I remember in 2015 when I first saw that go-kart wasm demo. It was exciting. But that was such a long time ago and we are only now starting to see webgpu roll out. I’m really looking forward to the new golden age of wasm and webgpu.
Recently it was shown that the chemical ISRIB can “undo” traumatic brain injury. It turns out that when you get a concussion, the mechanical stress results in a metabolic self defense mechanism being triggered. Everyone thought the neurons were dying but they were just themselves latent. ISRIB interferes with this defense mechanism, turning the neurons back on.
And it turns out that this metabolic defense mechanism is triggered in many scenarios, not just concussion.
I became involved in a group of people who were interested in taking ISRIB. We engaged in an effort to synthesize it, and along the way we dredged the internet for any information we could find about other people who had taken ISRIB — the molecule has been known about for a long time. There are a handful of plausible stories, and it appeared that ISRIB would have no effect in one person and be life changing for another, both seemingly healthy. The common pattern was increased intelligence, an insatiable appetite for new and novel information and a marked reduction in the amount of sleep needed to function.
We eventually came into contact with a group of Russians. They had already synthesized it and taken it. They reported the same effects from the accounts we had found. They also reported, surprisingly, the development of a tolerance among those who took it repeatedly. One person had an episode of very realistic hallucinations, dreams that seemed real. Another person gave it to his grandmother who was sick with dementia. She became lucid again but died a day or two later. We speculated that one of the reasons cells turn themselves off is because they are too dysfunctional to operate — so turning them back on brings the benefit of having that signal again in the case of neurons but also revives any dangerous behavior that was being suppressed. We acquired ISRIB from the Russians and the first person to get it didn’t notice an effect although he didn’t take much. At this point I fell out of contact because I was having a medical emergency from experimenting with a totally unrelated compound. It nearly killed me, I spent weeks in the asylum and still have lingering effects. After that my shulgin itch became satisfied permanently.
One interesting thing about cognitive diseases that are metabolically rooted like schizophrenia, dementia, etc is that there are simple ways to coax the cells into metabolizing carbohydrates correctly again, as this article demonstrates. There is also another kind of chemical completely that can be used for energy, beta hydroxy butyrate, totally bypassing the problem. The field of metabolic restoration is the next big thing for sure.
> Another person gave it to his grandmother who was sick with dementia. She became lucid again but died a day or two later.
Lucidity before death has been reported before for patients suffering from dementia and other neurological illnesses, so this might have been coincidence. The term is "Terminal Lucidity" if you want to search for it.
It always helps to expand abbreviations when talking about things that only a few readers will already know about. Typing it out is O(1), having N people look it up is O(N) if you allow me to abuse the notation like that ;)
>Typing it out is O(1), having N people look it up is O(N) if you allow me to abuse the notation like that ;)
Thank you; this is a perfect way to put it. I always include links, and ideally inline text, when posting because I always try to think from the perspective of a lazy and/or context-switch-averse reader reading the comment. (Easy to do, since that's my actual perspective 99.9% of the time.) One of my highest-upvoted HN comments was just pasting the contents of a tweet someone else posted to save people a click. (https://news.ycombinator.com/item?id=25260896)
ISRIB works just as well as "integrated stress response inhibitor." There are multiple stress response inhibitors in the body, so it's not like the name tells you anything. Both are just arbitrary names.
I am currently learning a lot about the cellular Integrated Stress Response for my research. It is fascinating. There is one curious problem I particularly love. Even though a lot of neuronal communication can be through transient calcium signaling, the ISR is also signaled through calcium. Because they use the same signal, it makes sense that something like overactive neurons could eventually lead to stress. And yet somehow the two signals are differentiated.
It really shows how everything in biology is basically a gaussian curve and you always want to be near the center, but if you steer too far towards either end things start to break down.
She became lucid again but died a day or two later. We speculated that one of the reasons cells turn themselves off is because they are too dysfunctional to operate — so turning them back on brings the benefit of having that signal again in the case of neurons but also revives any dangerous behavior that was being suppressed.
That's a pretty big leap to make given that you don't even know if there is, in fact, some kind of causal relationship between giving her ISRIB, her sudden lucidity and subsequent death. According to what you have said, it was a one off event and you are positing a hypothesis of how the body works based on a one off event where you don't even know if x led to y led to z and your hypothesis is based on the assumption those things were, in fact, causally related.
> because I was having a medical emergency from experimenting with a totally unrelated compound. It nearly killed me, I spent weeks in the asylum and still have lingering effects.
You should name this in case others might be, present or future, using the same substance.
It is an inhibitor of whats called the Integrated Stress Response. A “normal” cell is one that uses glucose to create energy and create additional fuel for mitochondria to make LOTS of fuel (caveat- not every cell, this varies a lot, but often enough). This fuel is used to power everything and keep it working well.
Under stress, a lot of that normal machinery is shut down, which means a neuron may not communicate anymore, as all these normal things need lots of energy.
I am not as sure on this point, but I think stress generally means a cell takes in less glucose; it shuts down mitochondria, and overall produces less energy.
Excessive blood sugar, then insulin spikes, and over time type 2 diabetes. It used to take a life time to acquire type 2 diabetes and historically it was called adult onset diabetes.
The first case of type 2 diabetes in a child was only diagnosed in the 1983...now it’s common in children. Generally about 1/3 of the US is prediabetic, this population will generally also suffer from other chronic (metabolic) conditions like inflammation and obesity.
If ISRIB works as well as research seems to suggest then we all need to keep an eye on it to make sure big pharma doesn't suppress it so then their own patentable products can exist in the market.
I’ve been playing morrowind on openmw since 2013. It’s such a fantastic project. It’s a stable and clean way to experience morrowind, but half the enjoyment is in the community surrounding it. The video updates have been a cherished ritual for me for many years now. And the website has a very thoughtful atmosphere with the strider lurking overhead. It’s honestly been an important part of my life. And this of course was all preceded by my original fascination with morrowind, which is certainly one of the finest video games ever made despite its user-hostile qualities. The soundtrack has never been equaled. The game was made in a time when video games weren’t a billion dollar industry and where the nature of the game reflected the nature of the people who made it — and morrowind was made by a band of intellectuals, idealists and pioneers. It simply does not happen that way anymore in mainstream games.
A massive number of people believe that the configuration of the stars or other celestial bodies will influence the outcome of their lives. They also believe that humans have achieved mastery of this celestial language. Millions of people believe very strongly that a divine force keeps track of the bad and good things that each person does, and will make each balance the other through happenstance. People really believe that. And the most shocking thing is that there are people who know about this and dont appreciate the fact that the world is an ocean of insanity that dashes all good things against the rocks. I know this for a fact because there was considerable surprise at the sudden popularity of “flat earthers.” Anyone who has any sense would not be surprised because this is tame stuff compared to religion, karma, horoscopes and all the other nonsense that preoccupies a terrifying number of people. Flat earth has echos of logic or at least the superficial appearance of sanity. I almost welcome it. But anyway I have been saying for many years that the dogma that has infected the liberal camp is very similar to the dogma that made Christianity so infamous. They are very similar: kernels of truth that deflect criticism of moral dogma that fuels a race to the bottom which ultimately results in hilarious contortions of the human condition and mental gymnastics that resist enlightenment no matter how blinding. The mistake is that people associate dogma with religion. The only true association is with stupid people. Soon wokeness and it’s dogma will be uncool and abandoned just like religion but the dogma will not die with wokeness.
And what scenario do you imagine when you imagine confronting dogma? You probably imagine painstaking effort being put into conveying reason to the afflicted. It’s always the same pensive expression on the face of that person. And that effort is always met by bulging veins up the neck and forehead. For all of history it has been pensive wincing at bulging veins and slamming fists. And the epiphany that I have had is that it is completely a fools errand to engage in that exchange. No matter how perfectly you do it, they won’t understand.
I contracted psychiatric illnesses after an acute stress event. There is a case report of a mans schizophrenia disappearing after having his bone marrow killed during cancer treatment.
The human brain does not process all things equally. It does not take the chain of integrations, leading from input of data to output of some opinion or intuition, as far as it might unless it sees fit, regardless of what you want. I had thought about this right-to-die issue many times. But in the first few seconds of being in the position of needing to die, an new understanding washed over me, new angles and insights, and a decade of contemplation was overturned. When the need to die is not emotional but totally objective, one assesses his options rationally and weighs the different methods against each other in a pragmatic way. As I looked at each path I might take, new details filled in that I had never thought of before. Each method of suicide is different, has a different risk of going wrong, a different outcome in the case of going wrong. And each is different for the burden left to those who have to clean up. But what difference does any of it make if you are ultimately going to die? When you enter into this situation you are playing a game where becoming a lifelong vegetable is a possibility — this is a nightmare scenario. When its you, it becomes real to you and you understand that vegetables can be lucid, have the capacity for immense suffering and are kept alive against their will possibly for decades. Many people read that and arrogantly say “well if I just shoot myself in the head then that’s not a problem.” But did that person know that shooting yourself in the temple might only destroy the part of the brain responsible for executive function, rendering you a vegetable? The proper way is to shoot yourself with the barrel against the back of the mouth so that the brain stem is destroyed and there is no possibility of living. That is the terrifying realization that comes to you when it’s your turn: this is like anything else, it’s a practical undertaking where there are details and things to go wrong and the only way to ensure a good result is to do it many times or be in the hands of an expert, neither of which are on the table. It’s a lot of stress.
The ultimate goal is to avoid suffering, and that includes being comfortable during a successful attempt, not just avoiding the I-have-no-mouth of being a vegetable. When it’s your turn, you all of a sudden realize that the brain remains active during and after the process of dying. And sure enough you will find the inconvenient fact buried: nobody is really dead until they are thoroughly dead. The idea of binary life/death only proliferated because for most of history science wasn’t around to illuminate the issue. You realize that people who are clinically dead are the most powerless, voiceless group of people in history and that their needs have been completely hidden or ignored even in the age of modern medicine, and that this weird and unfortunate situation has intersected with your story now and has completely fucked you over. You are tasked with cobbling together some kind of system that not only intelligently avoids the vegetable outcome, not only confronts the subtleties of what it really means to die and avoiding whatever strange things happen in the space between, but also performs flawlessly with an extremely low probability of failure. Because when it’s your skin that’s what you’ll want.
And of course this is the perfect situation for some kind of solution to have been developed. We often benefit from things that were developed over hundreds of years of trial and error. To realize you are at the bottom rung of that process is unpleasant. And you won’t until it becomes real to you.
The number of people who have a rational need for death, beyond and kind of doubt, is small at any given moment. It’s a minority group. Easy to sweep under the rug especially when the average person is not imaginative or able to think empathetically or creatively. Not able to understand until it’s them. I guess I’m guilty of that!
I was suffering from super bad bipolar episodes and a general mental health crisis recently when I came across a documentary about Cromwell. It was so inspiring to see someone struggle with the same problems and overcome them, accomplish such great things, and do it all before it was even recognized as a legitimate illness. I really came back from the brink thanks to that coincidence.
