links 11/20/2024: https://roamresearch.com/#/app/srcpublic/page/12-20-2024

• https://www.desmos.com/calculator an online graphing calculator
• https://www.complexsystemspodcast.com/episodes/warp-speed-joshua-morrison/ Patrick McKenzie and Joshua Morrison of OneDaySooner on pandemic preparedness
• https://ifp.org/the-case-for-clinical-trial-abundance a bunch of policy proposals from the Institute for Progress on reforming clinical trial rules to reduce the cost of bringing drugs to market

I don't want automatic messages; that seems too inhuman. I do want things like reminders to follow up with people I haven't talked to for a while, with context awareness for social appropriateness. like, i wouldn't know how to reach out to my roommate/best friend from college; we haven't talked in 16 years! but maybe the right app could keep that from happening in the first place, or create a new normalized type of social behavior that's "reaching out after a long time apart" or whatever.

links 12/18/2024: https://roamresearch.com/#/app/srcpublic/page/12-18-2024

• https://hearth.ai/thesis  keeping track of people you know. as an inveterate birthday-forgetter and someone too prone to falling out of touch with friends, I bet there are ways for AI tools to do helpful things here.
• https://www.statista.com/chart/33684/number-of-confirmed-human-h5n1-cases-by-exposure-source H5N1 cases by state. mostly California, mostly livestock handlers. 61 cases so far.
• https://www.theintrinsicperspective.com/p/consciousness-is-a-great-mystery Eric Hoel says that "consciousness researchers" straightforwardly agree on what consciousness is.
  • Consciousness is:
    • the subjective experience of perceiving; Thomas Nagel's "what it is like to be a bat"; qualia
    • awake states (as opposed to dreamless sleep, anaesthesia, coma, etc)
    • things we are mentally aware of (perceptions, thoughts, emotions, etc) as opposed to things we are not aware of (most autonomic processes, blindsight, "subconscious" motives)
  • the fact that we do not have a scientific account of what consciousness is made of, doesn't mean consciousness doesn't exist or is inherently mystical or incoherent. Isaac Newton had never heard of "H20" but he knew what water is. The point of science is to give explanations for the things we know about experientially but don't fully understand.
  • A "theory of consciousness" would allow us to, given some monitoring data of brain activity in an organism, determine whether the organism is conscious or not, and what it is conscious of.
    • is the anaesthesia patient conscious?
    • is the locked-in patient conscious?
    • which animals have consciousness?
  • I've long had a vague sense of suspicion around consciousness research and the idea of qualia, but I've never really been able to put my finger on why.
    • When defined crisply like this, it does seem clear that consciousness is a real, mundane thing (if a nurse says "the patient is unconscious" there's no confusion about what that means).
    • But why is consciousness mysterious? why is it a "hard problem"?
      • David Chalmers' "hard problem of consciousness" refers to the difficulty of explaining how physical processes give rise to subjective experiences. Even if you explained a lot of brain mechanisms that have to go on for us to consciously experience something, would that really cross the explanatory gap?
        • I think this is what has turned me off "consciousness", because I don't get why there's supposed to be a gap.
        • If we had some full explanation based on patterns of brain activity, like "you consciously perceive a bright light precisely when when the foo blergs the bar", then...I think there wouldn't be any mystery left!
          • I agree that e.g. "you see a bright light when the visual cortex is stimulated" is not enough, because you don't see it if you're unconscious, and we don't have a necessary-and-sufficient physical correlate of consciousness. but, like, Eric Hoel and apparently a lot of mainstream neuroscientists are saying that we could find such a thing.
        • I guess you could keep asking "ok, the foo blerging the bar produces the phenomenon we experience as consciousness, but why does it?" and it would be hard to come up with any experimental way to even approach that question...
          • but that's an "explanatory gap" that comes up everywhere and we're usually happy to live with.
          • it also depends what kind of "why" you want.
            • if you're asking "why does it produce consciousness" as in "what's the efficient cause?" or "how does it work to produce consciousness?" then I think all how-does-it-work questions are going to have to be about physical (or algorithmic) processes. and if you say "well but my subjective experience is not even really commensurate with these kinds of objectively observable processes, it's a different sort of thing, how can it ever emerge from them" then...you are SOL? "how" questions will never satisfy you?
            • if you're asking "why does it produce consciousness" in a final-cause sense, like what is the use of consciousness, then I think we can have fruitful ideas. "why don't organisms operate on pure blindsight" is an interesting question! (pace Peter Watts, i think it must have some evolutionary function or we wouldn't have it.)
        • I think p-zombies are stupid, obviously just because you can verbally say you're "imagining" something exactly the same down to every physical detail, but magically different in its properties, doesn't mean it's possible!
    • ok, so: my beef with "consciousness studies" is primarily with the non-physicalists who say that even if we had a perfect neural correlate of consciousness, we still wouldn't understand consciousness as a subjective experience. but what I didn't realize, is that there are neuroscientists interested in consciousness who just want to find that neural correlate, and don't necessarily have any weird philosophical assumptions.
• https://www.science.org/doi/10.1126/science.abj3259
  • The global neuronal workspace theory of consciousness says that consciousness is produced by an "interconnected network of prefrontal-parietal areas and many high-level sensory cortical areas."
    • early sensory processing is unconscious.
    • stimuli are sometimes attended to (made conscious), a process which involves sending (pre-processed) signals about the stimuli through the prefrontal and parietal areas which control executive function, and distributing them to a bunch of other areas of the brain as part of the current working context.
  • IIT is an information-theoretic theory of consciousness; it says that consciousness is measured by the power of a neuronal network to influence itself. "The more cause-effect power a system has, the more conscious it is."
•  

why wouldn't you want regexes?

links 12/16/2024: https://roamresearch.com/#/app/srcpublic/page/12-16-2024

https://people.mpi-sws.org/~dg/teaching/lis2014/modules/ifc-1-volpano96.pdf the Volpano-Smith-Irvine security type system assigns security levels to variables (like "high" and "low" security). You can either use type checking or information theory inequalities to verify properties like "information can't flow from low to high security."

• https://romyholland.substack.com/p/what-nobody-told-me-about-abortion a personal essay about the experience of abortion
  • tbh I was pretty alienated by this. this was mostly an essay about grief. I feel bad for her, of course, but I was kind of curious about the details of the physical/procedural experience and we don't get much of that.
  • some people feel grief about abortion, some don't. I've never had an abortion or miscarriage, but I've had children, and I can tell you, I didn't feel a seismic unprecedented maternal love
• https://www.hollywoodreporter.com/movies/movie-news/fifth-season-makeready-1236069133/  apparently there's a new script deal for an AI-based movie called Alignment
• https://mtlynch.io/human-code-reviews-1/  advice on being polite in code reviews

• https://www.rosemarykirstein.com/ Rosemary Kirstein's blog, author of the Steerswoman series. I love the books; the blog is mostly travel/event updates but she seems like a lovely person and has many SFF book recommendations.

   

plausible...but surely walking isn't "consummatory"? And turning on the DBS doesn't cause "automatic/involuntary" walking movements.

links 12/13/2024:

 https://arxiv.org/pdf/2407.00695 Minimo, an RL agent for jointly learning both conjectures and proofs in Peano from "intrinsic motivation"

• what is "intrinsic motivation" in RL?
  • https://arxiv.org/pdf/2203.02298 intrinsic motivation mechanisms include:
    • reward shaping, i.e. comparing the expected value of two possible states, so that the agent gets an incremental "reward" when it moves to a state with higher expected value
    • rewards based on novelty rather than expected success, such as assigning more reward to visiting novel states, or assigning more reward to states with high prediction error relative to the agent's model of the world
    •  
• https://github.com/p-doom/gc-minimo gc-Minimo, the "goal-conditional" version that involves subgoals
• https://pdoom.org/ AI organization, research aimed at AGI; young, educated European team, they seem smart (to my unsophisticated eye) and idealistic (they want to share/open-source as much as possible, in contrast to secretive for-profit AI labs)
• https://news.mit.edu/2024/noninvasive-imaging-method-can-penetrate-deeper-living-tissue-1211  new non-invasive laser imaging technique; label free; 700 nm deep.
  • aka, not useful for subcutaneous imaging in living mammals, but possibly quite useful for non-destructive imaging of organoids (mentioned in the article) or maybe invertebrates, embryoids, other small living things;
  • maybe also nondestructive imaging of surface cells in live mammals:
    • skin
    • eyes
    • surgically exposed tissues
      • when you're operating on a tumor, it's important to make sure you have clean margins; would tumor cells look different under this sort of "metabolic" imaging?
• https://xenaproject.wordpress.com/2024/12/11/fermats-last-theorem-how-its-going/ ongoing project to translate a proof of Fermat's Last Theorem into Lean.
  • https://xenaproject.wordpress.com/what-is-the-xena-project/ the Xena Project is a project to get undergraduate math majors to formalize things in Lean.
    • "One could imagine things like formally verified course notes, which would later turn into some searchable database, and then to a tool which attempts example sheet questions by applying theorems from the course".
    • "No available system currently has all of an undergraduate pure mathematics degree, so undergraduates can even contribute to research projects. Over ten Imperial maths undergraduates have contributed to Lean’s maths library, and there are plenty of students at other universities in the UK and beyond who have also got involved."
• https://reactormag.com/the-vampire-p-h-lee/ eerie, touching short story: what if, in early-2010's Tumblr, there were active vampire and werewolf communities?
• https://www.za-zu.com/blog/playbook how to cold-email at scale. apparently if you just send a bajillion emails from one account it can get marked as spam; there are methods to circumvent this.
• https://en.m.wikipedia.org/wiki/Kray_twins celebrity-esque 1960's British gangsters.
• https://www.nature.com/articles/s41591-024-03306-x
  • today in What Can't The Hypothalamus Do: stimulate the lateral hypothalamus and you get improved walking in recovery from spinal cord injury in mice, rats, and 2 humans.
    • appears to be specific to Vglut2 neurons (as shown by optogenetics)
    • got the patients to be able to climb stairs and walk 50 m, when they couldn't before, after 3 months of rehab (they had both had their spinal injury for many years prior without being able to walk/climb).
    • you can see from the emg data that both patients have way more leg muscle activation when trying to walk or raise their knees from a lying position when the DBS is on vs off
  • how crazy is this? the standard lists of things the lateral hypothalamus does don't include motor function. mostly it's autonomic stuff, arousal, hunger, and motivation/mood.
    • otoh it does directly innervate the motor cortex, spinal cord, cerebellum, etc
    • https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.639313/full and there's some evidence that stimulating orexin neurons in the lateral hypothalamus induces movement (in mice) and hypothalamic orexin neurons are necessary for motor adaptation to sensory feedback https://www.jneurosci.org/content/42/32/6243
• https://www.cognition.ai/blog/devin-generally-available  this worries me from a mundane security point of view, though maybe I'm excessively paranoid; do you really want an AI agent autonomously mucking about in your code repo and pushing changes? I've heard the argument that this doesn't really introduce more risk than a new junior developer (who might likewise be error-prone or even a crook) but my mind is not at ease.
• https://ideaharbor.xyz/ a cute site where people can post project ideas. some of them are not, y'know, possible. "Batteries that can store the internet in them for when your connection goes down."

"Schizo" as an approving term, referring to strange, creative, nonconformist (and maybe but not necessarily clinically schizophrenic) is a much wider meme online. it's even a semi-mainstream scientific theory that schizophrenia persists in the human population because mild/subclinical versions of the trait are adaptive, possibly because they make people more creative. And, of course, there's a psychoanalytic/continental-philosophy tradition of calling lots of things psychosis very loosely, including good things. This isn't one guy's invention!

if you are literally worried about the risk of inducing hallucinations, i would be more cautious about things like overusing recreational drugs or not getting enough sleep, and less paranoid (lol) about talking to people or engaging with ideas. 

links 12/10/24: https://roamresearch.com/#/app/srcpublic/page/12-10-2024

• https://hedy.org/hedy Hedy, an educational Python variant that works in multiple languages and has tutorials starting from zero
• https://www.bitsaboutmoney.com/archive/debanking-and-debunking/ Patrick McKenzie on "debanking"
  • tl;dr: yes, lots of legal businesses get debanked; no, he disagrees with some of the crypto advocates' characterization of the situation
  • in more detail:
    • you can lose bank account access, despite doing nothing unethical, for mundane business/credit-risk related reasons like "you are using your checking account as a small business bank account and transferring a lot of money in and out" or "you are a serial victim of identity theft".
      • this is encouraged by banking regulators but fundamentally banks would do something like this regardless.
    • FINCEN, the US treasury's anti-money-laundering arm, shuts down a lot of innocent businesses that do some kind of financial activity (like buying and selling gift cards) without proper KYC/AML controls. A lot of bodegas get shut down.
      • this is 100% a gov't-created issue and it's kind of tragic.
    • FDIC, which guarantees bank deposits in the event of a bank run, is also tasked with making rules against banks doing things that might lead to bank runs.
      • You know what might cause a run on a bank? A bunch of crypto-holders suddenly finding out their assets are worthless or gone, and wanting to cash out. To some extent, FDIC's statutory mandate does entitle it to tell banks not to serve the crypto sector too heavily, because crypto is risky.
      • Another thing the FDIC is entitled to do is regulate banking products to ensure that consumers are not misled into thinking their money is in an FDIC-insured institution when it isn't. Under that mandate, a lot of crypto-based consumer banking/trading products have gotten shut down.
      • This does amount to "FDIC doesn't like crypto", but it is in fact FDIC's job to regulate banking in ways related to preventing consumers from losing their savings. Patrick McKenzie is fine with this; given the picture he presents, if you are not fine with this, it basically means you're not fine with the existence of the FDIC. (Which is not an unheard-of position; it belongs in the same category as objecting to other New Deal innovations like going off the gold standard and creating the welfare state.)
    • Separately, In the Obama administration, Operation Chokepoint happened. the FDIC claimed that a wide variety of politically disfavored businesses (guns, pornography, fireworks, etc) were risky...because of the regulatory risk of FDIC disapproving of them.
      • unlike the crypto regulation, this is totally unrelated to things like bank run risk that are in FDIC's official mandate. It is simply using FDIC to punish businesses that someone in the government doesn't like. Patrick McKenzie considers it a "lawless" abuse of power.
    • The Fed & Treasury's refusal to allow Facebook to issue the Libra cryptocurrency was similarly politically motivated. Senators blamed Facebook (and the Cambridge Analytica scandal) for Trump's election and warned the CEOs of Visa, MasterCard, and Stripe not to engage with Libra. Patrick McKenzie also views this as the "naked exercise of power."
    • Politically motivated debanking of individuals is clearly possible -- it happened in Canada with the truckers' convoy. However, Patrick McKenzie does not think it is routine in the US today. It is a risk rather than a common reality.
    • However, he wants to insist that the "crypto agenda" of "crypto should be treated on an equal playing field with USD by the banking sector" is not going to protect ordinary people from getting debanked for being, say, bodega owners or gun enthusiasts or conservatives or pornographers. He views it as a crypto-specific lobbying agenda, pretty much separate from the civil-rights/authoritarianism issue of political debanking.
• https://austinvernon.site/blog/datacenterpv.html Austin Vernon's outline of how off-grid, solar-powered datacenters could work and be cost-effective
•  

it's an introspection/lived-experience/anecdotes from other people kind of thing, i don't have data, but yes i do believe this is true.

"Most people succumb to peer pressure", https://roamresearch.com/#/app/srcpublic/page/u3919iPfj

• Most people will do very bad things, including mob violence, if they are peer-pressured enough.
• It's not literally everyone, but there is no neurotype or culture that is immune to peer pressure.
  • Immunity to peer pressure is a rare accomplishment.
  • You wouldn't assume that everyone in some category would be able to run a 4-minute mile or win a math olympiad. It takes a "perfect storm" of talent, training, and motivation.
  • I'm not sure anybody "just" innately lacks the machinery to be peer-pressured. That's a common claim about autistics and loners, but I really don't think it fits observation. Lots of people "don't fit in" in one way, but are very driven to conform in other social contexts or about other topics.
  • Evidence that any culture (or subculture), present or past, didn't have peer pressure seems really weak.
    • there are environments where being independent-minded or high-integrity is valorized, but most of them still have covert peer-pressure dynamics.
  • Possibly all robust resistance to peer pressure is intentionally cultivated?
    • In other words, maybe it's not enough for a person to just not happen to feel a pull towards conformity. That just means they haven't yet encountered the triggers that would make them inclined to conform.
    • If someone really can't be peer-pressured, maybe they have to actually believe that peer pressure is bad and make an active effort to resist it. Even that doesn't always succeed, but it's a necessary condition.
• upshot #1: It may be appropriate to be suspicious of claims like "I just hang out with those people, I'm not influenced by them." Most people, in the long run, do get influenced by their peer group.
  • otoh I also don't think cutting off contact with anyone "impure", or refusing to read stuff you disapprove of, is either practical or necessary. we can engage with people and things without being mechanically "nudged" by them.
  • maybe the distinction between engaging in any way and viewing someone as your ingroup is important?
  • or maybe we just have to Get Good at resisting peer pressure (even though that's super hard and rare.) Otherwise the next time some terrible thing happens to be popular, we'll go along with it.
    • like...basic realism here. most things don't last forever, it is an extraordinary claim to say that your virtue would survive any change in your culture.
• upshot #2: "would probably have been a collaborator in Nazi Germany" is not actually that serious an accusation. it just means "like the majority of the population, not at all heroic." in good circumstances, non-heroes make perfectly fine friends and neighbors. in bad circumstances, they might murder you. that's what makes the circumstances bad!
  • and don't be too quick to assume that someone who's never been in bad circumstances would be a hero. it's just hard to tell ahead of time.

I agree, and I am a bit disturbed that it needs to be said.

At normal, non-EA organizations -- and not only particularly villainous ones, either! -- it is understood that you need to avoid sharing any information that reflects poorly on the organization, unless it's required by law or contract or something. The purpose of public-facing communications is to burnish the org's reputation. This is so obvious that they do not actually spell it out to employees.

Of COURSE any organization that has recently taken down unflattering information is doing it to maintain its reputation. 

I'm sorry, but this is how "our people" get taken for a ride. Be more cynical, including about people you like.

I'm still on Roam and using it every day. For me, it's not "a lot of work", it's what's necessary to keep track of my thoughts to the point that I feel like my mental workspace is clean. I've journaled a lot since I was a kid. I think better in writing. 

This is my permanent diary. I will probably have it for the rest of my life, if they keep supporting it. Twenty years from now, I'll want to know what I was doing today!

I also log literally all links of "general interest" in my browsing history in my public Roam. does anyone care? Probably not, but it matters to me.

Roam doesn't make me smarter. To be honest, in my current life I don't especially need to be smarter. But I do think it makes me more consistent and coherent. It helps me realize when I've had a thought before, and what thoughts I keep coming back to. It helps me "listen to my own voice", which is an antidote to peer pressure. And it helps me see change over time -- what things I've said in the past that seem foolish now, how long it takes me to emotionally process things (sometimes years!), etc. 

links 12/9/24

• https://gasstationmanager.github.io/ai/2024/11/04/a-proposal.html
  • a proposal that tentatively makes a lot of sense to me, for making LLM-generated code more robust and trustworthy.
  • the goal: give a formal specification (in e.g. Lean) of what you want the code to do; let the AI generate both the code and a proof that it meets the specification.
  • as a means to this end, a crowdsourced website called "Code With Proofs: The Arena", like LeetCode, where "players" can compete to submit code + proofs to solve coding challenges. This provides a source of training data for LLMs, producing both correct and incorrect (code, proof) pairs for each problem specification. A model can then be trained "given a problem specification, produce code that provably meets the specification".
    • In real life, the model would probably use the proof assistant's verifier directly at inference time, to ensure it only returned code + proofs that the automatic verifier confirmed were valid. It could use the error messages and intermediate feedback of the verifier to more efficiently search for code + proofs that were likely to be correct.
• https://en.wikipedia.org/wiki/Post-quantum_cryptography  I know nothing about this field but it sure looks like the cryptography people have come a long way towards being ready, if and when quantum computers start being able to break RSA
• https://en.m.wikipedia.org/wiki/Freik%C3%B6rperkultur  the German tradition of public nudity
• https://theconversation.com/japanese-scientists-were-pioneers-of-ai-yet-theyre-being-written-out-of-its-history-243762  this piece is gratuitously anti-Big Tech, but does present an interesting part of the history of neural networks.
  • In general I wonder why Americans tend to be blind to Japanese scientific/technological innovation these days! A lot of great stuff was invented in Japan!
• https://scratch.mit.edu/projects/editor/?tutorial=getStarted  a popular kids' programming language designed for making games and animations.
• https://bayesshammai.substack.com/p/conditional-on-getting-to-trade-your Ricki Heicklen on adverse selection
• https://www.complexsystemspodcast.com/episodes/teaching-trading-ricki-heicklen/ Patrick McKenzie and Ricki Heicklen on teaching trading. (It's mostly focused on the kind of quant finance you might see at a firm like Jane Street, not about managing your personal stock portfolio.)
• https://www.nature.com/articles/s41592-024-02523-znew nucleotide transformer model just dropped. Can be fine-tuned to do things like predict whether a sequence is a promoter, enhancer, or splice site.
• https://thecausalfallacy.com/p/disorder-at-the-starbucks I'm more civil-libertarian, but Charles Fain Lehman seems to be the thoughtful tough-on-crime advocate to keep an eye on.
  • I tend to think that the public will demand a certain level of safety and pleasantness in their environments no matter what, and it's the civil libertarian's job to find a way to deliver that without infringing anybody's rights and while avoiding undue cruelty/harm to those suspected of crime or viewed as "disorderly." If the public is unsatisfied, they will demand "tough on crime" policies sooner or later; we need to ensure that when they do, we end up with something reasonable and effective rather than overkill.
  • In that context, Lehman does seem concerned with using the least-harsh solutions where available. He recognizes that usually, if you want to deter a fairly mild public nuisance, you don't need to arrest or jail anybody, you just have cops and ordinary citizens tell troublemakers to knock it off, with escalating to tougher enforcement being an option that's usually not needed. We're on the same page that (valid) rules should be enforced, and that enforcement ultimately has to be backed by physical force, but ideally we wouldn't resort to force often. That's a reasonable basis for beginning to negotiate on policy.
  • OTOH his picture of reducing crime is entirely about calling for more enforcement, rather than addressing other points of failure like the lack of accountability (eg qualified immunity) for police generally. Lack of funding and tight restrictions on enforcement activities are not the only reason police might fail to enforce laws and catch criminals; sometimes they are gang-affiliated themselves, or are not bothering to do their jobs, in the fashion typical of any employee with infinite job security. When a police department is seriously dysfunctional, you're not going to get better public safety by giving it more funding and more freedom to operate.

• https://www.natesilver.net/p/part-ii-the-failed-rebrand-of-kamala Nate Silver on the failures of the Harris campaign
  • tl;dr: he thinks they defaulted to a weak message of "generic Democrat" because they lacked the conviction to push any other distinctive brand (and in some cases the situation made alternatives infeasible).
• https://www.biorxiv.org/content/10.1101/2024.08.29.610411v1  you can generate novel proteins with RFDiffusion and a new model called ChemNet by selecting for properties of a reaction site that indicate a better catalyst of a particular chemical reaction.
  • We're getting closer to designing new proteins to solve particular (chemical reaction) problems.
• https://worksinprogress.co/issue/the-world-of-tomorrow/ excellent Virginia Postrel article on progress aesthetics and why we have to go beyond nostalgia for the retro-future.
• https://minjunes.ai/posts/sleep/index.html how could we mimic the effects of the "short sleeper gene" so that everyone could get by on less sleep?
• https://www.complexsystemspodcast.com/episodes/defrauding-government-jetson-leder-luis/ Patrick McKenzie and Jetson Leder-Luis on defrauding the government.
  • the optimal amount of fraud is not zero; anti-fraud enforcement trades off against ease of use and we (as a nation) generally don't want to make it super hard to get government benefits
  • nonetheless benefits fraud does indeed happen. kind of a lot. "let's bill Medicare for stuff we don't do" or "let's take unemployment insurance for fake SSNs" or "let's take PPP funds for anything and everything, they literally said that we wouldn't have to pay back the "loan""
  • the US government is much more upset about any amount of money going to terrorists or foreign enemies than it is about larger amounts of money going to ordinary crooks or just people who are ineligible for the benefits in question. we almost have two processes for these types of "fraud"?
  • Jetson thinks government fraud-detection agencies are underfunded.
• https://www.complexsystemspodcast.com/episodes/fraud-choice-patrick-mckenzie/ Patrick McKenzie on fraud
  • most fraud prevention is managed by the financial sector, which is generally a good thing (far less expensive than court cases)
    • though it does often lead to the industry not really caring whether you are a fraudster or a fraud victim. either way you're a risk, which the bank doesn't like.
  • "one reason to buy services from the financial industry and not from the government is that the financial industry finds the statement “stealing from businesses is wrong” to be straightforwardly uncontroversial. A business owner would need to put some thought into whether they trust your local police department or district attorney to have the same belief. I apologize to non-American readers of this piece who believe I am spouting insanity. It has been an interesting few years in the United States."
    • I am an American and this sounds kind of Big If True to me too.
  • the reason firms put up annoying hurdles for their customers is often to screen for fraudsters. I already knew this, but somehow i did not realize that when they ask you for a phone call, they are not doing this because they hate you for being shy/neurodivergent, that too is a way to screen out scammers using fake identities.
• https://chrislakin.blog/p/bounty-your-bottleneck Chris Lakin claims he can completely solve (psychological) insecurity through coaching. He's very young and new at this, but the pay-for-results model is unusually client-friendly.
• https://screwworm.org/ these people want to use gene drives to eradicate screwworm, a parasite that infects animals in South America.
• https://christopherrufo.com/p/counterrevolution-blueprint Chris Rufo is a troll on Twitter, but this is a pretty sober/earnest proposal for how all affirmative action, racial quotas, etc can be eliminated from the Federal Government. I am not qualified to opine on whether this is feasible or whether it will have harmful unintended consequences.
• https://en.wikipedia.org/wiki/Adragon_De_Mello example of a "child prodigy" who was pushed into it by his emotionally abusive father and didn't like it at all
• https://parthchopra.substack.com/p/what-i-learned-working-at-a-high  somewhere hidden behind the business-speak of this article, there is clearly an actual story about some Shit That Went Wrong. but unfortunately he is likely not free to disclose it and I am not familiar enough with this company to know what it was.
• https://www.medrxiv.org/content/10.1101/2024.05.16.24307494v1.full.pdf this is the OpenWater tFUS study on depression. Not sham-controlled, things like this fail to replicate all the time, but they do register an effect.

• https://www.darpa.mil/work-with-us/heilmeier-catechism good advice for how to write proposals

   

Funding individuals doesn't seem at all ruled out by our mission and I agree it's a good thing.

 IANAL and I don't know much about how that interacts with tax deductibility.

links 12/4/2024: https://roamresearch.com/#/app/srcpublic/page/12-04-2024

• https://substack.com/home/post/p-149058187 Gena Gorlin hosts a discussion on "psychological safety"
• https://psychiatryonline.org/doi/full/10.1176/appi.ajp.21080800  new antidepressant just dropped: bupropion + dexmethorphan, appears to be more effective than bupropion alone
  • registering my concern that someday we will find that NMDA inhibitors do something bad to cognition. but all these recent studies are 6-week only and don't report any side effects that look like cognitive impairment, but maybe wouldn't have been able to pick it up even if it existed.
• https://slatestarcodex.com/2015/07/13/things-that-sometimes-work-if-you-have-anxiety/ Scott Alexander on anxiety treatments.
  • "Azapirones (example: BuSpar) is, unusually, a rare drug which is specifically targeted at anxiety, rather than a being a repurposed antidepressant or something. BuSpar is very safe, not at all addictive, and rarely works. Every so often somebody comes out with a very cheerful study saying something like “Buspar just as effective as benzodiazepines if given correctly!” and everybody laughs hysterically and goes back to never thinking about it."
• gabapentin for anxiety -- meh, some positive results but they're not extraordinary.
  • https://www.nature.com/articles/s41380-021-01386-6
  • https://onlinelibrary.wiley.com/doi/full/10.1155/2017/6045017

  • https://onlinelibrary.wiley.com/doi/full/10.1155/2017/6045017

     

"three cultures of self-criticism" https://roamresearch.com/#/app/srcpublic/page/zzRZnCLd_

• non-self-critical culture (Barbarians):
  • baseline assumptions:
    • people generally think they are okay and good, and they are generally right.
    • self-criticism is rare.
    • if someone is being self-critical, guilty, ashamed, etc, that indicates an unusual problem.
  • implications:
    • intense self-criticism will be taken as evidence of something actually wrong with the person -- either they really did screw up quite badly, or they have poor judgment.
    • criticism is direct and overt.
      • if someone objects to what you've done, they'll tell you straight out, and expect that this will clear the air and lead to a resolution of the problem.
      • "negative" judgments are not necessarily intended, or expected, to be painful; the listener may very well disagree with the judgment or find it helpful feedback.
      • as a corollary, nobody assumes that an ambiguous comment or facial expression is a hint at criticism or disapproval. The default assumption is that people are fine with you, that you're fine, and if there's a problem it'll become obvious.
• pro-self-criticism culture (Puritans):
  • baseline assumptions:
    • people are generally deeply flawed; we are constantly screwing up, sinning, etc. this is the universal or near-universal human condition, not something limited to unusually bad people. but it really is genuinely Bad and Not Okay.
    • people tend to be complacent -- by default we engage in far too little self-criticism. We are screwing up without knowing it. We let ourselves off the hook, make excuses for ourselves, ignore warning signs. It takes active, continual effort to be vigilant against our own flaws.
  • implications:
    • intense self-criticism and guilt is normative. virtuous people will not think well of themselves. in fact, if someone does think well of themselves, that means they're lazy and have low standards.
      • corollary: an intensely self-critical or guilty person is not assumed to be an unusually bad person or to have a mental health problem; they are just doing what we're all supposed to do!
    • criticism can be harsh and intentionally painful, because the assumption is that it needs to be "strong enough" to overcome natural human complacency
    • it's also common to read criticism into subtle or ambiguous signs. the assumption is that there are always more problems than the obvious ones; it's never safe to presume things are fine.
• counter-self-criticism culture (Therapy Patients):
  • baseline assumptions:
    • people generally are too self-critical. most people are basically fine but torture themselves over minutiae.
    • complacency -- failing to self-criticize enough about genuine faults -- is literally monstrous. complacent people are rare, and pathological; we might call them sociopaths. you absolutely would not want to be one, and you're almost certainly not.
    • "healing" or "growth" means learning to quiet the overactive inner critic. this is very difficult; people need help with it.
    • everybody always needs validation and reassurance that they're ok, and the kindest thing you can do for anyone is give them permission not to worry or self-criticize. the cruelest thing you can do is trigger their insecurities and intensify their (already painful) self-criticism.
  • implications:
    • self-criticism is not normative; it's an affliction we all suffer from and long to be freed from.
      • like sin in pro-self-criticism cultures, misery in counter-self-criticism culture is seen as Genuinely Terrible, Deeply Not Okay, but also a part of the human condition, not a sign that something has gone unusually wrong with you. you're mentally ill, like everyone else.
    • criticism is mild and gentle, or suppressed altogether, because it's assumed everybody is already torturing themselves and doesn't need other people piling on.
      • corollary: it's common to read a lot of criticism or disapproval into subtle or ambiguous signals because it's assumed that people are holding back their true negative opinions. The absence of reassurance or validation is considered a sign of severe, harsh disapproval.
• relationships:
  • Barbarians see Puritans as totally excessive, and see Therapy Patients as trying to counteract a problem that one can just...not have.
  • Puritans see both Barbarians and Therapy Patients as dangerously complacent.
  • Therapy Patients see Puritans as a familiar enemy -- something they understand but reject and want to get away from, like an unhappy childhood home -- and see Barbarians as incomprehensible, alien, insane, not-even-human. 

links 12/03/2024: https://roamresearch.com/#/app/srcpublic/page/12-03-2024

• https://sashachapin.substack.com/p/my-mind-transformed-completely-and Sasha Chapin on how meditation changed him
  • it doesn't seem clear to me whether this is better or not!
  • reduced anxiety seems great, but reduced sense of narrative drama is a big cost. part of what makes life seem meaningful to me is the sense of being part of a story, and if anything i feel like my current arc involves gaining abilities to envision myself as inside a narrative.
• https://www.wired.com/story/murderbot-she-wrote-martha-wells/ Martha Wells seems like a lovely person
• https://www.orcasciences.com/articles  recommended by Ben Reinhardt, great example of rigorous analyses of potential future technologies.
  • https://www.orcasciences.com/articles/checking-my-prejudices-on-materials-decarbonization eg: where does it make economic sense to use electrochemical or biological manufacturing? (compared to "thermochemical", fossil-fuel-powered). For biomanufacturing, only for complex molecules like proteins; for electrochemical processing, mostly metals and things with big voltage potentials in the chemical reaction (zinc, cobalt, copper, lithium, etc) but not simple organic molecules (methane, ethanol, etc)
• https://www.biotech.senate.gov/press-releases/interim-report/ "US National Security Commission on Emerging Biotechnology", a congressional advisory committee led by Jason Kelly of Gingko Bioworks
  • their purpose seems to be getting biotech-friendly policies through congress, with the rationale that this is good for national security/defense.
  • a lot of naive boosterism about biomanufacturing without engaging with the question of "is this better than alternative manufacturing techniques?"
• https://www.aria.org.uk/request-for-opps/ new opportunities for program managers at ARIA: lead a scientific research program!

links 11/26/2024: https://roamresearch.com/#/app/srcpublic/page/11-26-2024

• https://chrislakin.blog/archive  sensible, but not actionable for me, advice on becoming less insecure.
• https://abundance.institute pro-progress think tank, where Eli Dourado works
• The Myth of Er is the final scene of Plato's Republic.
  • it is a very strange story. in the afterlife, the good are rewarded in heaven and the bad are punished in hell; and then everyone lines up to choose their new reincarnated life. they get to see how each possible life will play out. people who have led unhappy lives often prefer to reincarnate as animals. people who were only virtuous out of habit and went to heaven often choose to be all-powerful tyrants, not realizing how this will backfire and hurt them. people who have learned philosophy are more likely to choose lives of virtue; they also "forget less" about their past lives by drinking from Lethe.
    • so in one sense it's straightforwardly a pitch for philosophy...but it has more moving parts than would seem to be necessary just to make that point.
      • most myths/stories about "good is rewarded, evil is punished" don't have this homeostatic mechanism where the good are most likely to turn bad (since Heaven makes them complacent) and the bad are more likely to turn good (since Hell makes them wish for a better next life.) why put that in?
    • how does this whole reincarnation thing relate to the rest of the Republic, which is ambiguous between being a plan for an ideal city and a metaphor for the ideal internal organization of the soul?
  • https://beccatarnas.com/2013/10/17/the-myth-of-er/
• http://strangehorizons.com/fiction/the-spindle-of-necessity/
• war in the Middle East
  • https://www.fairobserver.com/politics/fo-exclusive-the-israel-iran-conflict-is-getting-more-dangerous/
  • https://indianexpress.com/article/world/iran-vows-response-israeli-airstrikes-escalating-tensions-9688373/
  • https://www.aljazeera.com/news/2024/11/2/khamenei-warns-israel-us-of-crushing-response-for-actions-against-iran
  • https://www.aljazeera.com/news/2024/10/26/israel-strikes-iran-what-we-know-so-far-and-whats-next
• what went wrong with Gingko Bioworks?
  • first of all, their stock price crashed after short seller Scorpion Capital reported that most of their "revenue" was from self-funded "related parties" that often had the same staff and office space...aka they weren't "really" selling to other companies much at all.
  • but what was the underlying technical problem? why couldn't they sell biomanufactured compounds profitably?
    • one possibility: they were focusing on compounds that could be synthesized chemically, much more cheaply, that you would only grow from microbes if you wanted some sort of "all-natural" label
    • another possibility: their service was limited to (parallelized, automated) yeast strain optimization in very small samples -- 384-well plates. they didn't do scale-up (growing the yeast in large reactors) and they didn't do downstream processing (extracting the product from the yeast). this may have lowered their rate of generating successful products, because many failures happen in the parts of the process they didn't specialize in.
      • this is the manufacturing equivalent of what, in drug discovery, would be a CRO that only does a certain range of in-vitro screens. obviously many things that pass the screens will fail in animals or clinical trials. and obviously the value of an early screening service is quite low compared to the value of a successful end product.
  • https://www.reddit.com/r/biotech/comments/1cwlpj3/whats_wrong_with_ginkgo_bioworks/
  • https://www.technologyreview.com/2021/08/24/1032308/is-ginkgos-synthetic-biology-story-worth-15-billion/
  • https://www.pagetwentyone.com/post/ginkgo-bioworks-rise-and-fall-of-15-billion-biotech-unicorn
  • https://www.reddit.com/r/ginkgobioworks/comments/qgx2t1/updated_ginkgo_partner_tracker/
  • https://healthandwealth.substack.com/p/ginkgo-bioworks-part-2
  • https://www.living.tech/articles/ginkgo-bioworks-original-sin
  • https://www.nanalyze.com/2023/03/ginkgo-bioworks-bait-switch/
  • https://seekingalpha.com/article/4691850-ginkgo-bioworks-broken-narrative
  • https://medium.com/@kahunacapbio/ginkgo-bioworks-cell-program-success-and-failure-7eb988c6d549
  • https://scorpioncapital.s3.us-east-2.amazonaws.com/reports/DNA1.pdf
  • https://foundrytheory.substack.com/ I'm gonna be real with you -- for all the bad results, I love Gingko's marketing. It makes me sad when people slam "hype" because this is so beautiful. Aesthetically tasteful, intellectually stimulating, emotionally inspiring. Everything they've done on the marketing front is just the best. and tbh it's worked for them -- the one thing even the damning reports show is how great they are at starting early-stage conversations with Fortune 500 companies. (they just rarely get all the way to actual products, revenue, and happy customers.) I'll be sad if the end of the ZIRP era means the end of pretty design and delightful copy.
• https://www.isomorphiclabs.com/ AI-for-bio company
• https://www.maximumnewyork.com/p/political-capital-savings-plan
  • I'm sure Daniel Golliher is doing a healthy thing but I struggle to get on board myself.
    • I think he's probably right that in order to actually make a political impact you have to pick a very small issue (like basketball courts in your city) to spend a lot of time on and you have to, um, have friends.
    • I looked into public art one time -- how do people get their murals etc into public spaces? -- and the answer was, simply, that they are full time on that project. they live eat sleep and breathe public art. now, do I like pretty things? yes. do I care so much about public art in particular that i would want to be full time on it? no.
    • Given that I don't want to spend my life on the issues "small enough" that i could actually shift them, it is absolutely rational for me not to participate in politics and to find it an uncongenial place! i can make a way bigger impact, much faster, with the reputational capital (and literal money) I've built up in more SV-adjacent circles than I can by grinding on NYC neighborhood issues.
• https://www.nature.com/articles/s41593-024-01784-3
  • Is connectomics actually useful for anything? here’s strong evidence for “yes.”
  • Mapping how neurons connect and using graph clustering gives you (anatomically sensible) functional distinctions into systems like “oculomotor” (which governs eye movements) and “axial” (which governs movements along the body axis.)
  • Looking at the spectrum of the graph also predicts a chunky “wiring diagram”. Simulating the dynamics of this wiring diagram recapitulates real electrophysiology. In other words, just doing mathy graph stuff allowed the researchers to infer a modular organization at an intermediate scale between neurons and gross anatomy, a useful scale for predicting neural behavior. This is literally “cutting reality at the joints”.
  • One thing that has frustrated me as an amateur learning neuroscience is that we have a microscale (cells) and a macroscale (brain anatomy) but function — the brain’s ability to carry out specific tasks — has to happen at some kind of meso-scale regarding the interaction of groups of neurons. Clearly there’s redundancy — it’s possible for two different neuron-by-neuron patterns of activity to reflect “the same” functional behavior — so we need a “unit of function” that’s “all the activity patterns that do the same thing” — probably that coincides somewhat with spatial co-location, similar cell type, etc, but not at all necessarily! Only once you have “units of function” can you talk about the brain like a machine, know what its “state” is and how that “state” would change under specific interventions, simulate it efficiently, etc.
  • To understand brain function, we’d need to be able to discern human-interpretable “parts” of brain activity, like “remembering your grandmother just is the fizz blorking the buzz”…but we don’t seem to know what the “fizz”, the “buzz” or “blorking” are. We’d need to have “chunky things” in the brain-activity space, the way molecules, cells, or anatomical structures are “chunky things” at the micro and macro scales. And I felt like “what am I missing? does anybody in neuroscience even care about chunky-things? am I wrong to care? or do I just have the wrong keyword?”
  • This paper definitely seems like an example of “chunky things neuroscience”, which is encouraging!

links 11/25/2024

• https://www.theguardian.com/commentisfree/2024/nov/17/how-to-survive-the-broligarchy-20-lessons-for-the-post-truth-world-donald-trump
  • I was looking forward to a genuine practical how-to, but this isn't really it; while I can't argue with the value of "stick to your principles even in the face of authoritarianism" and "people who think they'll be targeted by authoritarians need to be especially mindful of communications & payments privacy" I think this author is envisioning scenarios worse than I think are likely.
• https://nadia.xyz/jhanas  unusually straightforward explanation of one person's experience learning the jhanas
• https://en.m.wikipedia.org/wiki/The_Shop_Around_the_Corner
• https://www.complexsystemspodcast.com/episodes/drug-development-ross-rheingans-yoo/ Ross Rheingans-Yoo on drug development
• https://www.aljazeera.com/news/2024/11/13/what-do-we-know-about-the-north-korean-troops-joining-russias-war North Korean troops are now supporting Russia in the Ukraine war.
• https://www.complexsystemspodcast.com/episodes/money-movement-erik-torenberg/ Erik Torenberg on finance
• https://drdevonprice.substack.com/p/i-dont-feel-safe-around-cis-women a rant about a particular kind of cis women who feel entitled to be extremely rude and intrusive because they assume "women = inherently benign".
• reading about the Inca:
  • https://en.m.wikipedia.org/wiki/Inca_cuisine
  • https://en.m.wikipedia.org/wiki/Inca_mythology
  • https://en.m.wikipedia.org/wiki/Inca_Empire
• https://www.wrecka.ge/against-the-dark-forest/ not very solution-oriented piece about problems with the internet
  • ok, you blame Big Tech, and you see "Dark Forest" discourse as insufficiently hard on Big Tech.
  • you also think that retreat to "private" nooks is not adequate (I agree) and that different cultures around the world should get to choose their own forms of online networking instead of being lumped into a US-centric paradigm (sure) and that we need ways to connect around the world (yes)...but what do you propose and who will pay for it etc are the questions coming to my mind
• https://endpts.com/trump-picks-hopkins-researcher-marty-makary-to-lead-the-fda/ 

  • moderately reformist, critical of COVID-19 response but not of vaccines per se

     

From the POV of this piece, whether you want process or outcome neutrality...depends. You're being "neutral" so you can enlist the trust and cooperation of a varied range of people, in order to pursue some purpose that all of you value. Do the relevant people care more about process or outcome? 

Another way to look at it is that it's ultimately always a question of process. "Ensuring equality/neutrality of outcome" means "I propose a process that makes adjustments so that outcomes end up in a desirable "neutral" configuration." Then the questions are: a.) does that process result in that "neutral" configuration? b.) is that configuration of outcomes what we want? c.) is the process of adjustment itself objectionable? (e.g. "whether or not material equality is desirable, I don't believe in forced redistribution to equalize wealth").

When you are building an institution that aims at neutrality, ultimately you're proposing a set of processes, things the institution will do, and hoping that these processes engender trust. "I can't accept the likely outcome of this process" and "I can't accept the way this process works" are both ways trust can break down. 

links 11/22/2024: https://roamresearch.com/#/app/srcpublic/page/11-22-2024

• https://www.slowboring.com/p/can-we-have-a-family-friendly-high Matt Yglesias designs a family-friendly high rise. i want this! 

• https://www.experimental-history.com/p/underrated-ways-to-change-the-world 

   

I don't know where I got that last sentence; that's clearly bogus. If you knew that a certain drug, target, or research strategy was going to work, of course you could profit off it. That is literally what the biotech industry does.

While I still think all of the above is more-or-less true, I've since learned it's not the real reason. 

The real reason is that we don't (yet) have a way to noninvasively measure blood hormone levels as they fluctuate throughout the day. You'd have to keep your study subjects hooked up to an IV, or taking many blood tests a day, continuously for at least a month (because of the menstrual cycle). This is unpleasant and maybe unacceptably risky (infections!) What we need is noninvasive continuous hormone monitoring, which is currently at the prototype stage in a couple of university labs. 

Finding somebody who can do the math will be easy once the data exists.

ah. I'm now pretty bearish on Warburg. https://roamresearch.com/#/app/srcpublic/page/fBd011iWS

It's not a true "pan-cancer" phenomenon; the distribution of % of ATP due to glycolysis, across cancer cell lines, overlaps heavily with the same distribution for non-cancerous cells, i.e. you can't effectively distinguish cancer from non-cancer by its glycolysis activity.  Also, not all glycolysis-using cancers will actually die if you block glycolysis; some of them just adapt/evolve to use cellular respiration instead.  

So, glycolysis-inhibition drugs can, at best, be effective against the fraction of cancers that are truly obligate glycolysis-dependent...and even there, they'll be side-effect-heavy like conventional chemotherapy, since they'll also target glycolysis-dependent healthy cells (which are not rare!) In other words, even if a glycolysis inhibitor turns out to be effective against some cancers, it's not going to be anywhere near universally applicable.

The glycolysis-inhibitor drug candidate I used to be excited about was 3-bromopyruvate, which indeed was reported to eradicate some big tumors in rats and turned very advanced liver cancer necrotic in a human case study. 

The lead researcher, Young H. Ko, has since left Johns Hopkins -- she sued them in 2005 for race and gender discrimination after her contract was not renewed, but lost the case. She's now founded her own company, KoDiscovery (the website is pretty scammy-looking but I'm trying to suspend judgment) and has registered their first clinical trial with the FDA, currently ongoing in Korea.

Unfortunately a German alternative-medicine clinic is under investigation for manslaughter when three patients died after being administered the compound. (The article isn't claiming the clinic is at all affiliated with Ko or her company.)

The phase I/II trial is set to complete next year, so we'll have more information then. 

links 11/21/2024: https://roamresearch.com/#/app/srcpublic/page/11-21-2024

• https://goodscienceproject.org/articles/how-to-actually-reduce-the-administrative-burden-on-research/ instead of needing a majority to repeal rules (public choice works against you) we could instead have a national commission empowered to repeal rules unless vetoed by Congress by a deadline (public choice works for you!)
• https://wellcomeleap.org/dr/ Lynne Cox's program on frailty & resilience
• https://en.m.wikipedia.org/wiki/EMILY%27s_List
  • EMILY's List, founded in the 1980's, fundraises for pro-choice female political candidates. I'd heard of it but was surprised how successful it had been.
• https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1475-4975.1979.tb00377.x
  • Peter Unger, "Why there are no people."
  • he introduces a concept called a "nacknick", where things that are "suitably similar in shape" to a given example object are nacknicks, but things that are very differently shaped are not. he thinks this is logically incoherent and goes on to argue that "person" is a concept of this form.
    • but...most concepts work this way! they are approximate, not amenable to rigorous definition, defined by similarity to a prototypical example. I can live with this!
    • ...this seems to be a big factor in David Chapman's thinking, why he feels he has to decisively reject things like "philosophy" and "rationalism", because he apparently fell into severe clinical depression due to the idea that non-rigorous definitions are unacceptable?
      • this is idiosyncratic. now, i don't think it's necessarily avoidable or at all bad for one's intellectual output to be a mirror of one's personal concerns. but most depressed people are not depressed about non-rigorous definitions, and most people can handle hearing about non-rigorous definitions without getting depressed. this isn't some kind of universal root cause of the unhappiness of intellectuals!
        • speaking as an often-unhappy intellectual, I am FINE with some things not being amenable to rigorous definition but still being real things.
          • if anything, studying mathematics taught me that the rigorously formalizable and provable is a very tiny slice of the world.
• https://cacm.acm.org/opinion/between-the-booms-ai-in-winter/
  • history of AI in the 80's and 90's -- after the expert systems bust, we got embodied intelligence, genetic algorithms, artificial life (aka cellular automata & evolutionary game theory), Bayesian networks, hidden Markov models, and of course the revival neural nets w/ backprop.
  • yes, our founding ideas came from a so-called "AI winter".
• https://www.societylibrary.org/  has gotten a lot bigger with a recent funding infusion.
  • they have (AI-enabled) debate mapping, decision making toolkit, educational programs, and something called "Internet Government" which doesn't exist yet. https://www.internetgovernment.org/
• https://www.cesifo.org/DocDL/cesifo1_wp11414.pdf
  • American MTurkers don't prefer male to female politicians in a simulated voting task; Republicans and male Democrats are about as likely to "vote" for a female as male politician, while female Democrats are more likely to vote for a woman.
• https://www.lesswrong.com/s/qXZLFGqpD7aeEgXGL Richard Ngo's "Replacing Fear" sequence.
  • it's mostly IFS-based, which i find not especially useful.
    • I don't think it makes sense to conceptualize myself as made of stable sub-personalities, like an internal "cast of characters".
      • i can certainly go into a hypnagogic/imaginative trance state and allow such entities to emerge, but if I do a subsequent session, they do not "naturally" emerge the same way again, and it seems like a bad idea to deliberately force or train myself to have sub-personalities.
        • i either want to observe my mind impartially, seeing it as it is, or I want to shape myself to be be better.
        • If I don't naturally already have multiple sub-personalities, artificially inducing them doesn't seem like an improvement.
    • I do sometimes find it useful to think of myself as having fluctuating moods, motives, and concerns, and do "dialogue" between the ones that are active at any one time.
      • but unlike IFS, I don't expect them to be necessarily permanent, and I don't necessarily need them to be character-like (having a distinctive appearance, personality, etc.)
        • moods are styles/vibes that encompass my whole experience of life while I'm in them
        • motives feel like pressures or inclinations to move/act in a certain direction;
          • not like little inner people, if anything more like little "simulated/anticipated" muscle movements
        • concerns might be a type of motive, "i gotta remember to track/account-for/care-about this thing"
          • again, it's either an abstract thought or a pattern of muscle-tension/planned-movement/etc. it just is not like a little inner person.
• most industrial enzyme generation is fermentation of filamentous fungi -- molds like Aspergillus and Penicillium. this is done somewhat differently than yeast or bacterial culture.
  • https://en.wikipedia.org/wiki/Solid-state_fermentation it's most efficient and cheapest to grow these filamentous fungi on solid plant matter with only a little bit of fluid.
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC9025306/
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC7123961/
  • https://microbialcellfactories.biomedcentral.com/articles/10.1186/1475-2859-10-68
  • https://www.redalyc.org/journal/1871/187158163062/html/
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC5358476/
  • https://defoortconsultant.com/bio-economy-and-technology-the-challenges-of-industrial-fermentation/
  • https://www.susupport.com/knowledge/fermentation/challenges-microbial-fermentation-manufacturing
  • https://www.davidmoore.org.uk/21st_Century_Guidebook_to_Fungi_PLATINUM/REPRINT_collection/Pandy_solid-state-fermentn2003.pdf
  • https://www.sciencedirect.com/science/article/pii/S2452072116300144
• https://www.elidourado.com/p/personal-aviation Eli Dourado notes that "light-sport" aircraft FAA certification requirements have expanded, allowing something more like a 4-seat "flying car"-like personal aircraft, with extensive autopilot, to be affordable and legal to fly with an amateur pilot's license. 

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
  •  

My intuition is to get less excited by single projects (a Double Crux bot) until someone has brought them all together & created momentum behind some kind of "big" agglomeration of people + resources in the "neutrality tools" space. 

I didn't know about all the existing projects and I appreciate the resource! Concrete >> vague in my book, I just didn't actually know much about concrete examples.

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.

 I agree that more people should be starting revenue-funded/bootstrapped businesses (including ones enabled by software/technology).  

The meme is that if you're starting a tech company, it's going to be a VC-funded startup. This is, I think, a meme put out by VCs themselves, including Paul Graham/YCombinator, and it conflates new software projects and businesses generally with a specific kind of business model called the "tech startup".  

Not every project worth doing should be a business (some should be hobbies or donation-funded) and not every business worth doing should be a VC-funded startup (some should be bootstrapped and grow from sales revenue.) 

The VC startup business model requires rapid growth and expects 30x returns over a roughly 5-10 year time horizon. That simply doesn't include every project worth doing. Some businesses are viable but are not likely to grow that much or that fast; some projects shouldn't be expected to be profitable at all and need philanthropic support.

I think the narrative that "tech startups are where innovation happens" is...badly incomplete, but still a hell of a lot more correct than "tech startups are net destructive". 

Think about new technologies; then think about where they were developed. That process can ever happen end-to-end within a startup, but more often I think innovative startups are founded around IP developed while the founders were in academia; or the startup found a new use for open-source tools or tools developed within big companies. There simply isn't time to solve particularly hard technical problems if you have to get to profitability and 30x growth in 5 years. The startup format is primarily designed for finding product-market fit -- i.e. putting together existing technologies, packaging them as a "product" with a narrative about what and who it's for, and tweaking it until you find a context where people will pay for the product, and then making the whole thing bigger and bigger. You can do that in 5 years. But no, you can't do literally all of society's technological innovation within that narrow context! 

(Part of the issue is that we still technically count very big tech companies as "startups" and they certainly qualify as "Silicon Valley", so if you conflate all of "tech" into one big blob it includes the kind of big engineering-heavy companies that have R&D departments with long time horizons. Is OpenAI a "tech startup"? Sure, in that it's a recently founded technology company. But it is under very different financial constraints from a YC startup.)

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.

Shreeda Segan is working on building it, as a cashflow business. they need $10K to get to the MVP. https://manifund.org/projects/hire-a-dev-to-finish-and-launch-our-dating-site

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 11/07/2024: 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 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

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 10/30/2024: 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

"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 10/28/2024: 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 10/25/24: 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)
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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.

I don't think it was articulated quite right -- it's more negative than my overall stance (I wrote it when unhappy) and a little too short-termist.

I do still believe that the future is unpredictable, that we should not try to "constrain" or "bind" all of humanity forever using authoritarian means, and that there are many many fates worse than death and we should not destroy everything we love for "brute" survival.

And, also, I feel that transience is normal and only a bit sad. It's good to save lives, but mortality is pretty "priced in" to my sense of how the world works. It's good to work on things that you hope will live beyond you, but Dark Ages and collapses are similarly "priced in" as normal for me. Sara Teasdale: "You say there is no love, my love, unless it lasts for aye; Ah folly, there are episodes far better than the play!" If our days are as a passing shadow, that's not that bad; we're used to it.

I worry that people who are not ok with transience may turn themselves into monsters so they can still "win" -- even though the meaning of "winning" is so changed it isn't worth it any more.

I thought about manually deleting them all but I don't feel like it.

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 [[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
  •