My experience is not, of course, that it happens constantly, but that many people expect you to be able to do it immediately on demand. As someone who’s easily startled it isn’t always easy for me!
sarahconstantin
Karma: 8,370
The Uses of Complacency
links 4/21/25: https://roamresearch.com/#/app/srcpublic/page/04-21-2025
Pope Francis dead:
Gavin Leech on how he uses & doesn’t use LLMs
https://www.gleech.org/llms
he’s not actually that abstemious compared to me. some differences include that he actually knows regexes fluently so doesn’t use em for formatting; and that he doesn’t like flattery.
Mostly I also feel creepy using it as a replacement for directly reading a source or for writing anything I actually care about. I don’t want a replacement for my own mind. My most common LLM use case is “replacement search engine”, followed by “accountability buddy/cheerleader”
https://statmodeling.stat.columbia.edu/2025/04/17/drowning-in-junk-science-is-there-any-hope-at-all/ Andrew Gelman now thinks in at least some fields the problem isn’t (only) bad research methodology, it’s the mindset that research is a formality you have to get through in order to do the advocacy you actually want to do.
https://malcolmocean.com/2024/01/guru-dynamics-i-can-show-you-how-to-trust-yourself/ Malcolm Ocean on self-trust is just correct, and has a wholesome goodwill that I’m very fond of. A lot of his ideas are obvious to me (having thought through a lot of the same topics independently) but I wish I lived in a world with a thousand Malcolms. He is actually interested in how minds work and how you can manage em well without self-harm or cruelty or authoritarianism; in an era when a lot of people are leaning into “maybe self-harm and cruelty and authoritarianism are good actually” he has stuck to his values, even through marriage and fatherhood.
https://www.lesswrong.com/posts/rH492M8T8pKK5763D/agree-retort-or-ignore-a-post-from-the-future old Wei Dai post making the point that obviously one ought to be able to call in arbitration and get someone to respond to a dispute. people ought not to be allowed to simply tap out of an argument and stop responding.
this is not what I believe.
first of all, it goes against ordinary norms about consensual social interactions, where any party can withdraw association whenever they want unless they have made a binding commitment not to.
“What about courts? people can be compelled to testify.”
Ok, cool, but that’s the law of the land. Your idea for norms in a rational society is an idea, and it has neither persuaded me to accept them nor taken political power in the territory I live in.
second of all, it is costly. Are you saying that my time and energy can be called up, indefinitely, to participate in an argument, and I have to either concede that you’re “right” or keep arguing until I persuade you? what if I really don’t want to be on the record saying things that I may have been pressured into saying, or confused about, especially on a sensitive topic? what if you are incredibly stubborn and refuse to be persuaded no matter how strong my arguments are?
“no, you get to stop, but you should have to explicitly say you are no longer participating in the discussion before you can stop.”
well, that’s better, but I still think it’s too much of an imposition to require. it still takes some time and willpower to explicitly assert one is tapping out. I think it’s not unreasonable to expect people to take a hint sometimes and accept silence or a change of subject as a sign of lack of interest in continuing the discussion.
here is my position:
I do not commit to be accountable to just anybody for being fully logically rational.
I do, as a point of honor, try to avoid leaving up false or misleading information in my writing, and will try to correct it or remove it if I’ve found I’ve made a factual error. I do not want anybody to mistakenly believe a falsehood on my account.
But I do not commit to admitting I believe anything that I can’t win an argument against. Even if (someone claims) that given other things I’ve said I logically must believe it. Frankly, if for whatever reason, including aesthetic and social ones, I am not willing to say something in print or out loud, then by gum you do not get to make me say it.
You can judge me for my choices however you like. But you don’t get to compel them unless you have the literal legal or physical power to do it.
I also do not commit to continue engaging in conversations I don’t want to, answering questions I don’t want to, etc, outside of an explicit committed obligation (e.g. if it’s part of my job.) I am unusually generous with my time and candor, as people go, but that is my choice, not my obligation.
https://en.m.wikipedia.org/wiki/Lebo_M this is the guy responsible for the African choruses in The Lion King as well as many other movies. Close collaborator with Hans Zimmer
https://en.wikipedia.org/wiki/Muscari grape hyacinths are not hyacinths at all. Genus Muscari rather than Hyacinthus. (Same family though.)
family Asparagaceae, containing asparagus. https://en.wikipedia.org/wiki/Asparagaceae
wait. I thought asparagus was a fern? no it isn’t! despite their feathery fern-like leaves, asparagus ferns, tree ferns, plumosus ferns, and others are angiosperms, or flowering plants. they have seeds, not spores.
https://classicalchristian.org/the-lost-tools-of-learning-dorothy-sayers/ Dorothy Sayers’ famous essay proposing a medieval-inspired “classical education” curriculum for the present day
Prodromes and Biomarkers in Chronic Disease
links 4/4/25: https://roamresearch.com/#/app/srcpublic/page/04-04-2025
https://www.science.org/doi/10.1126/science.adr3675
thalamic nuclei are involved in consciousness, active in a task that distinguishes conscious from unconscious visual perception
https://www.precigenetics.com/ nondestructive image-based epigenetics of single cells. how do they do it??? founded by Parmita Mishra
https://transformer-circuits.pub/2025/attribution-graphs/methods.html
individual neurons are polysemantic; not great for interpretability. we need larger interpretable “circuits” or chunks that have a definite purpose.
“cross-layer transcoders” read from one layer and write to all following ones; they are meant to replicate the output of the multi-layer perceptron of the input layer & residual stream. the CLT’s feature activations are given by the inner product of the CLT encoder matrix and the residual stream activations at layer l. but we also have the decoder matrix so we can run this in reverse and get an estimate of the original model’s MLP at any layer.
then you just train the model with the CLTs, all the while trying to minimize a loss given by the squared errors between estimated & actual MLPs, and a sparsity penalty for the CLT matrix’s feature activations
we can replace the original network with a network made of features (rather than the original neurons) which are sparsely encoded (because we asked them to be.) the sparsity means we’re getting rid of polysemanticity and the new neurons “mean” more uniquely-defined things.
new network:
Its input is the concatenated set of one-hot vectors for each token in the prompt.
Its neurons are the union of the CLT features active at every token position.
Its weights are the summed interactions over all the linear paths from one feature to another, including via the residual stream and through attention, but not passing through MLP or CLT layers. Because attention patterns and normalization denominators are frozen, the impact of a source feature’s activation on a target feature’s pre-activation via each path is linear in the activation of the source feature. We sometimes refer to these as “virtual weights” because they are not instantiated in the underlying model.
Additionally, it has bias-like nodes corresponding to error terms, with a connection from each bias to each downstream neuron in the model.
from this they build an “attribution graph”—the input string is encoded into tokens, each token can “flow” towards one or more neurons, the weights tell you which paths are important, and you can observe that neurons do things like “continue this acronym” or “say d”
features can be associated with words, text placements like “numbers ending in 6” or “first two letters of an acronym”, or concepts (like sports)
there’s also “say [string]” features that activate immediately preceding [string]
you can test interpretations by replacing a layer with the feature decoder equivalent, and suppressing given features; this changes what the LLM outputs in predictable ways.
https://www.science.org/doi/10.1126/science.adr3675 [[neuroscience]]
thalamic nuclei are involved in [[consciousness]], active in a task that distinguishes conscious from unconscious visual perception
https://www.precigenetics.com/ nondestructive image-based epigenetics of single cells. how do they do it??? founded by [[Parmita Mishra]]
https://transformer-circuits.pub/2025/attribution-graphs/methods.html [[mechanistic interpretability]] [[AI]]
individual neurons are polysemantic; not great for interpretability. we need larger interpretable “circuits” or chunks that have a definite purpose.
“cross-layer transcoders” read from one layer and write to all following ones; they are meant to replicate the output of the multi-layer perceptron of the input layer & residual stream. the CLT’s feature activations are given by the inner product of the CLT encoder matrix and the residual stream activations at layer l. but we also have the decoder matrix so we can run this in reverse and get an estimate of the original model’s MLP at any layer.
then you just train the model with the CLTs, all the while trying to minimize a loss given by the squared errors between estimated & actual MLPs, and a sparsity penalty for the CLT matrix’s feature activations
we can replace the original network with a network made of features (rather than the original neurons) which are sparsely encoded (because we asked them to be.) the sparsity means we’re getting rid of polysemanticity and the new neurons “mean” more uniquely-defined things.
new network:
Its input is the concatenated set of one-hot vectors for each token in the prompt.
Its neurons are the union of the CLT features active at every token position.
Its weights are the summed interactions over all the linear paths from one feature to another, including via the residual stream and through attention, but not passing through MLP or CLT layers. Because attention patterns and normalization denominators are frozen, the impact of a source feature’s activation on a target feature’s pre-activation via each path is linear in the activation of the source feature. We sometimes refer to these as “virtual weights” because they are not instantiated in the underlying model.
Additionally, it has bias-like nodes corresponding to error terms, with a connection from each bias to each downstream neuron in the model.
from this they build an “attribution graph”—the input string is encoded into tokens, each token can “flow” towards one or more neurons, the weights tell you which paths are important, and you can observe that neurons do things like “continue this acronym” or “say d”
features can be associated with words, text placements like “numbers ending in 6” or “first two letters of an acronym”, or concepts (like sports)
there’s also “say [string]” features that activate immediately preceding [string]
you can test interpretations by replacing a layer with the feature decoder equivalent, and suppressing given features; this changes what the LLM outputs in predictable ways.
links 4/1/24: https://roamresearch.com/#/app/srcpublic/page/04-01-2025
https://www.worksinprogress.news/p/the-prehistoric-psychopath using a nice big dataset of modern hunter-gatherers and prehistoric archaeological sites, what do we find about ancient violence?
[[Stephen Pinker]] is right that hunter-gatherers and subsistence farmers (contemporary and prehistoric) had much higher rates of violent death than moderns, even including the world wars of the 20th century.
however, hunter-gatherers seem much less violent than subsistence/preindustrial agricultural societies, which make more and bigger wars.
low populations and few resources are an incentive to avoid wars with neighboring tribes, generally by physically staying out of their way.
most hunter-gatherer deadly violence is murder, not war.
murder declined in Europe with the rise of states in the Middle Ages/Early Modern period. stateless societies had more revenge killings and less law enforcement.
murder in hunter-gatherer societies is not considered acceptable; most murder is done by “sociopaths” violating the community norms; hunter-gatherers have methods, like capital punishment, to keep “sociopaths” from terrorizing the group.
possibly “sociopaths” are more likely to become chiefs or leaders in larger, more hierarchical agricultural societies, and lead them in wars?
humans are far less prone to violently assaulting other humans than primates are to members of their own species, but human violence is much deadlier than primate-on-primate violence. we have more self-control, better coordination and weapons, and more vulnerable bodies.
https://arxiv.org/pdf/2006.15191
“Is SGD a Bayesian sampler? Well, almost.” empirically, the functions learned by common neural net architectures with stochastic gradient descent are close to the functions learned by Bayesian inference over the data with Gaussian processes.
https://www.cs.toronto.edu/~duvenaud/distill_bayes_net/public/ how Bayesian neural networks can improve generalization
https://www.reddit.com/r/DrWillPowers/comments/1iy708b/at_this_point_for_me_an_estradiol_lab_level_in/ Will Powers on hormone therapy
https://www.sully.ai/ AI agents for health care
https://astera.org/residency/ Astera residency applications open
https://press.asimov.com/articles/nobel-duel the story of the race to characterize CRF
https://jasonbenn.com/tools-for-thought-social-media-posts/50-days meditation personal experience
https://jasoncrawford.org/the-dilution-of-precise-concepts Jason Crawford on how concepts get diluted
links 3/31/25: https://roamresearch.com/#/app/srcpublic/page/03-31-2025
https://www.noahpinion.blog/p/how-brazil-built-a-world-beating
The 7th biggest airplane manufacturer is Embraer, a Brazilian company. How did that happen?
it came out of a state aeronautical institute founded by aviation pioneer Casimiro Montenegro Filho in the 1940s; military-run, well-funded, and famously competitive as an engineering school.
Embraer was founded in 1969 as a state-run spinout company using a prototype developed by a student. They focused on a specific niche: small commuter planes for the local market.
Brazil is very big and has bad roads; there’s high demand for domestic air travel.
Embraer was privatized in 1994 as part of an overall economic liberalization strategy in response to the hyperinflation and falling GDP of the early 1990s. At this point, Embraer got more investment from the private markets and branched out to regional jets and exports.
“classic industrial policy” playbook: strong government support at first, which was later taken away; focus on exports and keeping up with the technological frontier.
https://www.cell.com/cell-metabolism/pdf/S1550-4131(23)00303-0.pdf
“Death-seq”—identify dead or dying cells as those which have detached from the surrounding tissue, and do RNA-seq on dead vs. live cells to identify the expression properties characteristic of cell death.
Then do a genome-wide CRISPR knockout screen on cultured fibroblasts, induce senescence with doxorubicin, and see which gene knockouts make senescent cells more or less susceptible to being killed by the senolytic compound ABT-263. then Death-seq the lot.
they find hits, particularly SMAC/DIABLO, a mitochondrial protein whose knockout inhibits senolysis with multiple BCL-inhibiting senolytics. Going the other way, SMAC mimetic drugs promote senolysis.
Senescent but not proliferating cells get their cell membranes depolarized during senolytic treatment.
systemic SMAC] mimetic + senolytic combination therapy in a mouse model of idiopathic pulmonary fibrosis reduces senescent cell markers & reduced the histological severity of pulmonary fibrosis.
the combo also helps with liver function in a mouse model of NASH
what about doing Death-Seq with no drug? what gene knockouts predispose to all sorts of cell death (apoptotic or not)?
they get 13 markers of senescent cell death. most are novel. one is expected (BCL2L1)
bad news for senescence markers: the Tabula Muris Senis (single-cell sequencing atlas of mice at different ages) simply does not contain cells with multiple genetic markers of senescence in the aged animals!
“Despite an increase in both the percent of cells expressing Cdkn2a and expression levels of Cdkn2a increasing when pooling cells across 23 organs, we were unable to find cells with multiple markers of senescence in physiologically aged mice in either atlas, in accordance with another recent independent cell atlas dataset.”
https://www.chicagotribune.com/1994/02/08/sour-note-metropolitan-opera-dumps-soprano-kathleen-battle Operatic soprano Kathleen Battle got fired from the Met for being unprofessional and “nasty”, which is really saying something.
https://957benfm.com/2025/02/18/timothee-chalamet-method-a-complete-unknown/ Timothee Chalamet sang and played his own songs as [[Bob Dylan]] in “A Complete Unknown”, got a dialect coach and movement coach, didn’t use a cell phone, and gained 20 pounds for the role.
https://www.thecrimson.com/article/2025/3/28/hms-researcher-detained/ Kseniia Petrova, a bioinformatician at Harvard Medical School, is currently detained by ICE in Louisiana after her visa was revoked because she didn’t declare some biological samples at customs when reentering the country.
“When she told a CBP officer who questioned her that she feared political persecution if she returned to Russia, the agency decided to detain her instead, according to one of the petitions filed by her lawyer, Gregory Romanovsky.”
https://www.lesswrong.com/posts/JFWiM7GAKfPaaLkwT/the-vision-of-bill-thurston Legendary topologist Bill Thurston, famous for his extraordinary abilities to visualize in 4 and 5 dimensions, had no visual depth perception, due to strabismus. He said that he did high-dimensional visualization exactly the same way he had to do 3D visualization—by reconstructing it from 2D projections.
https://en.m.wikipedia.org/wiki/Jharkhand
heavily forested state in India
very tricky “guess where these people originated from their faces” quiz
links 3/28/25: https://roamresearch.com/#/app/srcpublic/page/03-28-2025
https://docs.google.com/forms/d/e/1FAIpQLSc5RvEk4ufotM52v5mKHF7iZOh0Ls_cMDLd5TXn7YOVa62VZQ/viewform Anna Gat offers free mentoring calls to women & immigrants
https://chatgpt.com/share/67e6ae4a-2138-800f-8e33-f1c50857859f Deep Research report says that 19th-20th c metals companies (Rio Tinto, US Steel, Alcoa, Timet) could routinely make double-digit profits.
https://www.science.org/content/blog-post/alkanes-mars there are alkanes—big organic molecules—on Mars. these can be produced by abiotic processes, but usually that makes shorter chains than these. so....life? We Shall See.
https://archive.is/20250326022231/https://www.nytimes.com/2025/03/25/opinion/ezra-klein-podcast-santi-ruiz.html Ezra Klein and Santi Ruiz on DOGE.
these are reasonable people. it’s clear to both of them that you do not solve the federal debt with workforce cuts—most of the money is in entitlements.
Ruiz is a bit more hopeful than Klein that the conspicuous cuts to (small and sometimes even cost-effective) liberal-coded programs like PEPFAR are the necessary concession to Trump voters (who want to own the libs but may want to keep their Medicare) before serious budget cuts can begin.
Klein is suspicious that the whole program is just punishing Trump’s political enemies, which, as a Democrat, even a moderate who accepts the need for fiscal discipline, he has no reason to support.
links 3/27/25: https://roamresearch.com/#/app/srcpublic/page/03-27-2025
https://www.secondperson.dating/p/navigation-by-moonlight
essentialist? sure. but this seems like an approximately right version of what “feels natural” to me and gets missed by most men I know.
most self-help revolves around “if you have a problem, here’s how to take action to fix it”, and there’s a frame from which every version of this is missing the point.
sometimes the thing that is needed is not solving the problem but encouragement & support in the existing situation, reassurance that it’s a normal situation to be in and doesn’t reflect poorly on you, hope that things will get better...
sometimes the real “need” isn’t a solution to the alleged problem but sympathetic social support itself. the “problem” being complained about is just a pretext; if it were “solved” you’d pick another problem to complain about; the point is that you need friends who care about you. this is a real need! people suffer without it! yet another book of advice on how to solve today’s problem yourself is not going to help you acquire friends who would take care of you if you were completely helpless.
obviously if you like a guy and you are following vaguely feminine social scripts your first option is going to be “make yourself conspicuously attractive and show interest in him” rather than “ask him out.” it’s not that asking is totally taboo, but it’s not the default first move! most people start out by trying to execute the briefs assigned to them by society, and only reject those expectations if they find them intolerable.
https://www.ggd.world/p/how-do-radical-ideas-go-mainstream
mostly, reforms to social mores (and IMO feminism was a good one) happen through a process of “mainstreaming” that sands off the radical rough edges and makes them palatable to the general public. IMO this is also a good thing; it’s what makes social change a process of persuasion and winning-over rather than an arbitrary dictate.
the weirdness of the past 15 years or so is that a bunch of changes skipped straight from Tumblr to the boardroom, leaving everyone else puzzled and dismayed. For a lot of little social-mores things—like “should we have people in videos describe their appearance for the benefit of the blind?”—it’s not clear what the objectively right answer is, but it is clear that persuading most people to agree (on virtually any halfway-sane policy) is better than springing a baffling new policy on them and then having predictably bitter conflict over it.
https://www.startrek.com/news/shirts-and-skins-in-tos
the command uniforms in Star Trek were green, not gold. their shifting color is an artifact of lighting.
https://thechinaproject.com/2023/06/15/chinas-war-on-drugs-from-incarceration-to-rehabilitation/ a laudatory piece on China’s approach to drug addiction. it’s described as “compassionate” and “humane” but the bottom line is that drug use is not treated as a crime but rehab is mandatory for all. outpatient first, and then in state-run facilities if the person isn’t going to the outpatient rehab.
FW25 Color Stats
links 3/25/25: https://roamresearch.com/#/app/srcpublic/page/03-25-2025
low dose aripiprazole papers
https://www.psychiatrist.com/pcc/four-cases-chronic-pain-improved-dramatically-following/
4 cases of chronic pain responding to 2mg/day aripiprazole
https://journals.sagepub.com/doi/abs/10.1345/aph.1R387
torsades de pointes after 5 days on 2.5 mg. (pt had diabetes, hypertension, and stroke history though)
https://en.m.wikipedia.org/wiki/Polyethylene_glycol
ethylene glycol is antifreeze. many of them stacked together is polyethylene glycol, which is Miralax.
so why is antifreeze toxic but PEG not?
https://claude.ai/share/17d8e7b4-ffd5-4c96-9ca2-fe71c69d828a because the toxicity of ethylene glycol actually comes from the metabolites when it’s broken down by alcohol dehydrogenase. if you make a big polymer of PEG, ADH no longer metabolizes it, so it passes through the digestive system harmlessly.
https://www.thenewatlantis.com/publications/will-anyone-vote-for-abundance
yeah everybody reasonable likes Good Things, but in real life we don’t have a Good Things party, we have Republicans and Democrats.
https://thehumanist.com/magazine/fall-2024/features/the-distinction-between-imaginary-science-and-magic Ted Chiang’s categorization seems pretty much right; science fiction or “imaginary science” is about processes in an impersonal universe, whereas magic & fantasy are about a universe that relates to people the way people relate to each other.
https://en.m.wikipedia.org/wiki/Imipramine
did we have antidepressants in the 1950′s? yes. came out 1957.
AI “Deep Research” Tools Reviewed
links 3/24/25: https://roamresearch.com/#/app/srcpublic/page/03-24-2025
https://www.statecraft.pub/p/how-to-commit-a-coup Edward Luttwak’s thoughts on foreign policy and the CIA’s refusal to recruit people who know foreign languages (because people who travel abroad are thought too risky to clear)
pregnancy affects thyroid hormone levels.
TSH is typically lower during pregnancy, while T3 and T4 are higher. this means that using non-pregnant reference ranges may miss cases of hypothyroidism relative to “normal” pregnancy levels. https://pmc.ncbi.nlm.nih.gov/articles/PMC4758281/
https://pmc.ncbi.nlm.nih.gov/articles/PMC6358369/ study showing lower TSH and higher TF in first trimester pregnancy vs. nonpregnant controls
https://www.vox.com/future-perfect/405263/covid-media-coronvirus-masks-lab-leak-public-health Kelsey Piper on how the media screwed up the coronavirus
https://www.popehat.com/p/incomplete-primer-caselaw-appertaining-bigfoot-aka-sasquatch-lnu Ken White looks at legal cases related to Bigfoot or Sasquatch. (I miss his humor posts.)
https://www.complexsystemspodcast.com/episodes/gary-leff-frequent-flier-programs/ Patrick McKenzie interviews Gary Leff on the business of frequent flyer miles
This was the author’s claim—thanks for the counter-evidence!
Book Review: Affective Neuroscience
links 02/27/25: https://roamresearch.com/#/app/srcpublic/page/02-27-2025
https://blog.sentinel-team.org/p/sentinel-minutes-for-week-82025 blog of Sentinel, a team of forecasters concerned about catastrophic risks; might be a good news digest for straightforward politics/war/etc
https://eristicstest.com/ everyone’s favorite new personality test
https://benexdict.io/p/empathy-hardware Benedict Hsieh personal essay
https://www.shinzen.org/resources/articles/ Shinzen Young on meditation
https://www.ben-evans.com/benedictevans/2025/2/17/the-deep-research-problem OpenAI’s Deep Research spot-check; it’s error prone. sources don’t always say what the bot says they say.
https://www.nature.com/articles/s41586-024-08508-4 is this a mRNA cancer vaccine that works? on pancreatic cancer???
not so much. this is examining the difference in survival between vaccine responders and nonresponders. It’s substantial! but only 8⁄16 treated patients responded. not clear how it stacks up to other pancreatic cancer treatments.
but there are lovely single-cell sequencing techniques to see that the vaccine can induce long-lived T cells
endometriosis only occurs spontaneously in primates
https://www.sciencedirect.com/science/article/abs/pii/S0021997512000072 mandrill
https://pb.copernicus.org/articles/4/77/2017/ rhesus monkey
https://academic.oup.com/humrep/article-abstract/27/8/2341/712472 olive baboon (this one is induced)
https://academic.oup.com/humrep/article-abstract/10/3/558/648290#google_vignette baboons with endometriosis have reduced NK activity
https://academic.oup.com/humrep/article-abstract/22/1/272/2939374 it can get into the colon in baboons
https://academic.oup.com/humrep/article-abstract/11/9/2022/616104 baboons with endometriosis have more retrograde menstruation (but not all baboons with retrograde menstruation get endometriosis)
what works on endometriosis in primate studies?
https://www.sciencedirect.com/science/article/abs/pii/S1642431X17302498 Icon immunoconjugate
https://academic.oup.com/endo/article-abstract/151/4/1846/2456726 pioglitazone
https://academic.oup.com/biolreprod/article-abstract/97/1/32/3869077 simvastatin
https://www.sciencedirect.com/science/article/pii/S0015028212024338 aromatase inhibitors
can you selectively kill ectopic endometrial cells in endometriosis?
https://journals.sagepub.com/doi/abs/10.1177/1933719113485298 the endometrial stromal cells are CD10+
more on this: https://en.wikipedia.org/wiki/Neprilysin
https://link.springer.com/article/10.1007/s10815-023-02772-5 yes they’re thinking about cell therapies
https://www.publicbenefitinnovationfund.org/ Public Benefit Innovation Fund, accepting applications for AI projects that benefit social services
links 2/25/25: https://roamresearch.com/#/app/srcpublic/page/02-25-2025
https://en.m.wikipedia.org/wiki/Cherenkov_radiation blue glow from particles moving faster than the speed of light in a medium (like water)
https://dsq-sds.org/index.php/dsq/article/view/5824/4684
https://en.m.wikipedia.org/wiki/Muir_Woods_National_Monument Muir Woods, home of the old-growth coast redwoods, was originally preserved by politician William Kent. But when a water company planned to build a dam (which would flood the woods) and threatened to use eminent domain when Kent objected, he had to donate the park to the federal government in order to actually preserve it as a place of natural beauty.
https://www.osv.llc/our-fellows O’Shaunessy Ventures fellows
surrogate endpoints in clinical trials are generally evaluated with a meta-analysis, in which the trial-level correlation between the surrogate and “gold standard” endpoint is compared. Do trials that find a larger treatment vs. control effect on the surrogate endpoint also find greater effects on the “gold standard” endpoint? Mostly these are done in only a handful of diseases, primarily cancer where things like response rate or progression-free survival are compared to the “gold standard” of overall survival.
https://open.library.ubc.ca/soa/cIRcle/collections/ubctheses/24/items/1.0072082 lesion count as a surrogate for relapse rate in [MS
https://www.sciencedirect.com/science/article/abs/pii/S0895435608001698 LDL as a surrogate in statin trials
https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.18217 PET complete response as a surrogate in follicular lymphoma
https://www.sciencedirect.com/science/article/abs/pii/S0003496724224262 serum urate is a poor surrogate for gout flares!
https://ascopubs.org/doi/abs/10.1200/jco.2005.08.156 PSA is a poor surrogate for survival in prostate cancer
https://www.sciencedirect.com/science/article/abs/pii/S0272638616002146 protein urea as a surrogate in kidney disease
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(18)30314-0/abstract albuminuria isn’t great as a surrogate in kidney disease
https://www.sciencedirect.com/science/article/pii/S2666168322026842 progression-free survival is ok as a surrogate in metastatic urothelial cancer
https://www.bmj.com/content/bmj/375/bmj-2021-066381.full.pdf pathological complete response is a terrible surrogate for survival in early breast cancer
https://www.thelancet.com/pdfs/journals/eclinm/PIIS2589-5370(21)00010-9.pdf event-free survival is a much better surrogate in early breast cancer
https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools list of FDA-cleared companion diagnostics for determining who should use a therapeutic. these are almost all genetic tests for cancer mutations.
https://research.manjarinarayan.org/ Manjari Narayan’s personal website
https://etherospharma.com/our-team/ Laura Dugan, whom I funded for her work on carboxyfullerene SOD mimetics extending lifespan and preventing neurodegeneration, has a biotech company now; and Jack Scannell, the predictive validity guy, is the CEO!
Jack Scannell’s thesis: we have more and more ways to screen targets and drug candidates, but they have lower predictive validity, so more drugs fail in the clinic and the cost per successful drug keeps rising.
solution: care more about what screens, animal models, etc you use! just because it’s “industry standard” doesn’t mean it doesn’t suck!
melanocortin/leptin-related hereditary obesity
https://pubs.rsna.org/doi/abs/10.1148/radiology.168.2.3393649 you can measure liver iron overload with imaging in thalassemia
James M. Wilson discovered the AAV, the family of viruses most used in gene therapy
discoveries of cancer genes/mutations:
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1349-7006.2008.00972.x a chromosomal translocation with ALK in solid tumors (which was unknown before 2008)
Monica Hollstein discovered TP53 mutations and EGFR amplification in cancer
Robert A. Weinberg seems to have done a LOT of discoveries of oncogenes
Michael Stratton discovered BRAF and RAS and BRCA2 mutations in cancer; also established the Cancer Genome Project
Mary-Claire King discovered the BRCA1 susceptibility mutation for breast cancer
Mark Skolnick, founder of Myriad Genetics, sequenced BRCA1 and BRCA2
Jose Baselga developed Herceptin
John Mendelsohn developed cetuximab
Garth Powis discovered KRAS
https://www.appliedinvention.com/ Danny Hillis’s company
https://gsb-faculty.stanford.edu/benoit-monin/topics/do-gooder-derogation-moral-social-comparison/ people are especially eager to derogate “do-gooders” to alleviate feelings of comparative inadequacy. These are the sorts of studies that don’t replicate but I find the theory plausible.
https://en.wikipedia.org/wiki/John_Bull symbol of the UK
https://en.wikipedia.org/wiki/Brother_Jonathan precursor of Uncle Sam, symbol of New England
https://en.wikipedia.org/wiki/Tiny_Broadwick pioneering female aviator and parachutist
https://www.panoramaortho.com/wp-content/uploads/2017/09/History-of-DXA-2107-PDF.pdf bone density DXA scans date back to the 1980s
https://www.nature.com/articles/s41390-022-02101-z Claude Bachmann discovered NAGS deficiency, a genetic disease
https://everythingstudies.com/2022/05/24/the-political-is-personal/
links 1/21/2025: https://roamresearch.com/#/app/srcpublic/page/02-21-2025
https://en.wikipedia.org/wiki/Neurofilament_light_polypeptide a marker of axonal degeneration in Alzheimer’s, Huntington’s, ALS, MS
https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1471-4159.1996.67052013.x study linking levels of NfL to ALS: 1996
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1468-1331.2012.03777.x study linking levels of NfL to ALS severity/progression: 2012
https://www.nature.com/articles/312757a0 sequencing the HIV-1 virus -- 1984
https://www.nature.com/articles/324691a0 same group at the Pasteur Institute sequenced the HIV-2 virus in 1986
xhttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(96)05283-X/fulltext earliest trial (1996) I could find using viral load as an endpoint for HIV vaccines
https://en.wikipedia.org/wiki/Sitosterolemia lipid metabolic disorder
https://en.wikipedia.org/wiki/Fibrodysplasia_ossificans_progressiva rare disease that turns muscle and tendons to bone
https://www.nature.com/articles/ng1783 gene for fibrodysplasia ossificans progressiva
https://www.pennmedicine.org/news/publications-and-special-projects/the-research-legacy-of-penn-medicine/orthopaedics/fop history of research on the disease
https://en.wikipedia.org/wiki/Michael_Houghton discovered hepatitis C
https://en.wikipedia.org/wiki/Louis_M._Kunkel discovered dystrophin, the protein deficient in muscular dystrophy
https://www.discoverymedicine.com/Eric-P-Hoffman/2013/11/08/orphan-drug-development-in-muscular-dystrophy-update-on-two-large-clinical-trials-of-dystrophin-rescue-therapies/ trials using dystrophin as a biomarker in trials for muscular dystrophy
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60756-3/fulltext?keepThis=true&width=850&height=650&rss=yes&TB_iframe=true dystrophin used as a surrogate endpoint in muscular dystrophy trial
https://www.tandfonline.com/doi/abs/10.3109/10425179109008433 cytomegalovirus sequenced in 2009
https://www2.mrc-lmb.cam.ac.uk/bart-barrell-1944-2023/ Bart Barrell
https://profiles.ucl.ac.uk/1277-stephan-beck Stephan Beck
https://academic.oup.com/cid/article/62/9/1154/1745383 first study I could find (2016) using viral load as an endpoint for CMV antivirals
https://pmc.ncbi.nlm.nih.gov/articles/PMC2730307/ standard anthrax immunoassay, from 2002
https://www.nejm.org/doi/10.1056/NEJMoa2003715 SOD1 used as an endpoint in a trial for ALS
https://www.science.org/doi/abs/10.1126/science.1243292 first description of activated PI3K-δ syndrome, 2013
https://ashpublications.org/blood/article/130/21/2307/36662/Effective-activated-PI3K-syndrome-targeted-therapy lymph node size and naive B cells as endpoints in activated PI3K-δ syndrome trial
https://en.wikipedia.org/wiki/Activated_PI3K_delta_syndrome
https://www.nejm.org/doi/abs/10.1056/NEJM197911223012102 IGF-1 as a biomarker for acromegaly, 1979
more on IGFs in acromegaly: https://www.sciencedirect.com/science/article/abs/pii/0026049594901996
https://jamanetwork.com/journals/jama/article-abstract/257810 Niemann-Pick first described in 1928
https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure list of surrogate endpoints that the FDA accepted for drug approval/licensing
https://charlesyang.substack.com/p/2-years-at-doe what it’s really like at DOE
https://www.ams.org/journals/bull/2022-59-02/S0273-0979-2022-01759-4/S0273-0979-2022-01759-4.pdf this is the closest I could find to an exposition of the Bellman function method
https://en.wikipedia.org/wiki/Berl_Katznelson early Zionist; does not appear to be related to the mathematician
people often claim that the “female orgasm” is exclusive to humans, or cannot be detected in animals, but this is false
https://kinseyinstitute.org/pdf/womens%20orgasm%20annual%20review.pdf female orgasm has numerous objectively verifiable signs, from characteristic changes in breathing/heart rate to rhythmic vaginal contractions.
https://onlinelibrary.wiley.com/doi/abs/10.1002/ajp.1350010104 females of many species of primates make facial expressions and noises associated with pleasure during sex, and also show the characteristic vaginal contractions of female orgasm when stimulated
https://www.tandfonline.com/doi/pdf/10.3402/snp.v6.31883 evidence that female rats experience sexual pleasure
https://en.wikipedia.org/wiki/Leroy_Hood nvented the DNA sequencer, the protein sequencer, the peptide synthesizer, and many other methods
https://en.wikipedia.org/wiki/Eleftherios_Diamandis biochemist who first skeptically investigated Theranos’s claims and prompted John Carreyrou to do his famous investigative expose
links 4/22/25: https://roamresearch.com/#/app/srcpublic/page/04-22-2025
https://visakanv.substack.com/p/why-frame-studies Visakan Veerasamy’s outline for the new media studies project
https://www.leash.bio/ building a very big new database of molecules and their protein interactions, designed for training ML models on. This is the Way.
https://newsletter.rootsofprogress.org/p/sci-fi-without-dystopia Jason Crawford says yes, science fiction in high-tech settings can be dramatic without taking an anti-tech stance.
most of his examples are movies & TV but I think Vernor Vinge does an especially good job at telling stories that are centrally about tech, and involve tech far beyond our own, and are even in some ways “utopian”, but aren’t dull. Mostly they center on the problems at the edges of where the tech breaks down, or interpersonal conflicts where the tech defines the means at each party’s disposal.