcpublic/page/11-18-2024

• [[links]]
  • https://en.m.wikipedia.org/wiki/Nicholas_Roerich  I like his art; he seems to have led an interesting life
  • https://en.m.wikipedia.org/wiki/Maurice_Quentin_de_La_Tour Rococo portraits
  •  
  • https://www.zach.be/p/yc-is-wrong-about-llms-for-chip-design
    • this doesn't seem to be a coherent argument -- author claims both that LLMs will indeed be used by chip design companies to save on human labor, and that they're not very good and can only replace the more routine parts of a chip designer's work. But...this isn't "YC is wrong, there is not a startup opportunity in using LLMs for chip design!" even if it's true it's just a more measured and realistic picture of what LLMs will be doing in chip design!
      • and they even make sure to shill their own AI-for-chip-hardware startup, which they claim is working on challenges that nobody else is: https://www.normalcomputing.com/
  • https://www.programmablemutter.com/p/how-chaotic-is-trump-ii-going-to speculation about Donald Trump's foreign policy
  • https://en.m.wikipedia.org/wiki/Daniel_Defoe  i want to read his nonfiction
  • https://en.m.wikipedia.org/wiki/Kotex sanitary pads have been around since 1920
  • https://asteriskmag.com/issues/08/the-death-and-life-of-prediction-markets-at-google  the tl;dr: Google's first internal prediction market was intended to go public and stalled as the regulatory environment remained unfriendly; its successor focused on predictions about competitor activity rather than Google's own activity (which is less subject to "office politics" considerations blocking an honest assessment of Google's chances of success etc) and never intended to be public-facing, and is still in active use.
  • https://en.m.wikipedia.org/wiki/Fran%C3%A7oise_d%27Aubign%C3%A9,_Marquise_de_Maintenon
  • https://en.m.wikipedia.org/wiki/Madame_de_Pompadour  patroness of the French Enlightenment.
    • "who was that woman who was an influential mistress to the King of France, politically savvy and queen in all but name"? "which one? this just keeps happening"
  • https://nintil.com/dont-assume this is Jose Luis Ricon life advice, which unsurprisingly tells you to be less afraid of things and talk to people more.
    • shan't.
  • https://en.m.wikipedia.org/wiki/Bill_Monroe
  • https://calisphere.org/item/0bc1137c37161874ded76c71bf982409/  scary guys
  •  

links 11/07/2024: https://roamresearch.com/#/app/srcpublic/page/11-07-2024

• on Donna Karan
  • https://www.vogue.com/slideshow/donna-karan-seven-career-highlights-cold-shoulder
  • https://www.vogue.com/article/donna-karan-vintage
• https://du42p.r.a.d.sendibm1.com/mk/mr/sh/1f8JAEjGcfF85pENVqcuM6hh5D/tiVMw3KFimvC?fbclid=IwY2xjawGZnpRleHRuA2FlbQIxMQABHdHszEMzS3x1Xda2tTh60KMighJEJKDe30rsduQmFydSSyfTpK8mwG50vg_aem_IjjUQWdiwZf2AdgdLo9azA opinion on how hormonal contraception should be done differently -- I'm intrigued but I haven't yet checked these claims out
• http://esr.ibiblio.org/?p=8720 Eric S. Raymond on "user stories" done right and wrong
• https://endpts.com/biotech-industry-worries-over-potential-for-rfk-jr-ally-as-fda-pick/ Casey Means has been floated as the new pick for FDA head; apparently she's expressed concerns about vaccines and over-medication on the Joe Rogan podcast and has written a book about how most chronic diseases can be prevented by healthy lifestyles (which probably overstates the case)
• https://www.slowboring.com/p/the-tyranny-of-climate-targets Matt Yglesias on why a lot of aggressive climate targets are impossible to actually meet.
  • why do people try anyway? if it's "cheap talk", why is there so much costly, substantive follow-through? incentive misalignment, I suppose?
• https://www.gordian.bio/blog/the-in-vivo-screening-revolution/ Martin Borch Jensen on in-vivo screening 

links 10/30/2024: https://roamresearch.com/#/app/srcpublic/page/10-30-2024

• https://pmc.ncbi.nlm.nih.gov/articles/PMC10136898/ FRET is a biosensor modality.
  • "FRET is a non-radiative transfer of energy from an excited donor fluorophore molecule to a nearby acceptor fluorophore molecule...When the biomolecule of interest is present, it can cause a change in the distance between the donor and acceptor, leading to a change in the efficiency of FRET and a corresponding change in the fluorescence intensity of the acceptor. This change in fluorescence can be used to detect and quantify the biomolecule of interest."
  • advantages:
    • real-time
    • non-destructive
    • sensitive to very low concentrations (picomolar and nanomolar)
    • highly specific because it detects conformational changes in biological molecules
  • this article is from a not-great journal and the author clearly does not have English as a first language... at some point i will need a more reputable source, this was from googling FRET quickly
• https://www.astralcodexten.com/p/the-case-against-proposition-36 Clara Collier gives the narrow, evidence-based case that shorter jail sentences didn't cause California's property crime wave or drug overdose death epidemic, and longer jail sentences won't fix those problems
  • I'm pretty convinced but I don't follow this topic in great detail
• metastatic malignant peripheral nerve sheath tumor  is pretty bad -- median survival is only 8 months after metastases are detected. but one M.O. that seems to help in several case studies is "sequence the tumor, find a mutation, use a drug that's approved for other cancer types with the same mutation."
  • PD-L1 overexpression? use a PD-1 inhibitor! checkpoint immunotherapy stays winning.
    • https://www.spandidos-publications.com/10.3892/ol.2024.14556 sintilimab
    • https://aacrjournals.org/cancerimmunolres/article/7/9/1396/470072/PD-1-Inhibition-Achieves-a-Complete-Metabolic pembrolizumab
    • https://scholars.uthscsa.edu/en/publications/pembrolizumab-achieves-a-complete-response-in-an-nf-1-mutated-pd- pembrolizumab
    • https://ascopubs.org/doi/abs/10.1200/PO.18.00375 nivolumab
  • BRAF V600E mutation? try a BRAF inhibitor!
    • https://jnccn.org/view/journals/jnccn/11/12/article-p1466.xml vemurafenib
  • other Raf stuff: maybe sorafenib?
    • https://www.tandfonline.com/doi/abs/10.4161/cbt.7.6.5932
  • shit that doesn't work:
    • sirolimus https://onlinelibrary.wiley.com/doi/full/10.1155/2020/5784876
  • chemo is...not great but better than nothing. some partial responses, no complete responses, survival extended by maybe a few months. mostly it seems best to have doxorubicin in the mix.
    • https://onlinelibrary.wiley.com/doi/full/10.1155/2017/8685638
    • https://ascopubs.org/doi/abs/10.1200/JCO.2024.42.16_suppl.11583
    • https://www.sciencedirect.com/science/article/pii/S0923753419377907
    • https://ascopubs.org/doi/abs/10.1200/jco.2010.28.15_suppl.e20512
    • https://onlinelibrary.wiley.com/doi/full/10.1155/2011/705345 ok here's a complete response to chemo + surgery. it can ever happen.
    • https://ar.iiarjournals.org/content/40/3/1619.short case of long-term survival after keeping chemotherapy going a *really long time* at gradually decreasing dose and widening inter-treatment interval.
  • https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.33201 pazopanib, an angiogenesis inhibitor, similarly has a low response rate but can extend survival a bit
• https://proof-scaling-meeting.vercel.app/ formal verification conference
• https://chalmermagne.substack.com/p/death-by-a-thousand-roundtables what it's actually like to work in UK policy. sounds dismal.
• https://www.972mag.com/lavender-ai-israeli-army-gaza/ AI bombing. critical perspective on Israel.
• https://goingon.org/ a timeline-based, "citizen journalism" news site.
• https://statistics.berkeley.edu/about/news/steinhardt-announces-co-founding-transluce-non-profit-ai-research-lab AI interpretability nonprofit, Jacob Steinhardt
  • mech-interp seems like straightforwardly real and good work from a variety of perspectives on AI. helps with many risk scenarios including some x-risk scenarios; helps make the technology stronger & more reliable, which is good for the industry in the long run.
• https://blog.benjaminreinhardt.com/young-people-technical-training this is straightforwardly true, yes, you should learn technical stuff.
• https://www.washingtonpost.com/opinions/2024/10/28/jeff-bezos-washington-post-trust/ Jeff Bezos on why the Washington Post isn't endorsing a Presidential candidate. this is a solidly written persuasive essay; it seemed legit to me, but I could be persuaded otherwise.
•  

links 10/29/2024: https://roamresearch.com/#/app/srcpublic/page/10-29-2024

• https://www.theguardian.com/news/2024/oct/29/acute-psychosis-inner-voices-avatar-therapy-psychiatry  a therapist acting out the voices in your head might be an effective treatment for psychosis
• https://www.futurehouse.org/research-announcements/wikicrow SOTA (?) paper summarization from FutureHouse

links 10/23/24:

https://roamresearch.com/#/app/srcpublic/page/10-23-2024

• https://eukaryotewritesblog.com/2024/10/21/i-got-dysentery-so-you-dont-have-to/  personal experience at a human challenge trial, by the excellent Georgia Ray
• https://catherineshannon.substack.com/p/the-male-mind-cannot-comprehend-the
  • I...guess this isn't wrong, but it's a kind of Take I've never been able to relate to myself. Maybe it's because I found Legit True Love at age 22, but I've never had that feeling of "oh no the men around me are too weak-willed" (not in my neck of the woods they're not!) or "ew they're too interested in going to the gym" (gym rats are fine? it's a hobby that makes you good-looking, I'm on board with this) or "they're not attentive and considerate enough" (often a valid complaint, but typically I'm the one who's too hyperfocused on my own work & interests) or "they're too show-offy" (yeah it's irritating in excess but a little bit of show-off energy is enlivening).
  • Look: you like Tony Soprano because he's competent and lives by a code? But you don't like it when a real-life guy is too competitive, intense, or off doing his own thing? I'm sorry, but that's not how things work.
    • Tony Soprano can be light-hearted and always have time for the women around him because he is a fictional character. In real life, being good at stuff takes work and is sometimes stressful.
    • My husband is, in fact, very close to this "Tony Soprano" ideal -- assertive, considerate, has "boyish charm", lives by a "code", is competent at lots of everyday-life things but isn't too busy for me -- and I guarantee you would not have thought to date him because he's also nerdy and argumentative and wouldn't fit in with the yuppie crowd.
    • Also like. This male archetype is a guy who fixes things for you and protects you and makes you feel good. In real life? Those guys get sad that they're expected to give, give, give and nobody cares about their feelings. I haven't watched The Sopranos but my understanding is that Tony is in therapy because the strain of this life is getting to him. This article doesn't seem to have a lot of empathy with what it's like to actually be Tony...and you probably should, if you want to marry him.
• https://fas.org/publication/the-magic-laptop-thought-experiment/ from Tom Kalil, a classic: how to think about making big dreams real.
• https://paulgraham.com/yahoo.html Paul Graham's business case studies!
• https://substack.com/home/post/p-150520088 a celebratory reflection on the recent Progress Conference. Yes, it was that good.
• https://en.m.wikipedia.org/wiki/Hecuba  in some tellings (not Homer's), Hecuba turns into a dog from grief at the death of her son.
• https://www.librariesforthefuture.bio/p/lff
  • a framework for thinking about aging: "1st gen" is delaying aging, which is where the field started (age1, metformin, rapamycin), while "2nd gen" is pausing (stasis), repairing (reprogramming), or replacing (transplanting), cells/tissues. 2nd gen usually uses less mature technologies (eg cell therapy, regenerative medicine), but may have a bigger and faster effect size.
  • "function, feeling, and survival" are the endpoints that matter.
    • biomarkers are noisy and speculative early proxies that we merely hope will translate to a truly healthier life for the elderly. apply skepticism.
• https://substack.com/home/post/p-143303463 I always like what Maxim Raginsky has to say. you can't do AI without bumping into the philosophy of how to interpret what it's doing.

links 10/9/24 https://roamresearch.com/#/app/srcpublic/page/yI03T5V6t

links 8/7/2024

https://roamresearch.com/#/app/srcpublic/page/yI03T5V6t

links 10/4/2024

https://roamresearch.com/#/app/srcpublic/page/10-04-2024

links 10/2/2024:

https://roamresearch.com/#/app/srcpublic/page/10-02-2024