Right Through the Skull

Mar. 31st, 2026 02:05 pm
[syndicated profile] in_the_pipeline_feed

In today’s “Well, I’ll be darned” category is this paper, which described a way to get drug delivery into the brain that I never would have imagined. The authors are using a “calvarial” mechanism, and I’m certainly in a forgiving mood if you’ve never heard that word before, because I certainly hadn’t.

The calvaria, as it turns out, is the top of the skull, and the skull bones have a lot of anatomical detail in them. The inner and outer surfaces are compact bone, and there’s a layer of spongy “cancellous” bone between them. That contains red bone marrow, and there are channels through this tissue (diploic veins) in a rather complex network whose function is still open for debate. The most generally accepted explanation is one big function is as a cooling system for the brain itself (which after all is a very metabolically active organ).

But there are routes into the cranial cavity itself, because it turns out that the skull’s bone marrow is in close biological communication with the meningial layers around the brain. There are “skull-meninges channels” for immune cells that develop in that bone marrow to migrate into the brain, and the authors speculated that this might be a Trojan-horse route for therapeutic agents,

They injected drug-loaded nanoparticles into that central space of the skull bone layers, and found that indeed, immune cells take these up and then continue on their merry way into the brain loaded with this cargo. They especially go on to target sites of inflammation therein, which give you a real opportunity for targeted delivery. This was demonstrated with the clinically studied oligopeptide agent nerinetide (a neuroprotective), and found that it was effective in a neuroinflammation model at only 20% of the dose needed otherwise.

The authors have already tested this in human patients suffering from middle cerebral artery infarction (which sounds like a terrible event, I have to add). This was done in 20 patients randomized to get standard-of-care or that plus through-the-skull (“ICO”) treatment with Y-3, a neuroprotective already approved in China. For what it’s worth, the number of patients showing better clinical scoring was certainly higher in the ICO group, and the main thing you can take from that is that this certainly looks worthy of further work in a larger trial.

The tricky part, I think, will be narrowing down for that. There are obviously a number of drugs you could imagine delivering this way for a variety of conditions, and this delivery route is expected to be fairly drug-agnostic. Acute stroke sounds like it will continue to be a good proving ground, but there are plenty of others. And you could also imagine dropping in whole modified cells rather than just having them take up your drug payloads. A lot of work is in store, but the promise of totally skipping the blood-barrier line is certainly worth it.

The Ally

Mar. 31st, 2026 09:00 am
dorchadas: (Judaism Nes Gadol Haya Sham)
[personal profile] dorchadas
Yesterday, [twitter.com profile] worldbshiny took me to see the premier of The Ally at Theatre Wit. Originally I looked up the playwrite (Itamar Moses), looked up the main character's name (Asaf), and thought "Oh, I see why she invited me." Emoji Jewish with Torah and then I asked her about it and it turned out I was completely wrong--she invited me because I had invited her to go get pancakes at Hanabusa and she hadn't been able to make it due to being on a Disney cruise. Oops.

2026-03-30 - Theatre Wit does The Ally


The blurb for the play is:
When Asaf's student asks him to sign a manifesto condemning police brutality, he wants to help — until he realizes the petition says more than he's ready to stand behind. As the debate roars through his Midwestern campus and his ex-girlfriend takes the lead, Asaf is pulled into a political storm that tests his convictions and his sense of self. Will his fumbling entrée into activism help or hurt the cause?
...and really despite the framing, most of the play is about Asaf. He's the only character in every scene, he has a bunch of monologues about how he feels about things, and the way he feels is mostly "conflicted." Asaf has the classic affliction of the nice liberal, which is that he just wants to be on the right side and not really get involved in internal conflicts, and for most of his life he was able to do that. Even during his earlier activist days, he and his activist friends all agreed on their anti-racist, anti-surveillance state, anti-war objectives (his activist days were just during and before the 2003 US invasion of Iraq) and he never actually had to take a stand on something controversial. And when he does, it turns out you can't please everyone.

The play tries to cover basically all ground, sometimes to its detriment. If you've ever heard anyone use any argument about Israel and Palestine--right of return, Israeli territorial ambitions, Hamas rocket attacks, Mizraḥi voting patterns, land for peace, pinkwashing, the Damgana, the Nakba, whatever--it's in here, and mostly in a big argument scene in the second act where a bunch of characters get to make dramatic speeches opposing each other. Well, mostly opposing each other. Asaf is fond of saying he mostly agrees with other people, except for one small thing, and maybe we can talk about it and work it all out, you know?

Maybe. Not everything can be so easily worked out. There was what seemed like an intentional contrast between Asaf's interactions with his (non-Jewish) wife Gwen, who works as a community outreach manager at the college where he teaches, where they always start assuming the best intentions of each other and are willing to listen and hear each other's points of view, and his interactions with the other characters in the play which are characterized by a lot of misunderstanding (at best). There's a part near the end where Asaf confronts Nakia, his activist ex-girlfriend, and asks her to put in a section about antisemitism in her twenty-page manifesto that has room for police brutality, capitalist disinvestment, American imperialism, Israel, and French actions in Mali. Just a sentence, anything. And she says no.

After seeing the play I went and looked up some information about it because I had questions about the choices made, and it led to me to this article in the Forward about it which answered a lot of my questions already:
...how do I understand what new lens this will cause audiences to bring to it. A lot of the "rewrite" after Oct. 7, was me rereading through the eyes of "now." It was clear that the play has to take place pre-Oct. 7 because if it took place now it would be a completely different play, so then it was a question of how we experience it now. On a practical level, if someone says something that has been proven definitively wrong, is that intentional irony or foreshadowing on my part or does that seem like a mistake?
It was definitely the latter for me, though less so now that I know the play's context. Especially during the big argument scene, I was thinking that some of these people would probably not even be in the same room nowadays, much less be willing to talk to each other. That said, the part about tribalism--looking at the bad acts of our side and saying "Oh, those are just bad actors but we are basically good" and looking at the bad acts of the other side and saying "Those are expressions of your most fundamental beliefs, you monsters"--is true both now and forever, and the message that we function as the default enemy for Christian and Islamic societies (so, the majority of the developed world even now) delivered by a Jewish Ph.D student to Asaf is basically the main thesis of the excellent book Anti-Judaism: the Western Tradition. And I'm sure we can all relate to the guy who just wants everyone to get along.

The staging depicted above was static through the whole play, though for act two they moved the tables around. Location changes were depicted through lighting shifts, which worked for me but didn't work for [twitter.com profile] worldbshiny. I thought the ending was fantastic, Asaf sitting in a synagogue and engaging in התבודדות (hitbodedut, "solitude") as he tries to work out his conflicting imperatives, and I looked it up and found that this was the second-to-last scene in the original. There was a scene where Asaf goes to the march organized by Nakia and his wife is angry with him for being late to it, but Moses mentioned how they rewrote the scene several times and eventually just cut it because at that point, all the important parts of the play were done.

It runs through May 3rd.

Revving Up LNP Delivery

Mar. 30th, 2026 03:19 pm
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Now here’s something that I wouldn’t have guessed. As the world knows, lipid nanoparticles have been the key to getting mRNA vaccines to work, and they are useful for all other attempts to deliver RNA cargoes into cells and probably much besides. A huge amount of effort, time, and money has been put into trying to optimize them for these purposes - all sorts of different lipids and lipid mixes, close attention to size, morphology, and cargo loading, you name it.

But as this new paper notes, even with this, mRNA delivery can be rather spotty across different tissue types, for reasons that are still up for debate. The genetic background of the cells and tissues that youre trying to deliver to will clearly have an influence, but even going after what should be the same cell types you can see some real variation (and plenty of changes between in vitro and in vivo behavior). What’s not up for debate, sadly, is that if we’re going to have to just keep trying combinations of lipid carriers to get out of this problem, well, we could be at it a while: a four-component LNP could have up to ten billion potential combinations, given the number of candidates for each of those positions. 

The authors here note that culturing your target cells in different media leads to very different mRNA LNP outcomes. The standard cell media mixes are formulated to optimize cell growth in culture, and as such contain rather nonphysiological amounts of many nutrients. That was the impetus to develop human plasma-like medium (HPLM) to more closely mimic the in vivo situation. When they used that mix instead of the usual cell media, the authors saw the efficiency of the mRNA delivery drop sharply, which got them to thinking about the effects of all those extra components in the classic brews.

It turns out that the HPLM-grown cells show downregulation of several amino acid metabolic pathways (arginine, methione, and proline, for example), and the team hypothesized that this might have something to do with the impaired LNP uptake. Screening supplementation of individual amino acids in HPLM to bring their concentrations up to where they are in other media showed that extra methionine, arginine, and serine had a very significant effect on efficacy of mRNA delivery. Working on the concentrations of these in more detail, a mixture of 30x HPLM background in methionine, 10X arginine, and 30X serine performed well across the board, with five-to tenfold increases in delivery. Cells fed this mixture showed enrichment of endocytosis pathway proteins (but not those associated with endosomal escape, as far as could be seen). The clathrin-independent-carrier (CLIC) pathway seemed to be especially affected, and had already been flagged by other research as important for LNP success.

And convincingly, this amino acid supplementation idea worked in animals, showing greatly increased uptake of mRNA cargos both in model systems and with therapeutic cargos. And this worked not only for mRNA delivery, but for in vivo gene editing cargoes with CRISPR-Cas9 components as well. This is good news - it’s hard to see how anyone could have a problem with some extra amino acids being given along with the mRNA doses.

So it looks like the metabolic state of the target cells is indeed a key factor in hitting them with lipid nanoparticles, and that this can be easily modified with a cocktail of inexpensive, easily available and easily administered amino acids. I hope this idea gets some intensive scrutiny and that it works as well for others as it did here!

dorchadas: (Ping Kills)
[personal profile] dorchadas
So, last week we had to pull Laila out of school on Thursday in order to transfer her to the new school that would serve her IEP. This was so very important than the extremely-competent coordinator at her old school called us 15 minutes before the school day, right when we were getting ready to leave, and told us we had to stay home so that the process could complete. The extremely-competent coordinator then failed to actually send the necessary information to the new school in time for enrollment, so Laila is at home today.

Well, today we learned that the extremely-competent coordinator is out of office today and has still failed to send the necessary information to the new school, so in service of Laila getting a better education she'll be out of school for at least three days and possibly longer. All in her best interests, of course. Obviously the extremely-competent coordinator must be following best practices and is giving Laila a bit of time to get used to the prospect of going to full-day school.

Sarcasm aside, her being out of school might actually be a good idea today because she has a thick cough. But the continued pattern of Peirce's coordinator's idiocy is making me wonder how she even got the job (I'm assuming either seniority or nepotism). Further updates the longer Laila is out of school.

vital functions

Mar. 29th, 2026 10:15 pm
kaberett: Trans symbol with Swiss Army knife tools at other positions around the central circle. (Default)
[personal profile] kaberett

Reading. Preeeeetty much just progressing further through the She's A Beast archives, and continuing to develop opinions. I... think that's it? I think that's it; it has been A Busy Week.

Writing. Words Go Up: over 9.5k. Two more subsections titled. I continue to chew things over.

Listening. More Hidden Almanac. Technically up to May 2015, but I'm going to be going back over most of 2015 on account of Tragically, Some Dozing. (It is Car Noise, you see, and we have been. Travelling.)

Eating. A lot of food made for me by a variety of other people, notably including dosa + thali by Chai Station Chester, hot chocolate from [Knoops] in Chester, bread/cake/cookies/waffles by the Jaunty Goat and petits fours by Biscotti di Debora. Petits fours AMAZING; further thoughts possibly to follow.

Exploring. Southport Botanic Gardens, which struck me as much more of a park and rather less of a botanical garden than I'd quite expected based on the name, though perhaps this is because the fernery was closed by the time we got to it; very much enjoyed THE AVIARY.

Minimal exploration of Chester Zoo, once again culminating in staying in the bat cave until kicking out time.

Little bit of poking around Salisbury, feat. excellent tulips, excellent irises, FREE BLUE AGAPANTHUS that someone had divided, excellent bee doorknocker.

And then finally we made it HOME.

Making & mending. Progressed A's second glove some more! Stalled when I got to starting increases for the thumb gusset on account of my additional stitch markers were in the roof box and ... no.

Growing. Kept the lemongrass alive through The Travels. Acquired, as mentioned, a chunk of agapanthus. Unshockingly, the aubergine I sowed immediately before leaving has not sprouted, but hey, I'll turn the propagator back on. Nothing else seems to have died while I was away, hurrah.

Observing. MOON. The Dog. Creatures, including A having an excellent time Experiencing Bats (and also Flamingoes With Wings, A Rhinoceros, some grey-crowned cranes, and Monkeys).

Soft lock picking in real life

Mar. 27th, 2026 12:00 am
[syndicated profile] clayton_wramsey_feed

Last weekend, I played a fun little indie game called Real Life Soft Lock Picking. To play, just lose your phone, wallet, and keys all at the same time.

You will then be soft locked: despite every system in the world working as intended, you’ll be locked out of your home, unable to make any progress or even feed yourself. The only way out is by soft lock picking, where you have to escape from a soft lock with a mix of cleverness and extraordinary patience.

Homeward bound

Once soft locked, your first problem is going to be finding some way to eat and sleep. Having locked your front door, you can’t get into your home. I live alone, so there were no spare copies of my home key except my landlord’s — but naturally, since I was phoneless, I had no way to contact him.

In any event, I lost all my things late on a Saturday night, so it would be unreasonable to expect my landlord to be available anyway. Once soft-locked, you are at the mercy of others; luckily, I had a friend who was willing to feed and house me until I got my stuff back. I’m left wondering about the people who aren’t as fortunate as me: people who have just moved, or who are traveling, or parents with kids that will all need food and shelter on short notice. Even when resources for them exist, you still need a way to find them and reach them, and without a phone, money, or transportation, it’s nearly impossible.

Catch twenty-two factor authentication

Even with the most pressing issues solved, you’re still soft locked. Your best lead to finding your stuff is using a tool like Find My to locate your phone and hoping that your phone is in the same place as all your other valuables. However, you probably won’t even be able to access Find My, since everything will be locked by two-factor authentication.

Back in the day, you only needed a username and password to sign into anything. Since passwords leak all the time, most systems now demand that sign-ons from new devices pass two-factor authentication. Typically, this means that after trying the half-dozen or so passwords that you can remember, you will be greeted by a fun little message like this:

Let's make sure it's really you

[ ] [ ] [ ] [ ] [ ] [ ]

We’ve sent a text to your phone with a 6-digit code. Enter that code above in the next 10 minutes to prove it’s really you.

This leaves you with a circular problem:

  • You need to access your accounts to locate your phone.
  • You need to pass two-factor authentication to access your accounts.
  • You need your phone to pass two-factor authentication.

If I could get back into my apartment, I could at least use my laptop to try bypassing two-factor authentication. But after a morning texting him from a borrowed phone, my landlord wasn’t answering my texts, so that was right out.

After a few tries, I found that Apple’s authentication system is a fickle lover: sometimes, it will decide that your login attempt is cool enough to bypass two-factor authentication. With this in hand, I tracked down my phone (and all my other stuff) to the home of a confused gentlement who had accidentally grabbed the wrong bag.

Leaving keys around

In hindsight, it’s possible for a prudent person to leave themselves keys to make soft locks a little easier to pick. They can be physical, like leaving a real key with a friend, or metaphorical, like getting more ways to access your accounts. Maybe using just using Nix would have fixed this.

But expecting users to leave keys for themselves is a design mistake: Every backup method will eventuall fail. Users lose stuff and forget things all the time, and soft locking a user for that is just an exercise in automated cruelty. We make products to serve people, and not the other way around.

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Posted by Bret Devereaux

Hey folks! Another gap week because, as mentioned last week, I am at the annual meeting for the Society for Military History happening in Arlington. That said, we actually did have a major post this week, my 7,500 word primal cry concerning the current war in Iran. I know that won’t be for everyone – some of you read this to get away from current events – which is why I dropped it ‘off schedule’ midweek rather than having it replace this post.

That said, as I often do with weeks where I am at a conference, let me share the abstract of the paper I am delivering, “Unlearning the Marian Reforms:”

The transformation of the Roman army from the conscription-based citizen militia organized by maniples of the middle republic to the long-service professional army organized by cohorts in the early imperial period remains a topic of intense interest for specialists and non-specialists alike.  In recent years, however, the specialist understanding of this transformation has increasingly diverged from a non-specialist generalist vision which remains wedded to the notion of the ‘Marian Reforms.’  The idea of a set of reforms, occurring in the late second or early first century BC, which can be tied particularly or generally to the career of Gaius Marius (cos. 107, 104-100, 86) remains common in popular history and even academic textbooks and so permeates the non-specialist understanding of the Roman army’s transformation.  However, as this paper demonstrates, functionally every part of this narrative has come under attack and nearly all parts of it must now be discarded: there were no ‘Marian Reforms,’ ‘so-called’ or otherwise.

Instead, what has emerged from the scholarship is a prolonged process of change beginning far earlier in the second century and not entirely complete until at least the reign of Tiberius (r. 14-37 AD), in which Gaius Marius’ career forms only a single episode and not necessarily a particularly important one.  This new understanding of change in the Roman army now dominates the specialist scholarship but has not filtered through to general discussions of either Roman or military history.  This paper addresses this gap in understanding, outlining the key elements of the ‘Marian Reforms’ have been undermined and demonstrating that the notion of the ‘Marian Reforms’ as an event in the history of the Roman army is to be abandoned in generalist and textbook treatments, at it has already been in specialist ones.

Now normally this is a case where I have to hem and haw about how conference presentation papers aren’t really ready for publication even on a blog, but this conference paper is in fact a more-or-less direct translation of a blog post we have already had, “The Marian Reforms Weren’t a Thing.” Indeed, whereas my speaking time here (around 20 minutes) limits me to just around 2,800 words, the original post is about three times longer, with significantly more detail than I can fit into a conference paper. So you can in essence, read a longer, even more decompressed form of this argument! So feel free to go and read that if you missed it and to read my Iran War take if you want and didn’t catch it midweek and we’ll be back next week with something different (maybe Carthage themed?).

The Latest CAR-T Work

Mar. 27th, 2026 12:41 pm
[syndicated profile] in_the_pipeline_feed

The development of chimeric antigen receptor T-cell (CAR-T) therapy continues, and some really interesting new directions are being explored. As it stands, this treatment can be extraordinarily effective in some patients, and these are generally people who have been through every other option for their cancer therapy. But there are some real limitations, even for treating patients with the leukemia/myeloma type cancers that (so far) this mode is best suited for.

An obvious one is the sheer amount of time and effort involved. The patient’s own T cells have to be genetically engineered to go after a selection of antigens that is tailored to each person’s case, and the patients themselves have to be “lymphodepleted” with chemotherapy before these are infused back. It’s a difficult, expensive process, and (like anything in this category) is very hard on the patients themselves (although, to be sure, not as hard as dying from the disease some weeks or months later, which by this point is the only remaining alternative).

One long-sought goal has been the “off the shelf” CAR-T protocol, where the T cells don’t have to be painstakingly personalized, but can be prepared from the blood cells of other healthy donors, modified to take on the most widespread antigens as is. This has not been easy; let’s just leave it at that rather than review the landscape in detail. But several organizations are continuing to work on this. A team at Vanderbilt, for example, is running a trial that reported some interim results late last year: no dose-limiting tox or severe cytokine release so far, which is good, but it’s too early to get a read on efficacy. And a company called Allogene is running a trial to see if their CAR-T can delay relapse in treated lymphoma patients, which is an interesting idea that hasn’t really been put to the test. So there are a couple of layers of risk in there, which are well explained by Adam Feuerstein here at Stat. First results are supposed to appear next month.

Another idea is to produce the CAR-T cells right within the patient’s own body, rather than going through all that ex vivo work. For that, you’re talking gene therapy to introduce the chimeric antigen receptor into the patient’s T cells, and that’s a pretty bold move. A team in Wuhan has just reported some early data on a lentivirus vector they’re using for this purpose (technology that AstraZeneca bought from them last year), and another report also appeared recently.

It’s a mixed bag. In this latest paper, five patients with advanced multiple myeloma were studied and followed for months after a single i.v. infusion of the viral vector. There was no lymphodepletion done on the patients beforehand. No dose-limiting toxicity was seen, but all the patients experienced adverse events: four showed cytokine release syndrome, three of them developed infections, and there were also transient liver enzyme elevations. Unfortunately one of the five died outright from “immune effector cell-associated neurotoxicity”, which is of course Not Good. But the others all appear to have responded to the treatment, with three “stringent complete remissions”.

Monitoring the blood of these patients showed the uptake of the viral vector and production of the modified T-cells, as well as the gradual restoration of normal B cells along the way as the malignant ones (and presumably their precursors) were destroyed. The authors make the case that this is a distinct clinical course rather than just a faster version of the present CAR-T treatments, and it’s going to need a lot of close attention to understand all the differences. So this is promising and alarming at the same time: it looks like you really can treat refractory multiple myeloma in this fashion, but is there really going to be a 20% fatality rate as you try to do it? You have to hope - and AstraZeneca has to hope - that that’s not the case, but it’s the earliest of early days with this technique, and there’s a lot yet to learn.

Fentanyl's Membrane Behavior

Mar. 25th, 2026 01:25 pm
[syndicated profile] in_the_pipeline_feed

Here’s a look at one of the most famous opioid agonists in the world, fentanyl. You might think that by this point we would have a pretty thorough understanding of the drug’s behavior and the factors that lead to its (notorious) potency, but such GPCR ligands it seems that there’s always more to discover.

The authors here are working off recent results from patch-clamp receptor assays in whole cells that suggested that fentanyl (but not the classic opioid ligand morphine) can actually (re)activate the mu-opioid receptor after being washed out of the system. The hypothesis that this led to was that fentanyl  can partition into the cell membrane in a way that morphine can’t, and that this protects it from the washout step and acts as a local reservoir of drug that can continue to affect the membrane-bound opioid receptors. The new paper presents some detailed calculations about the membrane behavior of those two drugs along with a third agonist (isotonitazene) along with the antagonist naloxone.

You can see the structures of these four drugs and a simulation of the membrane region at right (the small red dots are water molecules; the larger orange balls are the phosphate end of the phospholipid bilayer). What they find, using advanced molecular dynamics calculations, is that there really do seem to be some large differences between fentanyl’s behavior and the others. Kinetically, it seems to penetrate the membrane much faster (100x or more compared the morphine). For one thing, morphine seems to be making more hydrogen-bond interactions with the phospholipid head groups, which slows down its progress. Other differences are how deep in the membrane the deprotonations of the amines in these molecules take place, and how many water molecules they are dragging along with them. (Remember, the general belief is that molecules need to be in neutral form for efficient transport through the membrane bilayer).

The simulations recapitulate the “membrane depot” idea for fentanyl (and do not show this effect for the other ligands). Fentanyl molecules permeate the cell membrane and can move rapidly in both directions (into the cytoplasm and back out onto the cell surface). It’s even possible that fentanyl might be hitting some lipid-facing binding spot in the mu-opioid receptor - that is, interacting directly from inside the membrane. 

The authors also did some real experimental work that verified the reactivation-after-washout results reported earlier, and they found that after such washouts that the cell membranes did continue to “leak” fentanyl molecules out into solution. There are still more details that need to be worked out, but so far the evidence is pointing in this direction.

Miscellanea: The War in Iran

Mar. 25th, 2026 04:04 am
[syndicated profile] acoup_feed

Posted by Bret Devereaux

This post is a set of my observations on the current war in Iran and my thoughts on the broader strategic implications. I am not, of course, an expert on the region nor do I have access to any special information, so I am going to treat that all with a high degree of uncertainty. But I am a scholar of military history with a fair bit of training and experience in thinking about strategic problems, ancient and modern; it is this ‘guy that analyzes strategy’ focus that I want to bring to this.

I am doing this post outside of the normal Friday order because it is an unusual topic and I want to keep making it clear that even as world events continue to happen – as they must – I do not want this blog to turn into a politics newsletter. I simply haven’t had the time to polish and condense these thoughts for other publication – the hard work of much writing is turning 3,500 words (or 7,500, as it turns out) of thoughts into 1,500 words of a think piece – but I need to get them out of my head and on to the page before it burns out of the back of my head. That said, this post is going to be unavoidably ‘political,’ because as a citizen of the United States, commenting on the war means making a statement about the President who unilaterally and illegally launched it without much public debate and without consulting Congress.

And this war is dumb as hell.

I am going to spend the next however many words working through what I think are the strategic implications of where we are, but that is my broad thesis: for the United States this war was an unwise gamble on extremely long odds; the gamble (that the regime would collapse swiftly) has already failed and as a result locked in essentially nothing but negative outcomes. Even with the regime were to collapse in the coming weeks or suddenly sue for peace, every likely outcome leaves the United States in a meaningfully worse strategic position than when it started.

Now, before we go forward, I want to clarify a few things. First, none of this is a defense of the Iranian regime, which is odious. That said, there are many odious regimes in the world and we do not go to war with all of them. Second, this is a post fundamentally about American strategy or the lack thereof and thus not a post about Israeli strategy. For what it is worth, my view is that Benjamin Netanyahu has is playing an extremely short game because it benefits him politically and personally to do so and there is a significant (but by no means certain) chance that Israel will come to regret the decision to encourage this war. I’ll touch on some of that, but it isn’t my focus. Likewise, this is not a post about the strategy of the Gulf states, who – as is often the sad fate of small states – find their fate largely in the hands of larger powers. Finally, we should keep in mind that this isn’t an academic exercise: many, many people will suffer because of these decisions, both as victims of the violence in the region but also as a consequent of the economic ripples.

But that’s enough introduction. What I want to discuss here is first the extremely unwise gamble that the administration took and then the trap that it now finds itself in, from which there is no comfortable escape.

Post-Publication Edit: Perhaps unsurprisingly, some of the discussions in the comments got quite heated, while I was off at a conference and not able to do as moderation as I normally might. It is fine to have strong views, but one ought to present and defend those views, not engage in empty personal attacks. I have removed significant chunks of the discussion which I viewed as unproductive. If the personal attacks resume, bans will follow.
Doubtless in the process I have removed some comments which could have stayed or missed some comments that should have been removed, but at the end of a three day conference and a five hour drive home, this was all the patience I had.

The Situation

We need to start by establishing some basic facts about Iran, as a country.

First, Iran is a large country. It has a population just over 90 million (somewhat more than Germany, about the same as Turkey), and a land area over more than 600,000 square miles (more than four times the size of Germany). Put another way Iran is more than twice as large as Texas, with roughly three times the population.

More relevantly for us, Iran is 3.5 times larger than Iraq and roughly twice the population. That’s a handy comparison because we know what it took to invade and then hold Iraq: coalition forces peaked at half a million deployed personnel during the invasion. Iran is bigger in every way and so would demand a larger army and thus an absolutely enormous investment of troops, money and fundamentally lives in order to subdue.

Via Wikipedia, a map of Iran. This is a very big country. It also has a lot of very challenging terrain: lots of very arid areas, lots of high mountains and plateaus. It is a hard country to invade and a harder country to occupy.

In practice, given that Iran did not and never has posed an existential threat to the United States (Iran aspires to be the kind of nuclear threat North Korea is and can only vaguely dream of being the kind of conventional threat that Russia is), that meant that a ground invasion of Iran was functionally impossible. While the United States had the raw resources to do it, the political will simply wasn’t there and was unlikely to ever be there.

Equally important, Iran was not a major strategic priority. This is something that in a lot of American policy discourse – especially but not exclusively on the right – gets lost because Iran is an ‘enemy’ (and to be clear, the Iranian regime is an enemy; they attack American interests and Americans regularly) and everyone likes to posture against the enemy. But the Middle East is a region composed primarily of poor, strategically unimportant countries. Please understand me: the people in these countries are not unimportant, but as a matter of national strategy, some places are more important than others. Chad is not an area of vital security interest to the United States, whereas Taiwan (which makes our semiconductors) is and we all know it.

Neither is the Middle East. The entire region has exactly two strategic concerns of note: the Suez Canal (and connected Red Sea shipping system) and the oil production in the Persian Gulf and the shipping system used to export it. So long as these two arteries remained open the region does not matter very much to the United States. None of the region’s powers are more than regional powers (and mostly unimpressive ones at that), none of them can project power out of the region and none of them are the sort of dynamic, growing economies likely to do so in the future. The rich oil monarchies are too small in terms of population and the populous countries too poor.

In short then, Iran is very big and not very important, which means it would both be very expensive to do anything truly permanent about the Iranian regime and at the same time it would be impossible to sell that expense to the American people as being required or justified or necessary. So successive American presidents responded accordingly: they tried to keep a ‘lid’ on Iran at the lowest possible cost. The eventual triumph of this approach was the flawed but useful JCPOA (the ‘Iran deal’) in which Iran in exchange for sanctions relief swore off the pursuit of nuclear weapons (with inspections to verify), nuclear proliferation representing the main serious threat Iran could pose. So long as Iran remained non-nuclear, it could be contained and the threat to American interests, while not zero, could be kept minimal.

That deal was not perfect, I must stress: it essentially gave Iran carte blanche to reinforce its network of proxies across the region, which was robustly bad for Israel and mildly bad for the United States, but since the alternative was – as we’ll see – global economic disruption and the prospect of a large-scale war which would always be far more expensive than the alternatives, it was perhaps the best deal that could have been had. For what it is worth, my own view is that the Obama administration ‘overpaid’ for the concessions of the Iran deal, but the payment having been made, they were worth keeping. Trump scrapped them in 2017 in exchange for exactly nothing, which put us on the course for this outcome (as more than a few people pointed out at the time).

But that was the situation: Iran was big and hostile, but relatively unimportant. The United States is much stronger than Iran, but relatively uninterested in the region apart from the uninterrupted flow of natural gas, oil and other products from the Gulf (note: the one thing this war compromised – the war with Iran has cut off the only thing in this region of strategic importance, compromised the only thing that mattered at the outset), whereas Iran was wholly interested in the region because it lives there. The whole thing was the kind of uncomfortable frontier arrangement powerful states have always had to make because they have many security concerns, whereas regional powers have fewer, more intense focuses.

Which leads us to

The Gamble

The current war is best understood as the product of a fairly extreme gamble, although it is unclear to me if the current administration understood they were throwing the dice in June of 2025 rather than this year. As we’re going to see, this was not a super-well-planned-out affair.

The gamble was this: that the Iranian regime was weak enough that a solid blow, delivered primarily from the air, picking off key leaders, could cause it to collapse. For the United States, the hope seems to have been that a transition could then be managed to leaders perhaps associated with the regime but who would be significantly more pliant, along the lines of the regime change operation performed in Venezuela that put Delcy Rodriguez in power. By contrast, Israel seems to have been content to simply collapse the Iranian regime and replace it with nothing. That outcome would be – as we’ll see – robustly bad for a huge range of regional and global actors, including the United States, and it is not at all clear to me that the current administration understood how deeply their interests and Israel’s diverged here.

In any case, this gamble was never very likely to pay off for reasons we have actually already discussed. The Islamic Republic of Iran is not a personalist regime where the death of a single leader or even a group of leaders is likely to cause collapse: it is an institutional regime where the core centers of power (like the Islamic Revolutionary Guards Corps or IRGC) are ‘bought in’ from the bottom to the top because the regime allows them access to disproportionate resources and power. Consequently if you blow up the leader, they will simply pick another one – in this case they picked the previous leader’s son, so the net effect of the regime change effort was to replace Supreme Leader Khamenei with Supreme Leader Khamenei…Jr.

But power in the Iranian regime isn’t wielded by the Supreme Leader alone either: the guardian council has power, the council of experts that select the Supreme Leader have power, the IRGC has power, the regular military has some power (but less than the IRGC), the elected government has some power (but less than the IRGC or the guardian council) and on and on. These sorts of governments can collapse, but not often. It certainly did not help that the United States had stood idle while the regime slaughtered tens of thousands of its opponents, before making the attempt, but I honestly do not think the attempt would have worked before.

The gamble here was that because the regime would simply collapse on cue, the United States could remove Iran’s regional threat without having to commit to a major military operation that might span weeks, disrupt global energy supplies, expand over the region, cost $200 billion dollars and potentially require ground operations. Because everyone knew that result was worse than the status quo and it would thus be really foolish to do that.

As you can tell, I think this was a bad gamble: it was very unlikely to succeed but instead always very likely to result in a significantly worse strategic situation for the United States, but only after it killed thousands of people unnecessarily. If you do a war where thousands of people die and billions of dollars are spent only to end up back where you started that is losing; if you end up worse than where you started, well, that is worse.

The problem is that once the gamble was made, once the dice were cast, the Trump administration would be effectively giving up control over much of what followed.

And if administration statements are to be believed, that decision was made, without knowing it, in June of last year. Administration officials, most notably Marco Rubio, have claimed that the decision was made to attempt this regime change gamble in part because they were aware that Israel was about to launch a series of decapitation strikes and they assessed – correctly, I suspect – that the ‘blowback’ would hit American assets (and energy production) in the region even if the United States did nothing. Essentially, Iran would assume that the United States was ‘in’ on the attack.

That is notable because Iran did not assume that immediately during the Twelve-Day War in 2025. Indeed, Iran did not treat the United States as a real co-belligerent even as American aircraft were actively intercepting Iranian missiles aimed at Israel. And then the United States executed a ‘bolt from the blue’ surprise attack on Iran’s nuclear facilities on June 22, 2025, catching Iran (which had been attempting to negotiate with the United States) by surprise.

The problem with that strike is that attacking in that way, at that time, meant that Iran would have to read any future attacks by Israel as likely also involving attacks by the United States. Remember, the fellow getting bombed does not get to carefully inspect the flag painted on the bomber: stuff blows up and to some degree the party being attacked has to rapidly guess who is attacking them. We’ve seen this play out repeatedly over the last several weeks where things explode in Iran and there is initially confusion over if the United States or Israel bombed them. But in the confusion of an initial air attack, Iran’s own retaliatory capability could not sit idle, waiting to be destroyed by overwhelming US airpower: it is a ‘wasting’ use-it-or-lose-it asset.

So Iran would now have to assume that an Israeli air attack was also likely an American air attack. It was hardly an insane assumption – evidently according to the Secretary of State, American intelligence made the exact same assessment.

But the result was that by bombing the Iranian nuclear facilities in June of 2025, the Trump administration created a situation where merely by launching a renewed air campaign on Iran, Israel could force the United States into a war with Iran at any time.

It should go without saying that creating the conditions where the sometimes unpredictable junior partner in a security relationship can unilaterally bring the senior partner into a major conflict is an enormous strategic error, precisely because it means you end up in a war when it is in the junior partner’s interests to do so even if it is not in the senior partner’s interests to do so.

Which is the case here. Because…

The Trap

Once started, a major regional war with Iran was always likely to be something of a ‘trap,’ – not in the sense of an ambush laid by Iran – but in the sense of a situation that, once entered, cannot be easily left or reversed.

The trap, of course, is the Strait of Hormuz and the broader Persian Gulf. The issue is that an enormous proportion of the world’s shipping, particularly energy (oil, liquid natural gas) and fertilizer components (urea) passes through this body of water. The Gulf is narrow along its whole length, extremely narrow in the Strait and bordered by Iran on its northern shore along its entire length. Iran can thus threaten the whole thing and can do so with cheap, easy to conceal, easy to manufacture systems.

And the scale here is significant. 25% of the world’s oil (refined and crude), 20% of its liquid natural gas and around 20% of the world’s fertilizer passes through the Strait of Hormuz which links the Persian Gulf to the Indian Ocean. Any of those figures would be enough for a major disruption to trigger huge economic ripples. And even worse there are only very limited, very insufficient alternative transport options. Some Saudi oil (about half) can move via pipeline to the Red Sea and some Emirati oil can move via pipeline to Fujairah outside of the Strait, but well over half of the oil and effectively all of the natural gas and fertilizer ingredients are trapped if ships cannot navigate the strait safely.

And here we come back to what Clausewitz calls the political object (drink!). Even something like a 50% reduction in shipping in the Gulf, were it to persist long term, would create strong global economic headwinds which would in turn arrive in the United States in the form of high energy prices and a general ‘supply shock’ that has, historically at least, not been politically survivable for the party in power.

And so that is the trap. While the United States can exchange tit-for-tat strikes with Iran without triggering an escalation spiral, once you try to collapse the regime, the members of the regime (who are making the decisions, not, alas, the Iranian people) have no reason to back down and indeed must try to reestablish deterrence. These are men who are almost certainly dead or poor-in-exile if the regime collapses. Moreover the entire raison d’être of this regime is resistance to Israel and the United States: passively accepting a massive decapitation attack and not responding would fatally undermine the regime’s legitimacy with its own supporters, leading right back to the ‘dead-or-poor-and-exiled’ problem.

Iran would have to respond and thus would have to try to find a way to inflict ‘pain’ on the United States to force the United States to back off. But whereas Israel is in reach of some Iranian weapons, the United States is not. Iran would thus need a ‘lever’ closer to home which could inflict costs on the United States. For – and I must stress this – for forty years everyone has known this was the strait. This is not a new discovery, we did this before in the 1980s. “If the regime is threatened, Iran will try to close the strait to exert pressure” is perhaps one of the most established strategic considerations in the region. We all knew this.

But the trap here is two sided: once the strait was effectively closed, the United States could not back off out of the war without suffering its own costs. Doing so, for one, would be an admission of defeat, politically damaging at home. Strategically, it would affirm Iran’s control over the strait, which would be a significantly worse outcome than not having done the war in the first place. And simply backing off might not fully return shipping flows: why should Iran care if the Gulf states can export their oil? An Iran that fully controls the strait, that had demonstrated it could exclude the United States might intentionally throttle everyone else’s oil – even just a bit – to get higher prices for its own or to exert leverage.

So once the strait was closed, the United States could not leave until it was reopened, or at least there was some prospect of doing so.

The result is a fairly classic escalation trap: once the conflict starts, it is extremely costly for either side to ever back down, which ensures that the conflict continues long past it being in the interests of either party. Every day this war goes on make both the United States and Iran weaker, poorer and less secure but it is very hard for either side to back down because there are huge costs connected to being the party that backs down. So both sides ‘escalate to de-escalate’ (this phrase is generally as foolish as it sounds), intensifying the conflict in an effort to hit hard enough to force the other guy to blink first. But since neither party can back down unilaterally and survive politically, there’s practically no amount of pain that can force them to do so.

Under these conditions, both sides might seek a purely military solution: remove the ability of your opponent to do harm in order to create the space to declare victory and deescalate. Such solutions are elusive. Iran simply has no real way of meaningfully diminishing American offensive power: they cannot strike the airfields, sink the carriers or reliably shoot down the planes (they have, as of this writing, managed to damage just one aircraft).

For the United States, a purely military solution is notionally possible: you could invade. But as noted, Iran is very, very big and has a large population, so a full-scale invasion would be an enormous undertaking, larger than any US military operation since the Second World War. Needless to say, the political will for this does not exist. But a ‘targeted’ ground operation against Iran’s ability to interdict the strait is also hard to concieve. Since Iran could launch underwater drones or one-way aerial attack drones from anywhere along the northern shore the United States would have to occupy many thousands of square miles to prevent this and of course then the ground troops doing that occupying would simply become the target for drones, mortars, artillery, IEDs and so on instead.

One can never know how well prepared an enemy is for something, but assuming the Iranians are even a little bit prepared for ground operations, any American force deployed on Iranian soil would end up eating Shahed and FPV drones – the sort we’ve seen in Ukraine – all day, every day.

Meanwhile escort operations in the strait itself are also deeply unpromising. For one, it would require many more ships, because the normal traffic through the strait is so large and because escorts would be required throughout the entire Gulf (unlike the Red Sea crisis, where the ‘zone’ of Houthi attacks was contained to only the southern part of the Red Sea). But the other problem is that Iran possesses modern anti-ship missiles (AShMs) in significant quantity and American escort ships (almost certainly Arleigh Burke-class destroyers) would be vulnerable escorting slow tankers in the constrained waters of the strait.

It isn’t even hard to imagine what the attack would look like: essentially a larger, more complex version of the attack that sunk the Moskva, to account for the Arleigh Burke’s better air defense. Iran would pick their moment (probably not the first transit) and try to distract the Burke, perhaps with a volley of cheap Shahed-type drones against a natural gas tanker, before attempting to ambush the Burke with a volley of AShMs, probably from the opposite direction. The aim would be to create just enough confusion that one AShM slipped through, which is all it might take to leave a $2.2bn destroyer with three hundred American service members on board disabled and vulnerable in the strait. Throw in speed-boats, underwater drones, naval mines, fishing boats pretending to be threats and so on to maximize confusion and the odds that one of perhaps half a dozen AShMs slips through.

And if I can reason this out, Iran – which has been planning for this exact thing for forty years certainly can. Which is why the navy is not eager to run escort.

But without escorts or an end to the conflict, shipping in the Gulf is not going to return to normal. Container ships are big and hard to sink but easy to damage. But while crude oil tankers are hard to set fire to, tankers carrying refined petroleum products are quite easy to set fire to, as we’ve seen, while tankers of liquid natural gas (LNG carriers) are essentially floating bombs.

The result is that right now it seems that the only ships moving through the strait are those Iran permits and they appear to have a checkpoint system, turning away ships they do not approve of. A military solution this problem is concievable, but extremely difficult to implement practically, requiring either a massive invasion of Iran’s coastline or an enormous sea escort operation. It seems more likely in both cases that the stoppage will continue until Iran decides it should stop. The good news on that front is that Iran benefits from the export of oil from the Gulf too, but the bad news is that while they are permitting some traffic, precisely because high energy prices are their only lever to make the United States and Israel stop killing them, they are unlikely to approve the transit of the kinds of numbers of ships which would allow energy markets to stabilize.

Just as a measure here, as I write this apparently over the last three days or so Iran has let some twenty ships through their checkpoint, charging fees apparently to do so. That may sound like a lot, but it is a quantity that, compared to the normal operation of the strait, is indistinguishable from zero. The Strait of Hormuz normally sees around 120 transits per day (including both directions). That scale should both explain why five or six ships a day paying Iran to transit is not going to really impact this equation – that’s still something like a 95% reduction in traffic (and all of the Iran-approved transits are outbound, I think) – but also why a solution like ‘just do escorts’ is so hard. Whatever navies attempted an escort solution would need to escort a hundred ships a day, with every ship being vulnerable at every moment from when it entered the Strait to when it docked for loading or offloading to its entire departure route. All along the entire Gulf coastline. All the time.

Likewise, even extremely punishing bombings of Iranian land-based facilities are unlikely to wholly remove their ability to throw enough threat into the Strait that traffic remains massively reduced. Sure some ship owners will pay Iran and others will take the risk, but if traffic remains down 90% or just 50% that is still a massive, global energy disruption. And we’ve seen with the campaign against the Houthis just how hard it is with airstrikes to compromise these capabilities: the United States spent more than a year hammering the Houthis and was never able to fully remove their attack capabilities. Cargo ships are too vulnerable and the weapons with which to attack them too cheap and too easy to hide.

There is a very real risk that this conflict will end with Iran as the de facto master of the Strait of Hormuz and the Persian Gulf, having demonstrated that no one can stop them from determining by force which ships pass and which ships cannot. That would, in fact, be a significant strategic victory for Iran and an enormous strategic defeat for the United States.

Peace Negotiations?

Which brings us to the question of strategic outcomes. As the above has made clear, I think the Trump administration erred spectacularly in starting this war. It appears as though, in part pressured by Israel, but mostly based on their own decisions (motivated, it sure seems, by the ease of the Venezuela regime-change) they decided to go ahead on the hopeful assumption the regime would collapse and as a result did not plan for the most likely outcome (large war, strait closure), despite this being the scenario that political leadership (Trump, Hegseth, Rubio) were warned was most likely.

The administration now appears to be trying to extricate itself from the problem has created, but as I write this, is currently still stuck in the ‘trap’ above. Now this is a fast moving topic, so by the time you actually read this the war well could have ended in a ceasefire (permanent or temporary) or intensified and expanded. Who knows! As I am writing the Trump administration claims that they are very near a negotiated ceasefire, while the Iranian regime claims they have rejected both of the United States’ interlocutors as unsuitable (‘backstabbing’ negotiators), while reporting suggests Israel may feel it in their interests to blow up any deal if the terms are too favorable to Iran.

That is a lot of uncertainty! But I think we can look at some outcomes here both in terms of what was militarily achieved, what the consequences of a ‘deal’ might be and what the consequences of not having a deal might be.

The Trump administration has offered a bewildering range of proposed objectives for this war, but I think it is fair to say the major strategic objectives have not been achieved. Initially, the stated objective was regime change or at least regime collapse; neither has occurred. The regime very much still survives and if the war ends soon it seems very plausible that the regime – able to say that it fought the United States and made the American president sue for peace – will emerge stronger, domestically (albeit with a lot of damage to fix and many political problems that are currently ‘on pause’ coming ‘un-paused’). The other core American strategic interest here is Iran’s nuclear program, the core of which is Iran’s supply of roughly 500kg of highly enriched uranium; no effort appears to have been made to recover or destroy this material and it remains in Iranian hands. Actually destroying (dispersing, really) or seizing this material by military force would be an extremely difficult operation with a very high risk of failure, since the HEU is underground buried in facilities (mostly Isfahan) in the center of the country. Any sort of special forces operation would thus run the risk of being surrounded and outnumbered very fast, even with ample air support, while trying to extract half a ton of uranium stored in gas form in heavy storage cylinders.

When the United States did this in Kazakhstan, removing about 600kg (so roughly the same amount) it required the team to spend 12 hours a day every day for a month to remove it, using multiple heavy cargo planes. And that facility was neither defended, nor buried under rubble.

Subsequently, administration aims seem to have retreated mostly to ‘fixing the mess we made:’ getting Iran to stop shooting and getting the Strait of Hormuz reopened and the ships moving again. They do seem to be asking for quite a bit more at the peace table, but the record of countries winning big concessions at the peace table which they not only haven’t secured militarily but do not appear able to do so is pretty slim.

Now it is possible that Iran blinks and takes a deal sooner rather than later. But I don’t think it is likely. And the simple reason is that Iran probably feels like it needs to reestablish deterrence. This is the second sudden bombing campaign the country has suffered in as many years – they do not want there to be a third next year and a fourth the year after that. But promises not to bomb them don’t mean a whole lot: establishing deterrence here means inflicting quite a lot of pain. In practice, if Iran wants future presidents not to repeat this war, the precedent they want to set is “attacking Iran is a presidency-ending mistake.” And to do that, well, they need to end a presidency or at least make clear they could have done.

Iran is thus going to very much want a deal that says ‘America blinked’ on the tin, which probably means at least some remaining nuclear program, a de facto Iranian veto on traffic in the strait and significant sanctions relief, along with formal paper promises of no more air strikes. That’s going to be a hard negotiating position to bridge, especially because Iran can ‘tough it out’ through quite a lot of bombing.

And I do want to stress that. There is a frequent mistake, often from folks who deal in economics, to assume that countries will give up on wars when the economics turn bad. But countries are often very willing to throw good money after bad even on distant wars of choice. For wars close to home that are viewed as existential? Well, the ‘turnip winter‘ where Germans started eating food previous thought fit only for animals (a result of the British blockade) began in 1916. The war did not end in 1916. It did not end in 1917. It did not end until November, 1918. Food deprivation and starvation in Germany was real and significant and painful for years before the country considered surrender. Just because the war is painful for Iran does not mean the regime will cave quickly: so long as they believe the survival of the regime is at stake, they will fight on.

There is a great deal of ruin in a nation.

Strategic Implications

So my conclusion here is that the United States has not yet achieved very much in this war on a strategic level. Oh, tactically, the United States has blown up an awful lot of stuff and done so with very minimal casualties of its own. But countries do not go to war simply to have a warwell, stupid fascist countries do, which is part of why they tend to be quite bad at warthey go to war to achieve specific goals and end-states.

None of the major goals here – regime change, an end to Iran’s nuclear ambitions – have been achieved. If the war ends tomorrow in a ‘white peace,’ Iran will reconstitute its military and proxies and continue its nuclear program. It is in fact possible to display astounding military skill and yet, due to strategic incoherence, not accomplish anything.

So the true, strategic gains here for all of the tactical effectiveness displayed, are functionally nil. Well what did it cost?

Well, first and foremost, to date the lives of 13 American soldiers (290 more WIA), 24 Israelis (thousands more injured), at least a thousand civilian deaths across ‘neutral’ countries (Lebanon mostly, but deaths in Kuwait, Iraq, Qatar, Bahrain, Saudi Arabia, etc) and probably at least a thousand if not more Iranian civilians (plus Iranian military losses). The cost of operations for the United States is reportedly one to two billion dollars a day, which adds up pretty quickly to a decent chunk of change.

All of the military resources spent in this war are in turn not available for other, more important theaters, most obviously the Asia-Pacific (INDOPACOM), but of course equally a lot of these munitions could have been doing work in Ukraine as well. As wars tend to do, this one continues to suck in assets as it rumbles on, so the American commitment is growing, not shrinking. And on top of spent things like munitions and fuel, the strain on ships, air frames and service personnel is also a substantial cost: it turns out keeping a carrier almost constantly running from one self-inflicted crisis to the next for ten months is a bad idea.

You could argue these costs would be worthwhile it they resulted in the destruction of Iran’s nuclear program – again, the key element here is the HEU, which has not been destroyed – or of the Iranian regime. But neither of those things have been achieved on the battlefield, so this is a long ledger of costs set against…no gains. Again, it is not a ‘gain’ in war simply to bloody your enemy: you are supposed to achieve something in doing so.

The next side of this are the economic consequences. Oil and natural gas have risen in price dramatically, but if you are just watching the commodity ticker on the Wall Street Journal, you may be missing some things. When folks talk about oil prices, they generally do so via either $/bbl (West Texas Intermediate – WTI – one-month front-month futures) or BRN00 (Brent Crude Oil Continuous Contracts). These are futures contracts, meaning the price being set is not for a barrel of oil right now but for a barrel of oil in the future; we can elide the sticky differences between these two price sets and just note that generally the figure you see is for delivery in more-or-less one month’s time. Those prices have risen dramatically (close to doubled), but may not reflect the full economic impact here: as the ‘air bubble’ created by the sudden stop of oil shipments expands, physical here-right-now prices for oil are much higher in many parts of the world and still rising.

Essentially, the futures markets are still hedging on the idea that this war might end and normal trade might resume pretty soon, a position encouraged by the current administration, which claims it has been negotiating with Iran (Iran denied the claim). The tricky thing here is that this is a war between two governments – the Trump administration and the Iranian regime – which both have a clear record of lying a lot. The Trump administration has, for instance, repeatedly claimed a peace deal between Ukraine and Russia was imminent, and that war remains ongoing. The markets are thus forced to try and guess everyone’s actions and intentions from statements that are unreliable. Cards on the table, I think the markets are underestimating the likelihood that this conflict continues for some time. Notably, the United States is moving assets into theater – an MEU, elements of the 82 Airborne – which will take some time to arrive (two weeks for the MEU which is still about a week out as I write this) and set up for operations.

In either case, while I am not an expert on oil extraction or shipping, what I have seen folks who are experts on those things say is that the return of normal operations after this war will be very slow, often on the order of ‘every extra week of conflict adds a month to recovery’ (which was Sal Mercogliano’s rule of thumb in a recent video). If the war ends instantly, right now, ship owners will first have to determine that the strait is safe, then ships will have to arrive and begin loading to create space in storage to start up refineries to create space in storage to start up oil wells that have been ‘shut in,’ some of which may require quite a bit of doing to restart. Those ships in turn have to spend weeks sailing to the places that need these products, where some of the oil and LNG is likely to be used to refill stockpiles rather than immediately going out to consumers. For many products, refineries and production at the point of sale – fertilizer plants, for instance – will also need to be restarted. Factory restarts can be pretty involved tasks.

This recovery period doesn’t just get pushed out by 24 hours each day it gets longer as more production is forced to shut down or is damaged in the fighting. As I write this, futures markets for the WTI seem to be expecting oil prices to remain elevated (above $70 or so) well into 2028.

Meanwhile, disruption of fertilizer production, which relies heavily on natural gas products, has the potential to raise food prices globally. Higher global food prices – and food prices have already been elevated by the impact of the War in Ukraine – are pretty strongly associated with political instability in less developed countries. After all, a 25% increase in the price of food in a rich country is annoying – you have to eat more cheaper foods (buy more ramen, etc.). But in a poor country it means people go hungry because they cannot afford food and hungry, desperate people do hungry, desperate things. A spike in food prices was one of the core causes of the 2010 Arab Spring which led in turn to the Syrian Civil War, the refugee crisis of which significantly altered the political landscape of Europe.

Via Wikipedia, a chart of the food price index, with the spikes on either side of 2010 clearly visible; they are thought to have contributed to the intense political instability of those years (alongside the financial crisis).

I am not saying this will happen – the equally big spike in food prices from the Ukraine War has not touched off a wave of revolutions – but that it increases the likelihood of chaotic, dynamic, unsettled political events.

But it does seem very clear that this war has created a set of global economic headwinds which will have negative repercussions for many countries, including the United States. The war has not, as of yet, made Americans any safer – but it has made them poorer.

Then there are the political implications. I think most folks understand that this war was a misfire for the United States, but I suspect it may end up being a terrible misfire for Israel as well. Israeli security and economic prosperity both depend to a significant degree on the US-Israeli security partnership and this war seems to be one more step in a process that very evidently imperils that partnership. Suspicion of Israel – which, let us be honest, often descends into rank, bigoted antisemitism, but it is also possible to critique Israel, a country with policies, without being antisemitic – is now openly discussed in both parties. More concerning is polling suggesting that not only is Israel underwater with the American public, but more Americans sympathize with Palestinians than Israelis for the first time in American history.

Again, predictions are hard, especially about the future, but it certainly seems like there is an open door to a future where this war is the final nail in the coffin of the American-Israeli security partnership, as it becomes impossible to sustain in the wake of curdling American public opinion. That would be a strategic catastrophe for Israel if it happened. On the security side, with Israel has an independent nuclear deterrent and some impressive domestic military-industrial production the country is not capable of designing and manufacturing the full range of high-end hardware that it relies on to remain militarily competitive despite its size. There’s a reason Israel flies F-35s. But a future president might well cut off spare parts and maintainers for those F-35s, refuse to sell new ones, refuse to sell armaments for them, and otherwise make it very difficult for Israel to acquire superior weapons compared to its regional rivals.

Economic coercion is equally dangerous: Israel is a small, substantially trade dependent country and its largest trading partner is the United States, followed by the European Union. But this trade dependency is not symmetrical: the USA and EU are hugely important players in Israel’s economy but Israel is a trivial player in the US and EU economies. Absent American diplomatic support then, the threat of economic sanctions is quite dire: Israel is meaningfully exposed and the sanctions would be very low cost for the ‘Status Quo Coalition’ (assuming the United States remains a member) to inflict under a future president.

A war in which Israel cripples Iran in 2026 but finds itself wholly diplomatically isolated in 2029 is a truly pyrrhic victory. As Thucydides might put it, an outcome like that would be an “example for the world to meditate upon.” That outcome is by no means guaranteed, but every day the war grinds on and becomes less popular in the United States, it becomes more likely.

But the United States is likewise going to bear diplomatic costs here. Right now the Gulf States have to shelter against Iranian attack but when the dust settles they – and many other countries – will remember that the United States unilaterally initiated by surprise a war of choice which set off severe global economic headwinds and uncertainty. Coming hot on the heels of the continuing drama around tariffs, the takeaway in many places may well be ‘Uncle Sam wants you to be poor,’ which is quite a damaging thing for diplomacy. And as President Trump was finding out when he called for help in the Strait of Hormuz and got told ‘no’ by all of our traditional allies, it is in fact no fun at all to be diplomatically isolated, no matter how powerful you are.

Of course the war, while quickly becoming an expensive, self-inflicted wound for the United States has also been disastrous for Iran. I said this at the top but I’ll say it again: the Iranian regime is odious. You will note also I have not called this war ‘unprovoked’ – the Iranian regime has been provoking the United States and Israel via its proxies almost non-stop for decades. That said, it is the Iranian people who will suffer the most from this war and they had no choice in the matter. They tried to reject this regime earlier this year and many were killed for it. But I think it is fair to say this war has been a tragedy for the Iranian people and a catastrophe for the Iranian regime.

And you may then ask, here at the end: if I am saying that Iran is being hammered, that they are suffering huge costs, how can I also be suggesting that the United States is on some level losing?

And the answer is simple: it is not possible for two sides to both win a war. But it is absolutely possible for both sides to lose; mutual ruin is an option. Every actor involved in this war – the United States, Iran, arguably Israel, the Gulf states, the rest of the energy-using world – is on net poorer, more vulnerable, more resource-precarious as a result.

In short, please understand this entire 7,000+ word post as one primal scream issued into the avoid at the careless, unnecessary folly of the decision to launch an ill-considered war without considering the obvious, nearly inevitable negative outcomes which would occur unless the initial strikes somehow managed to pull the inside straight-flush. They did not and now we are all living trapped in the consequences.

Maybe the war will be over tomorrow. The consequences will last a lot longer.

Laila's big office visit

Mar. 24th, 2026 01:51 pm
dorchadas: (Azumanga Daioh Chiyo-chan bus gas)
[personal profile] dorchadas
Laila had a doctor's appointment downtown today, so after their appointment they came to the office to see everyone. The last time she was here, she was still a toddler and we were trying to get her to walk. Now, she's in her shy phase and we were trying to get her to actually say something.

First, the good news--the doctor says that Laila is healing well and she's now cleared to do flips (but still no spins), and if she keeps healing like this she'll be fully healed sometime in May. Just need to keep on her to make sure she doesn't climb on too many things, because if she hits her head too hard she'll end up with a skull fracture.

Anyway, [instagram.com profile] sashagee brought Laila to the building and, in contrast to how things were during the Plague Years, they just waved me in and took me at my word--though in fairness, I had given a nengajо̄ to the receptionist so they knew my family by appearance already. We went up and showed Laila around, one of my co-workers gave her an apple and another one gave her a little clapper toy. Laila's in her shy phase so she quietly said "hi" and "thank you" and waved at people. Unfortunately some of her biggest cheerleaders weren't in the office, but she'll be back in the summer for another visit!

After we the visit was done Laila was very hungry, so we went down to the lobby again. There had been a miscommunication between [instagram.com profile] sashagee and I about when we were going out to lunch--she thought I meant today when I meant tomorrow--but I suggested going to the work canteen. Originally I thought I would have to go up there and bring their orders down, but I asked the security guard if I could bring them up and she just waved dismissively and said, "Sure," which is pretty convenient but definitely makes me feel a little less safe! We went up to the dining hall and I picked up my lunch I had already ordered, paneer from a place called The Clove, and [instagram.com profile] sashagee ordered a pastrami sandwich and we sat down and ate. Laila ate all the toppings and none of the bread from her half of the sandwich, but she was happy when the man working the register gave her a free rice krispy treat that they had left over at the end of the day. My paneer was fine, not great, but fine, and I threw it in the "okay" category of the restaurant lists.

After that, I walked [instagram.com profile] sashagee and Laila to the L and they went home!

Oh, almost forgot to mention--there was a "Tea Lab popup" at work today, which meant that I got to go into a room and make a few teabags that I can take home. I just made ones with green tea and added spearmint, rosehips, lavender, and dandelion in various proportions. I'm going to take them home and have them in the morning with my fish, rice, and pickles for breakfast.
[syndicated profile] in_the_pipeline_feed

Time to think like a biochemist! And that means paying close attention to energy transactions in a cell, because the science of thermodynamics makes it very, very clear there there is always a bill that has to be paid. Most of the time, the currency involved is of course ATP, since breaking that down to ADP gives you an immediate payout. ATP hydrolysis and the other sources of chemical energy (like acetyl-CoA) function as “battery packs” for all sorts of enzymatic processes. If you find an enzyme without one (like acetylcholinesterase), it means that it’s catalyzing a reaction that’s already thermodynamically favorable but just needs a rate increase - indeed, acetylcholine itself is synthesized by use of the energy in the acetyl CoA thioester bond, so breaking it back down is a favorable downhill process.

This new paper has found a new source of such stored energy, and it’s a neat one. There’s an evolutionarily conserved protein motif called the “death fold” that’s found in the proteins that effect deliberate cell death (apoptosis), and in several other processes like innate immunity cascades, inflammation signaling through nF-kappaB, and more. These are known to work by self-assembly - the different death-fold domains each interact only with others of their own type and rapidly make large multi-subunit structures made up just of those proteins. 

That’s all fine, but now look at it from a thermodynamic perspective. With respect to the death-fold proteins involved in immunity and inflammation, this assembly does not appear to be driven by any of those chemical battery sources that we know about - in fact, it doesn’t need one, because it seems to be thermodynamically favorable to start with. But if that’s the case, what’s the barrier to it happening spontaneously? How can you have large local concentrations of death-fold proteins without them suddenly rolling downhill into self-assembly? There have been some rather detailed arguments about the energetics of the whole system, but this new work seems like it’s answered the question.

And that answer is supersaturation. This is a phenomenon that you can demonstrate with one of those warming pads that you activate by clicking some sort of metal disk sitting inside them. It just sits around as a bag of goo until you do that, and then it gradually gets thicker as it gives off a pretty respectable amount of heat. These things are filled with a solution of sodium acetate, a very innocuous compound indeed with an interesting property.

In general, when you dissolve some substance you will often hit a limit beyond which no more can be dissolved. Think of dumping salt into a glass of water - as you stir it, you will dissolve the salt crystals, but eventually you’ll reach a point where no more of it goes in and you’ll be stirring a layer of salt on the bottom of the glass that will simply not go into solution for you. That is a saturated solution, but it’s important to note that the saturation amount is dependent on temperature: if you heat that glass up, you will be able to dissolve more salt, but if you then let it cool down the “carrying capacity” of the solution drops back down in turn and some of that salt is going to crystallize back out until you get to that saturation point at room temperature again.

This is of course how chemists do recrystallizations - making a “supersaturated” solution and letting it drop crystals back out again (preferably slowly and aesthetically!) But there are some odd cases, and sodium acetate is definitely one. You can get pure sodium acetate (anhydrous, no water present), but you can also get a crystalline form that has three water molecules in the crystal per molecule of sodium acetate (the trihydrate form). If you take some of that trihydrate and heat it up, that orderly arrangement breaks up and the water molecules are liberated, whereupon they dissolve the sodium acetate molecules. If you let that solution cool, you’d expect to get those trihydrate crystals forming again in the exact reverse process, but you don’t. The solution gets “stuck” in a higher-energy state because it’s difficult to recreate the trihydrate crystal form from that direction. You end up with a solution that’s (very) supersaturated with respect to sodium acetate trihydrate - the whole thing would turn solid again if it could just find a way to get there.

At the bench, chemists often try tricks like scratching the inside of a glass flask under the liquid surface to provide a bit of a kick and form some tiny crystals in such a solution, and that’s what clicking that metal disk does in the heat packs. You form a small number of microscopic sodium acetate trihydrate crystals that way, and that sets things off - now everything starts templating off of those and the whole solution starts coming apart again, with a release of that stored energy, which is given off as heat. (If you toss such a used heat back into boiling water, you can take it right back around again to the supersaturated solution).

This, it turns out, seems to be exactly what the death-fold-domain proteins are doing, but only the ones in the innate immunity pathways. The others need cellular energy to assemble, but this particular set can exist as supersaturated solutions under cellular conditions, piled up and ready to go if the right stimulus starts the cascade. The authors refer to this as a “phase-change battery”, and I think that’s exactly right - it’s a stored higher-energy state and it lets the proteins and their signaling network respond quickly without the need for an influx of energy from the rest of the cell. Note the differences, though, between this and the liquid-liquid phase separation found in intracellular condensate droplets. Those are reversible (unless of course something goes wrong, and there are some disease states that seem to be connected to such failures), but the immunity DFD protein assemblies are one-way. That’s in a general sense, too: for many innate immunity pathways, the instructions to the cell are “Kill yourself now before this infectious agent takes hold”.

The authors find evidence of evolutionary optimization of this behavior, leading to low saturation concentrations along with barriers to nucleation between individual proteins that give them the chance to pile up into supersaturated states. Their expression levels line up with this interpretation as well, and needless to say, it is very unusual to see proteins that are being expressed at greater than their saturation levels in the cell (!) But very interestingly, the paper shows that the amount of such supersaturation in different cell types seems to be quite well correlated with the lifespan of the cells. The inference is that relying on this mechanism, while useful (and deeply conserved in evolution), also comes with an unavoidable risk of sudden death if something manages to start the self-assembly and release the DFD proteins from their supersaturated state. So these factors have balanced out to a small and optimized group of them, and the cells expressing significant amounts of them are not allowed to hang around forever. The authors sum it up very well:

Our findings imply that cells perpetually await death. The theoretical cumulative certainty of stochastic nucleation over time appears to be reflected in the observed relationship of DFD supersaturation to mortality rates across human cell types. We speculate that this underpins a fundamental tradeoff between innate immunity and life expectancy, potentially contributing to age-related inflammation and stem cell exhaustion.

[syndicated profile] littletinythings_feed

New comic!

Great news for those who have been waiting to purchase Go Get a Roomie books!

The new online store is up and running, so on your marks... go get a book!-----> clovercomics.bigcartel.com/


˙˚ଘo(∗  ❛ั ᵕ ❛ั )੭່˙

[syndicated profile] in_the_pipeline_feed

Here’s a paper evaluating a popular AI/ML model for cofolding ligands and proteins, Boltz-2. This is of course a problem of extreme interest to the drug discovery community, as well as to all sorts of people working on cell biology, structural biology, and related fields. It’s been one of the goals for decades to start from scratch with a protein sequence and a small molecule and be able to say “Does this molecule bind to this protein? How well?”

And no, we really haven’t been able to do that, not in the way that we’d like (and certainly not on the scale that we’d like). The error bars on those binding predictions have generally been too wide, and that’s both on the underlying structure of the protein and on the energetic implications of how how it interacts with a given small-molecule ligand. And the computational burdens of even getting that far have generally been too great, given the number of conformations you’re likely to need to examine (and the way that you’ll need to evaluate which of those are most plausible relative to the others).

Protein structure from scratch was of course a notoriously hard problem for decades as well, but machine learning off the databases of known protein structures (AlphaFold, RosETTAFold and the like) have made terrific progress by identifying the often-reused structural motifs and their effects on overall tertiary protein structure as they’re combined. But protein-with-ligand, that one is still the Holy Grail. If we could get that to work well, and get the speed up and the computational overhead down, then we’d perhaps be able to finally achieve primary-screen nirvana in silico. No need to make and purify protein, no need to have a basement full of hundreds of thousands of small-molecule candidates in vials and plates. No robot arms, no fluorescent plate readers. Just fire up the computational hardware and software and go get some lunch instead.

Boltz-2 is one of the open-source alternatives to software like AlphaFold 3, all of which are trying to address this problem. And it is claimed to produce protein structures at AlphaFold levels of accuracy while simultaneously predicting binding affinity energies at a level similar to the most computationally intensive methods (like free energy perturbation) but hundreds of times faster. So as you can imagine, it and the other programs in this space have gotten a lot of attention.

As the paper linked above notes, so far it looks like this software is at its best when working with rather locked-down protein structures and known binding structures - that is, when working on Easy Mode. Unfortunately, we don’t spend much time on Easy Mode in the wonder drug factories. We have a lot of other things to worry about: proteins that don’t have much (or any) good experimental structural data, binding sites that depend crucially on the effects of water molecules, small-molecule cofactors, or on the binding of another ligand at a completely different allosteric pocket. And some of the binding events we’re looking at turn out (once we get real-world data) to involve significant shifts in the original protein structure and/or rather odd twists in the conformation of ligand molecules, neither of which are easy to compute your way to. (You end up paying a lot of energetic penalties if you try to advance step-by-step, and the system may well throw in the towel before the big unexpected energetic payoff at the end).

In this paper the authors use a set of 943 virtual-screen hits from some very large previous screening efforts (hundreds of millions of candidates), binding to ten different target proteins, and with the associated real-world in vitro binding data already in hand. Those comprise 364 true positives and 579 false positives, as discovered when those assays were run. The paper notes that so far no affinity-prediction systems have been able to really tell those true positives from false positives in this data set, so this is an adversarial challenge for sure, and just the thing to let a hot new piece of software get its virtual teeth into. Most of the targets, as it happens, are G-protein coupled receptors, althought the binding site diversity is still very high.

Boltz-2 ran through the 943 candidates at about two minutes per, and it got all of them into the right binding pocket (as it darn well should - all of these targets have ligand-bound structures in the PDB already). And its predictions for “Is this compound likely to be a good binder?” are notably better than any other method tested (with the exception of two targets on which it failed pretty thoroughly). So it really distinguished itself on finding the true positives. This did not seem to be due to similarities between these compounds and the Boltz-2 training set (which is something you always need to be wary of).

That said, its actual predictions of affinity were quite poor as compared to the experimentally determined values. And when the actual structures of the ligands in the binding pockets was examined, the Boltz-2 predictions were pretty far off of what is believed to be the actual situation. Even odder, the accuracy of distinguishing true positives did not seem to be affected by the quality of the docking poses, which is rather counterintuitive.

At this point the authors were mindful of a report that came out last year about AlphaFold 3 docking predictions. That work noted that AF3 poses and predictions seemed curiously insensitive to amino acid mutations in the binding site(s) that should severely affect such results. These clearly nonphysical results suggest a great deal of overfitting to the training data, or to particular trends in it, and caused those authors to warn people about relying too much on such deep-learning models. So the authors in this latest paper tried the same trick: introducing amino acid changes that would absolutely blow up important polar interactions between the ligands and their binding sites. We’re talking aspartic acid to alanine, that sort of thing, or dropping a proline into the hinge region of a kinase. These are grenades.

Unfortunately, Boltz-2 emerged from that challenge with predictions that were for the most part not statistically different from the ones generated from the wild-type structures. What’s more, the poses of the compounds in these messed-up binding sites seemed to have little in common with what it had generated earlier - i.e., it didn’t hang on to the other interactions it had found while just making the best of it with the abrogated ones. Further alanine-scan mutations (up to six per binding site!) made it clear the Boltz-2 just didn’t care much about such petty details.

Even reshuffling the target proteins completely and assigning random ones to the ligands (where they would be expected to have no binding whatsoever) only got rid of about half the true-positive recommendations. For the others, predictions of affinity seemed to be almost independent of what target they chose. This is not what you want. In fact, it’s the opposite of what you want. The authors “therefore advise remaining very skeptical with respect to affinity predictions” from the program (and others like it, you’d have to say) and I completely agree.

It is very tempting to look at the outputs of such software and to tell yourself that it must have a deep understanding of the physics and energetics of protein folding and compound binding. But that is an illusion. Large computational models do not understand anything, any more than LLM chatbots know what they are “saying”. We have built these systems to provide blurry copies of what were actually useful and pleasing outputs that we generated by our own efforts, and sometimes the results, the extruded simulated products, are worthwhile enough and sometimes they are not. In the case of overfitted models, which these seem to be, we are at great risk of just talking to ourselves and playing our own voices back to no good effect.

Understanding is still our human domain. And we need to understand not only the physics of small-molecule interactions, but the workings of our own tools.

vital functions

Mar. 22nd, 2026 10:39 pm
kaberett: Trans symbol with Swiss Army knife tools at other positions around the central circle. (Default)
[personal profile] kaberett

Reading. Finished my first pass through LIFTOFF by Casey Johnston! Will continue to use it as a reference work (tomorrow starts my third and final week of Phase 1 -- bodyweight practice of compound movements -- before I move on to doing things with Actual Weights...). I should probably note for the record that I have edited it as I've gone through to fix a fair few typos.

More She's A Beast archives (just reached February 2023!).

Tiiiiiny bit of a start on my Wicked Problems (Max Gladstone) reread, in a general spirit of wanting to have any idea at all of what's going on in Dead Hand Rule.

Writing. The document! is over! 9000!!! despite the fact that I've deleted a bunch of bits of variation-on-a-theme as I home in on what it is I actually want to say! I have gone "that will do" about my first draft of the introduction (it definitely needs ... more ... tweaking, but I think all the pieces are now there) and have moved on to the introduction to part the first, working title "What is pain?" I'm very close to having that Good Enough For Now, I think, whereupon... a chapter?!

Watching. 2026 Migraine World Summit. So much Migraine World Summit. BUT I managed to catch everything this year, and now I am working on condensing and transcribing my digital notes into my notebook. More to follow, possibly.

Listening. I caught up to where A had got to with Hidden Almanac (which I had theoretically heard all of but in practice was asleep for... some... of)! We had a long drive! We are now most of the way through 2014, I have learned about Pastor Drom's side hustle, and there is a crow named George.

Playing. Bit more Inkulinati? Tiny bit more Inkulinati.

Eating. Mooooore allotment lamb's lettuce. AND a bunch of TREETS from the local FANCY BAKERY, incl. double chocolate brownie (not quite dark and chocolatey enough for my tastes; too dark for A); bread pudding; and a rhubarb and ginger teacake.

This week I am also experimenting with lentil cakes (like rice cakes, but lentil) and Dr Karg's Pumpkin Seed Protein Thins. I find the former perplexing, in that they taste kind of like crispy seaweed snacks while also being completely the wrong shape and texture, and am much more into the latter (even eaten dry!) than I expected. A considers them alarming cardboard; I think I think they are enough like Ryvita, of which I am fond, to be of at least some interest? Might... get more of these. (Could in theory reverse engineer them but that sounds like a lot of effort.)

Exploring. Had another couple of Extremely Satisfactory errand-bimbles discovering People's Front Gardens.

Making & mending. I have FROGGED the experimental continental knitted portion of A's second glove (tension was bad; have decided I want these gloves Done more than I want to do enough continental knitting to get the tension right) and resumed; I have done A Little More Cuff.

Growing. Aubergines finally! belatedly! sown! Oca into the ground. Broad beans finally coming up. More garlic transplanted.

Observing. THE COOTS! HAVE! EGGS!

I declare victory

Mar. 20th, 2026 05:40 pm
dorchadas: (Teh sex)
[personal profile] dorchadas
After a couple dozen more hours, I've beaten all the original post-game content for Clair Obscur:

2026-03-19 - Gommaged Simon

This is the E33 ultimate superboss. I spent a while grinding while listening to podcasts and then fought him a few times. I could have fought him a lot more, learned the exact timing on his attacks, including all the double and triple attacks he does in later phases...but no. I abused a bunch of pictos to get extra actions, did damage stacking, stunned him at 40% health and then slammed him with a level 3 gradient attack to skip Phase 3 (that's the 16 million damage highest attack I did). That finished off my last achievement, making E33 the seventh game I've gotten all the achievements on.

Just need to do the new DLC area they added a couple months ago and then I can move on to something else.

happy equinox, etc

Mar. 21st, 2026 10:12 pm
kaberett: Trans symbol with Swiss Army knife tools at other positions around the central circle. (Default)
[personal profile] kaberett

Today was A Travel Day; yesterday, in preparation for same, I Ran Errands, including "acquiring Tiny Cake" and "visiting the pharmacy".

On the way from those two jobs to the next couple, I passed Several Good Things.

One was a new-to-me flavour of completely ridiculous daffodil:

a double daffodil, with white petals and inner trumpet, protruding past a much shorter orange outer trumpet

It's a double not in the sense of having a confusing froth of intermingled trumpets (as of Double Fashion or Double Camparnelle, both of which exist locally), but in the sense of having two nested trumpets, one shorter and orange, from which the longer white one protrudes. I have never! previously! seen a thing like this! I am really enjoying my current streak of encountering varieties of daffodil that make me go "what the fuck???"

Shortly thereafter I checked over my shoulder while crossing a tiny bridge and was startled and delighted to see A COOT UPON THE NEST that, last I passed it, was clearly still derelict. Obviously I went back and Gazed Upon It for Some Time and was eventually rewarded by it STANDING UP to reveal SEVEN??? (possibly) EGGS!!!

And the Egyptian goslings were peeping about the place when I subsequently passed them on my way back up the hill. A+ errands would run again.

Gap Week: March 20, 2026

Mar. 20th, 2026 09:37 pm
[syndicated profile] acoup_feed

Posted by Bret Devereaux

Hey folks! I was traveling this week to give an invited talk at Western Michigan University, so I don’t have a blog post ready for you. That’ll also probably be the case for next week (where I will be at the annual meeting of the Society for Military History), though at least there I will have an abstract to let you see.

Now I am always reticent to post up the text of talks that are intended to be delivered live, because the genres are different, they rely on different kinds of delivery and they often aren’t footnoted and such for written publication. But in this case, I can do something a bit different, because the main parts of my talk for Western Michigan University were based around things that I’ve written (and in one case, something someone else has written) which you can read. So this is a chance to plumb the archives, in a sense and in so doing, basically ‘read along’ a version of the talk I gave which is rather ‘meatier’ than what I could have said in the 45-or-so minutes I had to speak.

The core of my talk was the concept of ‘historical verisimilitude‘ that I’ve riffed on here: the use of the appearance of historical accuracy, or a claim to historical accuracy in the absence of the real thing to market or promote something, be that something a film or show or game or what I have begun terming a ‘history influencer’ who makes history-themed social media content.

My initial example of this at work was the disconnect in Assassin’s Creed:Valhalla between the emphasis on visual accuracy and the catastrophic fumbling of other forms of historical accuracy, which you can read about in my “Assassin’s Creed: Valhalla and the Unfortunate Implications.” I then expanded on this example with a broader one from 2000’s film Gladiator and its initial battle scene, arguing that once again what was prioritized was visual accuracy because that gave the viewers the – incorrect! – assumption that ‘the research had been done’ on the rest, which you can read about in our series on “Nitpicking Gladiator‘s Iconic Opening Battle.”

I then jumped to example of this as a rhetorical strategy deployed by marketing, grounded in a critique of how George R. R. Martin (and the marketing team for Game of Thrones) has framed historical accuracy, using the Dothraki as an example of how this can go badly wrong and perpetuate quite nasty stereotypes about real peoples through the supposedly ‘realistic’ (in fact, deeply flawed) depiction of a fantasy stand-in for those people. You can read about that in our series on the Dothraki, “That Dothraki Horde.”

From there I transition into talking about this strategy used by the aforementioned ‘history influencers,’ with a contrast between how differences in platforms between YouTube and Twitter produced very different environments: where YouTube’s long-form video nature pushed a lot of content creators towards more carefully researched historical content which was often actually quite valuable (I particularly focused, and again this was very brief, on arms-and-armor and historical dress channels), Twitter’s emphasis on ultra-short micro-blogging produced a very different environment.

For the part focused on Twitter, I leaned quite heavily on T. Trezevant’s “The Antiquity to Alt-Right Pipeline” published in Working Classicists in 2024, which I think is one of the most revealing investigations of this particular space and the incentives that the post-Musk Twitter algorithm, which appears to openly and quite strongly prefer frankly bigoted or xenophobic content, created. From my own observations, while some of the accounts that push this particular, generally badly historically misinformed, version of the ancient past emerged in the pre-Musk period of Twitter, Classics Twitter largely held its own until the algorithm was slanted against them, making it all but impossible for a lot of good Classics accounts to compete for eyeballs.

And then I closed with a plea for greater engagement by historians in these online spaces, albeit with a caution that picking your platform is important. The fact that historical verisimilitude, the pretense of historical accuracy or knowledge, is so frequently used as a marketing tool speaks to the public’s desire for an accurate knowledge of the past. Folks want to know what the past was really like, but of course regular folks often do not have the tools to tell what is reliable, rigorous and careful history vs. what is not. So as historians, we need to be more present in these kinds of spaces (though we ought to pick our platforms; there is little point ‘competing’ on Twitter if the deck is stacked against you) to help folks find the accurate historical knowledge they are seeking.

And that, in an abbreviated form (or an enlarged form if you read all of the links as you went!) was the talk! Very grateful for WMU for inviting me out to give it. Until next week!

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