Just an FYI. For any individual thinking of investing, one diligence question would be: "are any biotech/therapeutics-focused venture capital funds investing in this round?"
I agree with not investing in early-stage biotech startups unless you are a professional early-stage biotech startup investor or know your stuff to an implausible degree.
Wouldn't the risk of knowing your stuff to an implausible degree be that your decision making is likely better than that of the FDA or local equivalent, making your predictions risky due to the potential behaviours of less-informed agents?
Of course you could be expert in the mechanisms of drug regulators, but the safe bet then is surely to hire your skills out rather than gamble on startups...
If you're going to go round investing in early-stage biotech startups then the ins and outs of the FDA is probably about 50% of the "stuff" you need to know.
I used to invest in (publically traded but pre-revenue) biotech companies, I made a small profit in the end but spent way too much time stressing over trial results and FDA committee meetings etc. In terms of dollars per grey hair it was the worst way of making money that I had.
For me personally, over the past ten years, the best ways of making money have been (a) investing in just about anything you can think of that isn't a biotech company, and (b) going to work and doing my job.
With a few exceptions, seed rounds almost never work out in biotech because the later investors, especially VCs have so much leverage that seed investors almost always get diluted down to nothing. This is because the capital requirements are so great (hundreds of millions) and unlike in tech, the demand for capital is greater than the supply (though this seems to be turning)
Scott: This is important. DO NOT Post solicitations for investments. I do not know enough of your exact situation or of the nature of the solicitation to give competent legal advice to you.
But. It is generally illegal to sell securities unles you are a registered securities dealer. California's laws (and I am not a California lawyer) are very strict and they are enforced aggressively. Federal law is similar.
If I were you, I would take this information down.
I am retired. When I was in practice I was not "Big Law". I am not trying to get anybody to spend money on legal fees.
I do know a bit about securities law, a bit that grows more and more obsolete day by day. I used to teach CLE classes on the subject. But, that was in a previous millennium.
Scott is not a financial industry professional. Even professionals make mistakes. Goldman Sachs recently paid a ~3G$ fine to the SEC. And, their General Counsel just did the 21st century corporate equivalent of being a virgin who jumps into the volcano. No connection they say. And you believe them, don't you.
Scott is an uncompensated volunteer. He has no upside, but any involvement in fundraising for investment opportunities carries a downside risk. Scott no ability to control risk by contract, insurance, monitoring, or due diligence.
I am a volunteer too. I hope my advice is worth every penny you have paid for it. If you don't think I am right, you can just ignore me.
My theory is
No Control + No Monitoring + No Insurance + No Due Diligence = Big Risk. Big Risk + No Reward = Don't Do it.
Perhaps. The Federal Securities Act of 1933 defines: "the term “offer to sell”, “offer for sale”, or “offer” shall include every attempt or offer to dispose of, or solicitation of an offer to buy, a security or interest in a security, for value." The law and administrative lore are very extensive. If you had an upside in doing this, it might be worth thinking about, but if you had an upside, that would be a fact indicating legal involvement.
As you are an uncompensated volunteer, the safest thing to do is to stay far away.
Back in a previous millennium when I had hair and no belly, I worked in a law firm that was located hard by Wall Street in lower Manhattan. On a clement day, if we weren't too busy, my colleagues and I would occasionally walk over to the river, and we would lunch at Sloppy Louie's immediately adjacent to the Fulton Street Fish Market.
It was a very plain sort of place. The tables were picnic benches and the menu was fried or broiled fish, nothing fancy. We were sure that it was, like the Fish Market, run by the Mob. There was a sign over the cashier's seat imparting ageless Sicilian wisdom:
"Even a fish can't get in trouble if it keeps its mouth shut."
As I posted above, general solicitation of certain private placement offerings is legal, as of 2013, under Rule 506(c) of Regulation D, subject to various limitations, in particular that the issuer must take "reasonable steps" to verify accredited investor status.
Consider that the modal person "posting an email someone sent me saying 'our company is cool, email us if you want to invest'" who comes to the legal system's attention is less "Scott Alexander" than "author of the 'Penny Stock One Weird Trick Report.'"
I have no opinion on this, but just know that I definitely will never be able to read one of your comments without hearing it in Walter's voice and with his reasonable-then-screamy delivery. I appreciate it.
General solicitation for private placement offerings is allowed under Rule 506(c), since the 2012 JOBS Act. (However, I don't know whether there are restrictions on _who_ is allowed to perform those solicitations. And I don't know whether the company is intending to reply on 506(c), which requires them to take reasonable steps to verify the accredited investor status of their investors, or 506(b), which is more convenient because it does not require them to do that (but does not permit general solicitation.))
Thanks, Glenn. One of the nice things about being retired is that I no longer have to learn all of this dugash. I looked at the SEC pages on the JOBS act:
I think you could structure things to avoid a problem, but since Scott (and anyone else in his position) has no ability to audit the structure or monitor compliance, my advice (which is easily worth every penny you are paying for it) is still to stay away.
Your advice is certainly not unreasonable. I have kind of a pet peeve about "vetocracy by overcaution", where a valuable thing ends up prohibited-in-practice if _anybody_ near the thing believes it might be prohibited, or feels like it ought to be prohibited.
(This pet peeve brought to you mostly by software licensing, which is the absolute worst mixture of "overcautious lawyers" and "cranky software engineers who mistakenly believe themselves to be lawyers". Of course, I'm arguably in the latter category myself, so I have to be careful how much I shit-talk it.)
I think the email is supposed to be jonah@equatortherapeutics.com (you wrote puetics). Normally I wouldn’t be so pedantic but I could see somebody clicking that link and failing to send an email!
It's always an option, just vanishingly unlikely in most cases (unless you know some very sadistic people I guess...). The question with risk is not how bad is the less risky option but how horrific are the other options...
Weren't most of the "spontaneous combustion" cases people who fell asleep with a cigarette in hand, and basically turned into a human candle wick, and died of carbon monoxide poisoning before they burned up? Not sure if mitochondria would affect the frequency of that.
The Texas case sounds like a large enough sample size that you could get an idea of long-term side effects from DNP usage via a survey.
Also, doesn't most modern anti-aging thought revolve around slowing the metabolism (e.g. fasting), not speeding it up? It sounds like this stuff would make you die faster, even if you didn't have any major side effects from it.
Normally the proton gradient is used to produce ATP. With uncoupling it just makes heat and is arguably not really metabolism as it doesn’t produce anything.
Free radical production from mitochondria is partly dependent on the proton gradient. So by uncoupling you can dissipate the gradient and reduce free radical production which may be beneficial if the cell is under oxidative stress. Of course there are lots of critiques against the free radical theory of aging.
That doesn't quite make sense to me. DNP is actually making the cell pump *extra* protons over the gradient, because it still needs the same minimum number of calories to operate. The DNP is just creating a parasitic side-reaction where some of the energy consumed is wasted as heat rather than used to pump protons, creating a net caloric deficit.
If there's a certain number of free radicals generated per proton-pumping operation, I can't see how this effect would result in less free radicals generated. If anything, it might be more.
"DNP appears to mimic in part the neuroprotective and neurorestorative effects of exercise and fasting by increasing BDNF, lowering cellular stress and building cellular resiliency by mild increases in mitochondrial bioenergetics."
Basically, through slightly stressing mitochondria, you increase mitochondrial health, similar to exercise, cold exposure, and other stress related activities that have beneficial health effects.
After the proton gets pumped over the membrane the electron has to go through a series of complicated stages to get back to it, which each stage making its own ATP letting aerobic respiration be so much more efficient than anaerobic respiration. However, the high energy chemistry in a mitochondria is potentially dangerous, sometimes things break, and if one part of the chain breaks down you have lots of electrons backing up and becoming Problematic. Letting the protons bypass the normal process more easily mitigates that danger even though it causes more of the normal operation of the mitochondria.
But the same number of successful proton pumping operations are still happening, right? There's just a bunch of extra unsuccessful ones as well. It's possible that my inorganic chemistry background is letting me down here.
Right. The proton pumping setting up the potential happens just like before. It's the electron dancing down the potential ladder making ATP that fall back on to the soft proton when they trip, to strain a metaphor.
I think I get it - the theory here is that the extra protons create metastable states that trap rogue electrons without producing free radicals, right? That makes a certain amount of sense.
Thank you very much for taking the time to explain it to me.
Don't think electrons of the type you appear to be thinking are involved in making ATP. The electrons that come out of the citric acid cycle are passed along a chain of membrane-bound proteins until they reduce O2 to H2O. The reaction to create ATP from ADP is not a redox reaction and happens somewhere else.
As I understand it is the existence and magnitude of the proton gradient that increases free radical production. Thus by reducing the magnitude of the proton gradient you would get less free radical production. Cells can increase their uncoupling in response to oxidative stress. All else equal this decreases ATP production but still above minimum, well except for the lens cells for some unfortunate individuals. I also imagine that uncouplers should reduce your capacity for physical labor.
Isn't it the creating of the proton gradient by the electron transport chains that risks, well, leaking electrons? Does ATP synthesis itself even involve redox?
The electron transport chain where high energy electron goes from donor to acceptor ending up with the one of the best oxidisers (electron acceptor), oxygen creates the proton gradient. This the oxidative step. Then protons flowing back via ATP-synthase then puts a phosporyl group on ADP, making ATP. That is the phosphorylation step. Together they are oxidative phosphorylation.
I'm not a mitochondria expert but yes the electron leakage should be in the electron transport chain. But the bigger the proton gradient the more the electron chain leaks. You can read more in the introduction part of this paper: https://www.sciencedirect.com/science/article/pii/S000527281830135X#bb0060
No, the phosphorylation of ADP to create ATP is not a redox reaction. It's a thioesterification or condensation reaction. No atoms change oxidation state. I think the confusion arises because the phosphorylation is *coupled* to a redox reaction, which is the reduction of O2 to H2O. That's why it's called "oxidative phosphorylation." The reduction of O2 provides the energy for the otherwise energetically uphill phosphorylation reaction. But in mitochondria these reactions occur in different places. The reduction of O2 happens along the electron transport chain, while the phosphorylation of ADP happens in a nearby membrane-bound enzyme.
Tried getting it off Ali baba once but it was just orange died sawdust. Also my family decided I was on meth because I was involved with a seemingly mysterious substance tied to weight loss that might explode and they didn't understand my explanations...
Correction to "They pump protons across a membrane, creating pressure for electrons to travel the opposite direction." Actually they create pressure (potential) for electrons to travel in the *same* direction. When positive charge goes one way, negative charge also "wants" to go that way, following its potential energy gradient. Making electrons travel in the opposite direction would cost even more energy, defeating the purpose.
>They pump protons across a membrane, creating pressure for electrons to follow. This forms an electrical gradient...
I argue for removing "creating pressure for electrons to follow" entirely, because that misleadingly suggests that this pressure is somehow necessary or relevant for the potential difference. In reality, the proton concentration differential is enough.
Yes, that is a strange statement. In the first place, it's not true. The *electrostatic* field of H+ is very well shielded in water, that's why solvated H+ (i.e. pH < 7) is stable. So while there is a voltage across the membrane, it's not nearly enough to rip electrons loose from wherever they're bound and hustle them across the membrane. The gradient of H+ is purely in the chemical potential, as far as I know, and the same (entropic) driving force would exist even if the species in question were neutral. The only reason cells do it with charged species (H+ in the mitochondrion, Na+/K+ in neurons et cetera) is that the charge makes it difficult for these small atoms to cross back over the membrane anywhere and destroy the gradient, which they would otherwise do, because they are very polar and the membrane is nonpolar -- their solubility in the lipid bilayer is very low. Perhaps something else was meant, and I'm not understanding it.
This isn't how it works at all. The electron transport chain doesn't involve free electron movement or net electron movement across the membrane.
Electrons get transported from food (fat/carbohydrate) to oxygen via a series of reducible cofactors (the electron transport chain).
The proteins that catalyse these reactions use that energy to pump protons out of the lumen. The protons can (mostly) only come back through the FOF1 ATPase, which makes ATP when it happens.
Also, dinitrophenol doesn't "punch holes" in the membrane; it's not a pore (things that actually punch holes in membranes cause massive necrosis - I'm familiar with two examples, one of which is part of the immune system and one of which is snake venom). The trick with dinitrophenol is that it's acidic (at just the right level to be partially ionised at biological pH) and that it's lipophilic enough to pass through membranes *even while ionised* (the aromatic ring and the delocalisation of the charge over 6 atoms help with that). So, since the pH on the two sides of the membrane is different, it tends to lose its proton inside the lumen, pass out, pick it up outside and come back in.
It feels very weird to make drugs that make bodies less efficient. Like, if you don't need so many calories, there's a pretty easy solution!
But obviously it's not so easy in practice as human bodies are vastly complicated biochemical laboratories operating under sometimes faulty instructions.
I didn't feel like using a preexisting handle here, but couldn't come up with anything good on the spot, so I just typed the home row in order.
I've been using dvorak for 3-4 years now. I didn't have a very good reason for switching, mostly it just sounded amusing to see if I could reprogram my typing muscle memory. I've previously written a bit about it here: https://www.schlaugh.com/~/cdvhauo
Nice! I've never looked at Colemak before now. Definitely makes the right call regarding the positions of AZXCV for the keyboard shortcuts.
I'm a dvorak vim user who doesn't remap the movement keys HJKL, and it's not too bad. Colemak doesn't seem to do so well on this metric: JK (up/down) switched around and all 4 of them in the left pointer finger's domain.
Still, I would probably choose Colemak over Dvorak if I were to go do it over again.
Almost all drugs except for some newer ones are making some part of your body less efficient, though not this directly. It’s a lot easier to turn harmful machinery off than to insert useful new machinery.
That may well be, but it's hard to argue that mitochondria are harmful machinery. This is like punching a hole in your gas tank because you have a crush on the gas station attendant.
It's not about turning the whole energy-making process off, just safe ways to make it slightly less efficient since it's tuned to solve the obsolete problem of scarce calories
I've read that among a certain segment of the naturally thin population they naturally release excess calories as heat rather than storing them as fat.
I have always been on the thinner side, although I can gain weight, and I also "run hot". My appendages are frequently warmer than other people's. That could be because I have a higher core temperature or a higher peripheral temperature alone. I also have higher blood pressure so maybe there's just more convection of heat away from my core. Either way I'm shedding more heat than normal, and am more tolerant of cold temperatures and less tolerant of warm temperatures.
hm, this is interesting. i'm also on the thinner side and have been struggling to gain weight, but I definitely feel colder to the touch than average (which i always attributed to the lack of body fat to keep me warm, also im AFAB). that said, i am also more tolerant of cold temperatures than warm ones, so maybe (anecdotally ofc) there's some correlation there.
I'm thin and cold too, but I do fidget a lot - I have a tendency to twitch my leg rhythmically and such. This might contribute to excess calorie expenditure. It does seem to stop when I'm hungry, though I'm not going to claim that there's an actual energy management relationship there.
Every thin person is probably such due to a confluence of factors. I mostly attribute my thinness to the small portion sizes my mother fed me as a child.
Hey Jack, I would also fit this description - tall, hot, restless, need to jump in the river even in winter - and my wife (African, hates the cold, sleeps under 2 duvets) is worried about my blood pressure so we've been monitoring it over the past couple of weeks - it's definitely high and fluctuates wildly throughout the day, so I'm getting it checked out properly at the GP tomorrow. I like the idea of investing in big mitochondria though 🤣
> Some more evidence: people with anorexia fidget like crazy. This is the conventional wisdom among generations of psychiatrists, and has been confirmed in studies – see for example *Measurement Of Fidgeting In Patients With Anorexia Nervosa Using A Novel Shoe-Based Monitor*, which found anorexics fidget almost twice as much as healthy controls. This seems really damning to me. Consciously deciding to fidget is hard. If you don’t believe me, try to fidget as much as possible for the next two hours (the length of the study linked above) and see how well it goes. Most people just can’t do it. On the other hand, fidgeting (renamed to the more dignified “non-exercise activity thermogenesis”) is the classic strategy that the lipostat uses to maintain unconscious control over weight...
> A purely social paradigm of anorexia can’t explain the fidgeting; a biological paradigm outright predicts it.
Wow! Do you mean psychological paradigm? It's not that your conscious mind holds the mistaken belief that your fat when you're not. Or that you're attempting to control one part of your life when you can't control others. On a fundamental biological level your body thinks it's fat when it's not.
I would expect the social paradigm to explain the fidgeting as nervous movement, the logic being that it's a stressful condition or stressed people tend to develop anorexia. I don't find the idea convincing without further explanation.
Anecdotally: my friend who has low body-fat and was a sports players in his youth and early twenties used to run very hot all the time. Hot to the touch. When I was fit, more fit than usual, I also felt very warm.
On the other hand, people who are thin naturally have less insulation. This might just be one of those reverse causality situations - thin people are less insulated and so lose more heat.
Worth noting: tall people apparently have higher BMI than short people, which may well be because of the square-cube law.
First, I am disappointed that there is no "conscious uncoupling" joke in here. A missed opportunity! Second, pretty sure that instead of "all is not lost" (implying that nothing whatsoever is lost) you mean "not all is lost" (implying not everything is lost). Sincerely yours in logical pedantry,
Modern dictionaries aim to describe language as it is commonly used, not to prescribe how it should be. I think it's wrong to say they "allow" it - they observe that it gets used that way.
You'd think that, but that's because the English have an inferior practical philosophy of language. In contrast, the motto and job of the Royal Academy of Spanish (which writes the Spanish dictionary) is "to clean, make certain, and give splendor". This is why we Spaniards can have nice things, like not having spelling bees because the correspondence between the written and the spoken word is pretty much* unambiguous.
"All is not lost" is perfectly technically-correct if you just interpret it slightly differently - as "it is not the case that all is lost" ("is all lost?" "it is not"), rather than as "it is the case that all things are not-lost" ("what is not lost?" "all is")!
“All is not lost” I would formalize (well, quasi formalize; this is a comment section!) as (x) ~(Lx). “Not all is lost” as ~(x)(Lx). Those aren’t equivalent. Would you do it differently?
You can interpret "all is not lost" in one of two ways, or at least two that are clear to me at a glance. One is the way you're interpreting it; the other is the way that's equivalent to your formulation of "not all is lost". Personally, I find the latter interpretation more intuitive.
To interpret "all is not lost" as "it is not the case that all is lost", logically equivalent to "not everything is lost" or "out of all things, some are not lost", I would take it as an answer to the implicit question "is all lost?", which I think is what most people tend to mean when they use the phrase. "All is not lost" under this interpretation describes a world where we were worried that all might be lost, but then found out that this isn't true, and some things still remain. I think that's the connotation the phrase is reaching for in its standard usage.
(Equivalently to that implicit question, you could also read it as a contradiction of an implied previous statement: "All is lost!" "No it's not!")
To interpret it as "nothing is lost", I would take it as an answer to the implicit question "what is not lost?", answering with "all" i.e. "out of all things, none are lost". This interpretation feels more awkward to me, linguistically speaking. It's grammatically viable but it doesn't feel like the natural way to phrase the sentiment; an ordinary English speaker, trying to express "nothing is lost", would probably use those three words.
As for "not all is lost", I think we lose something by moving to this phrasing from "all is not lost"; specifically, it muddies the connection to the implied question or statement. Sentences of the form "X is Y" negate most straightforwardly to "X is not Y" in ordinary English usage. "Not all is lost" is also a valid negation here, but in my opinion it's deemphasizing that implicit relief and instead putting more emphasis on the implication that although not all things are lost, some of them probably are. Less relieved, more foreboding.
“Sentences of the form "X is Y" negate most straightforwardly to "X is not Y" in ordinary English usage.” Not when quantifiers are involved they don’t. That was my point. If I said “all tennis players own a racquet” you would not deny that by saying “all tennis players do not own a racquet.” That would be kinda dumb. You would correctly negate it as “not all tennis players own a racquet.” Same for “all is lost”.
In my experience, in ordinary colloquial English, it absolutely is the case that people will negate "X is Y" to "X is not Y" even when you could interpret the sentence as involving a logical quantifier, because most colloquial English-speakers aren't interpreting their sentences as involving logical quantifiers; and in this case, under my preferred interpretation, the word "all" is not in fact being used as a logical quantifier.
Consider the exchange: "Brown bear, brown bear, what do you see?" "ALL", as seen in a 2014 Tumblr meme, surely a valid example of colloquial English. "All" is not functioning as a logical quantifier here; it is a noun, meaning "the totality of things". That's a perfectly normal thing for the word "all" to mean.
"[The totality of things] is lost" is a sentence containing no logical quantifiers, only a noun, being linked to an adjective. Its straightforward negation is "[the totality of things] is not lost".
Or for a slightly more reputable source, Wiktionary gives an impressively detailed list of possible senses in which the word "all" can be used, and although the first one seems to be the logical-quantifier-style usage, the only examples given of that usage involve it quantifying over a specified subject; "all tennis players", in your example, or "all my friends", "all contestants", etc. in Wiktionary's. The next usage listed is as a (pro)noun, meaning "everything", with examples such as "she knows all and sees all" or "those who think they know it all". This is the usage category into which I believe "all is not lost" falls.
Exactly. Or when they say “all that glitters is not gold”, implying that even gold itself does not glitter, instead of “not all that glitters is gold.”
Just an FYI. For any individual thinking of investing, one diligence question would be: "are any biotech/therapeutics-focused venture capital funds investing in this round?"
I agree with not investing in early-stage biotech startups unless you are a professional early-stage biotech startup investor or know your stuff to an implausible degree.
Wouldn't the risk of knowing your stuff to an implausible degree be that your decision making is likely better than that of the FDA or local equivalent, making your predictions risky due to the potential behaviours of less-informed agents?
Of course you could be expert in the mechanisms of drug regulators, but the safe bet then is surely to hire your skills out rather than gamble on startups...
If you're going to go round investing in early-stage biotech startups then the ins and outs of the FDA is probably about 50% of the "stuff" you need to know.
I used to invest in (publically traded but pre-revenue) biotech companies, I made a small profit in the end but spent way too much time stressing over trial results and FDA committee meetings etc. In terms of dollars per grey hair it was the worst way of making money that I had.
What are the top ways of making money that you had? :D
For me personally, over the past ten years, the best ways of making money have been (a) investing in just about anything you can think of that isn't a biotech company, and (b) going to work and doing my job.
You know the joke about the foolproof method for making a small fortune in biotech?
I’ve heard that same joke applied to developing a new ski resort
With a few exceptions, seed rounds almost never work out in biotech because the later investors, especially VCs have so much leverage that seed investors almost always get diluted down to nothing. This is because the capital requirements are so great (hundreds of millions) and unlike in tech, the demand for capital is greater than the supply (though this seems to be turning)
Generally correct. Although this is becoming less true as capital comes flooding into the sector.
Presumably youre not, but If you’re an investor - direct or indirect - make sure to disclose.
I'm not.
Scott: This is important. DO NOT Post solicitations for investments. I do not know enough of your exact situation or of the nature of the solicitation to give competent legal advice to you.
But. It is generally illegal to sell securities unles you are a registered securities dealer. California's laws (and I am not a California lawyer) are very strict and they are enforced aggressively. Federal law is similar.
If I were you, I would take this information down.
Posting an email someone sent me saying "our company is cool, email us if you want to invest" is legally equivalent to selling securities?
There is a marginal risk here. I'd recommend against it too.
All right, I've deleted. Jonah can post it himself if he wants, unless someone's going to tell me even having it on the blog is a risk.
I would not let anyone solicit for investments on my blog. Substack might have a Section 230 defense, but a blogger probably does not.
I'd ask your lawyer about that.
This feels like a good example of big law selling insecurities 🤸🏾♀️
I am retired. When I was in practice I was not "Big Law". I am not trying to get anybody to spend money on legal fees.
I do know a bit about securities law, a bit that grows more and more obsolete day by day. I used to teach CLE classes on the subject. But, that was in a previous millennium.
Scott is not a financial industry professional. Even professionals make mistakes. Goldman Sachs recently paid a ~3G$ fine to the SEC. And, their General Counsel just did the 21st century corporate equivalent of being a virgin who jumps into the volcano. No connection they say. And you believe them, don't you.
Scott is an uncompensated volunteer. He has no upside, but any involvement in fundraising for investment opportunities carries a downside risk. Scott no ability to control risk by contract, insurance, monitoring, or due diligence.
I am a volunteer too. I hope my advice is worth every penny you have paid for it. If you don't think I am right, you can just ignore me.
My theory is
No Control + No Monitoring + No Insurance + No Due Diligence = Big Risk. Big Risk + No Reward = Don't Do it.
As theories go, I think that one is pretty good.
Perhaps. The Federal Securities Act of 1933 defines: "the term “offer to sell”, “offer for sale”, or “offer” shall include every attempt or offer to dispose of, or solicitation of an offer to buy, a security or interest in a security, for value." The law and administrative lore are very extensive. If you had an upside in doing this, it might be worth thinking about, but if you had an upside, that would be a fact indicating legal involvement.
As you are an uncompensated volunteer, the safest thing to do is to stay far away.
Back in a previous millennium when I had hair and no belly, I worked in a law firm that was located hard by Wall Street in lower Manhattan. On a clement day, if we weren't too busy, my colleagues and I would occasionally walk over to the river, and we would lunch at Sloppy Louie's immediately adjacent to the Fulton Street Fish Market.
It was a very plain sort of place. The tables were picnic benches and the menu was fried or broiled fish, nothing fancy. We were sure that it was, like the Fish Market, run by the Mob. There was a sign over the cashier's seat imparting ageless Sicilian wisdom:
"Even a fish can't get in trouble if it keeps its mouth shut."
As I posted above, general solicitation of certain private placement offerings is legal, as of 2013, under Rule 506(c) of Regulation D, subject to various limitations, in particular that the issuer must take "reasonable steps" to verify accredited investor status.
Every time I see that phrase my blood boils. Accredited investor? Might as well say aristocracy.
Consider that the modal person "posting an email someone sent me saying 'our company is cool, email us if you want to invest'" who comes to the legal system's attention is less "Scott Alexander" than "author of the 'Penny Stock One Weird Trick Report.'"
I have no opinion on this, but just know that I definitely will never be able to read one of your comments without hearing it in Walter's voice and with his reasonable-then-screamy delivery. I appreciate it.
Ditto and also join the chorus that exploring the edges of the securities laws is a lousy hobby.
General solicitation for private placement offerings is allowed under Rule 506(c), since the 2012 JOBS Act. (However, I don't know whether there are restrictions on _who_ is allowed to perform those solicitations. And I don't know whether the company is intending to reply on 506(c), which requires them to take reasonable steps to verify the accredited investor status of their investors, or 506(b), which is more convenient because it does not require them to do that (but does not permit general solicitation.))
"reply on" should be *"rely on", obviously.
Thanks, Glenn. One of the nice things about being retired is that I no longer have to learn all of this dugash. I looked at the SEC pages on the JOBS act:
https://www.sec.gov/spotlight/jobs-act.shtml
I think you could structure things to avoid a problem, but since Scott (and anyone else in his position) has no ability to audit the structure or monitor compliance, my advice (which is easily worth every penny you are paying for it) is still to stay away.
Your advice is certainly not unreasonable. I have kind of a pet peeve about "vetocracy by overcaution", where a valuable thing ends up prohibited-in-practice if _anybody_ near the thing believes it might be prohibited, or feels like it ought to be prohibited.
(This pet peeve brought to you mostly by software licensing, which is the absolute worst mixture of "overcautious lawyers" and "cranky software engineers who mistakenly believe themselves to be lawyers". Of course, I'm arguably in the latter category myself, so I have to be careful how much I shit-talk it.)
I think the email is supposed to be jonah@equatortherapeutics.com (you wrote puetics). Normally I wouldn’t be so pedantic but I could see somebody clicking that link and failing to send an email!
FYI, Chubbyemu recently released a video regarding a DNP overdose in a young man attempting to lose weight https://youtu.be/ChPeG19qKUo
I came here to post this.
Maybe we've gone wrong as a society if burning to death from the inside is the less risky option.
It's always an option, just vanishingly unlikely in most cases (unless you know some very sadistic people I guess...). The question with risk is not how bad is the less risky option but how horrific are the other options...
Fire Walk with Me
The candle that burns twice as fast . . . I guess some will always prefer to go out with a bang, rather than just fade away.
Alternate use: a poetic new form of political protest?
In other news, the Wikipedia page on self-immolation warns: "Self-immolation does not guarantee death for the burned."
I'm still wondering if there were more reports of spontaneous combustion back in the '30's.
Weren't most of the "spontaneous combustion" cases people who fell asleep with a cigarette in hand, and basically turned into a human candle wick, and died of carbon monoxide poisoning before they burned up? Not sure if mitochondria would affect the frequency of that.
The Texas case sounds like a large enough sample size that you could get an idea of long-term side effects from DNP usage via a survey.
Also, doesn't most modern anti-aging thought revolve around slowing the metabolism (e.g. fasting), not speeding it up? It sounds like this stuff would make you die faster, even if you didn't have any major side effects from it.
Normally the proton gradient is used to produce ATP. With uncoupling it just makes heat and is arguably not really metabolism as it doesn’t produce anything.
Free radical production from mitochondria is partly dependent on the proton gradient. So by uncoupling you can dissipate the gradient and reduce free radical production which may be beneficial if the cell is under oxidative stress. Of course there are lots of critiques against the free radical theory of aging.
Good for general health, probably, but also probably not good for male fertility though.
That doesn't quite make sense to me. DNP is actually making the cell pump *extra* protons over the gradient, because it still needs the same minimum number of calories to operate. The DNP is just creating a parasitic side-reaction where some of the energy consumed is wasted as heat rather than used to pump protons, creating a net caloric deficit.
If there's a certain number of free radicals generated per proton-pumping operation, I can't see how this effect would result in less free radicals generated. If anything, it might be more.
Regarding low dose DNP, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468406/
"DNP appears to mimic in part the neuroprotective and neurorestorative effects of exercise and fasting by increasing BDNF, lowering cellular stress and building cellular resiliency by mild increases in mitochondrial bioenergetics."
Basically, through slightly stressing mitochondria, you increase mitochondrial health, similar to exercise, cold exposure, and other stress related activities that have beneficial health effects.
After the proton gets pumped over the membrane the electron has to go through a series of complicated stages to get back to it, which each stage making its own ATP letting aerobic respiration be so much more efficient than anaerobic respiration. However, the high energy chemistry in a mitochondria is potentially dangerous, sometimes things break, and if one part of the chain breaks down you have lots of electrons backing up and becoming Problematic. Letting the protons bypass the normal process more easily mitigates that danger even though it causes more of the normal operation of the mitochondria.
But the same number of successful proton pumping operations are still happening, right? There's just a bunch of extra unsuccessful ones as well. It's possible that my inorganic chemistry background is letting me down here.
Right. The proton pumping setting up the potential happens just like before. It's the electron dancing down the potential ladder making ATP that fall back on to the soft proton when they trip, to strain a metaphor.
I think I get it - the theory here is that the extra protons create metastable states that trap rogue electrons without producing free radicals, right? That makes a certain amount of sense.
Thank you very much for taking the time to explain it to me.
Don't think electrons of the type you appear to be thinking are involved in making ATP. The electrons that come out of the citric acid cycle are passed along a chain of membrane-bound proteins until they reduce O2 to H2O. The reaction to create ATP from ADP is not a redox reaction and happens somewhere else.
As I understand it is the existence and magnitude of the proton gradient that increases free radical production. Thus by reducing the magnitude of the proton gradient you would get less free radical production. Cells can increase their uncoupling in response to oxidative stress. All else equal this decreases ATP production but still above minimum, well except for the lens cells for some unfortunate individuals. I also imagine that uncouplers should reduce your capacity for physical labor.
Isn't it the creating of the proton gradient by the electron transport chains that risks, well, leaking electrons? Does ATP synthesis itself even involve redox?
The electron transport chain where high energy electron goes from donor to acceptor ending up with the one of the best oxidisers (electron acceptor), oxygen creates the proton gradient. This the oxidative step. Then protons flowing back via ATP-synthase then puts a phosporyl group on ADP, making ATP. That is the phosphorylation step. Together they are oxidative phosphorylation.
I'm not a mitochondria expert but yes the electron leakage should be in the electron transport chain. But the bigger the proton gradient the more the electron chain leaks. You can read more in the introduction part of this paper: https://www.sciencedirect.com/science/article/pii/S000527281830135X#bb0060
No, the phosphorylation of ADP to create ATP is not a redox reaction. It's a thioesterification or condensation reaction. No atoms change oxidation state. I think the confusion arises because the phosphorylation is *coupled* to a redox reaction, which is the reduction of O2 to H2O. That's why it's called "oxidative phosphorylation." The reduction of O2 provides the energy for the otherwise energetically uphill phosphorylation reaction. But in mitochondria these reactions occur in different places. The reduction of O2 happens along the electron transport chain, while the phosphorylation of ADP happens in a nearby membrane-bound enzyme.
Tried getting it off Ali baba once but it was just orange died sawdust. Also my family decided I was on meth because I was involved with a seemingly mysterious substance tied to weight loss that might explode and they didn't understand my explanations...
Props to all the good people on AliBaba who look out for their customers by sending them sawdust instead of dangerous drugs that could kill them.
In my life I have still managed to buy motorcycles and guns, so alas it is to limited avail; high risk tolerance, uhhh, finds a way
So it actually worked for you?
How did you determine it was sawdust?
Correction to "They pump protons across a membrane, creating pressure for electrons to travel the opposite direction." Actually they create pressure (potential) for electrons to travel in the *same* direction. When positive charge goes one way, negative charge also "wants" to go that way, following its potential energy gradient. Making electrons travel in the opposite direction would cost even more energy, defeating the purpose.
Argh, you're right, thanks, fixed.
>They pump protons across a membrane, creating pressure for electrons to follow. This forms an electrical gradient...
I argue for removing "creating pressure for electrons to follow" entirely, because that misleadingly suggests that this pressure is somehow necessary or relevant for the potential difference. In reality, the proton concentration differential is enough.
Yes, that is a strange statement. In the first place, it's not true. The *electrostatic* field of H+ is very well shielded in water, that's why solvated H+ (i.e. pH < 7) is stable. So while there is a voltage across the membrane, it's not nearly enough to rip electrons loose from wherever they're bound and hustle them across the membrane. The gradient of H+ is purely in the chemical potential, as far as I know, and the same (entropic) driving force would exist even if the species in question were neutral. The only reason cells do it with charged species (H+ in the mitochondrion, Na+/K+ in neurons et cetera) is that the charge makes it difficult for these small atoms to cross back over the membrane anywhere and destroy the gradient, which they would otherwise do, because they are very polar and the membrane is nonpolar -- their solubility in the lipid bilayer is very low. Perhaps something else was meant, and I'm not understanding it.
This isn't how it works at all. The electron transport chain doesn't involve free electron movement or net electron movement across the membrane.
Electrons get transported from food (fat/carbohydrate) to oxygen via a series of reducible cofactors (the electron transport chain).
The proteins that catalyse these reactions use that energy to pump protons out of the lumen. The protons can (mostly) only come back through the FOF1 ATPase, which makes ATP when it happens.
Also, dinitrophenol doesn't "punch holes" in the membrane; it's not a pore (things that actually punch holes in membranes cause massive necrosis - I'm familiar with two examples, one of which is part of the immune system and one of which is snake venom). The trick with dinitrophenol is that it's acidic (at just the right level to be partially ionised at biological pH) and that it's lipophilic enough to pass through membranes *even while ionised* (the aromatic ring and the delocalisation of the charge over 6 atoms help with that). So, since the pH on the two sides of the membrane is different, it tends to lose its proton inside the lumen, pass out, pick it up outside and come back in.
It feels very weird to make drugs that make bodies less efficient. Like, if you don't need so many calories, there's a pretty easy solution!
But obviously it's not so easy in practice as human bodies are vastly complicated biochemical laboratories operating under sometimes faulty instructions.
We ought to put the calories to work digging ditches and filling them back in so that they'll have something to do and will have earned their wages.
"Pumping protons across a membrane that diffuse back" actually seems like the microbiology analogue of what you suggest.
Very Keynesian. I approve.
It’s also a reference to an older SSC post: https://slatestarcodex.com/2018/05/16/basic-income-not-basic-jobs-against-hijacking-utopia/
Another dvorak user? I'm curious when and why you learned it.
If your username is an ironic reference, that's cool too.
Guilty!
I didn't feel like using a preexisting handle here, but couldn't come up with anything good on the spot, so I just typed the home row in order.
I've been using dvorak for 3-4 years now. I didn't have a very good reason for switching, mostly it just sounded amusing to see if I could reprogram my typing muscle memory. I've previously written a bit about it here: https://www.schlaugh.com/~/cdvhauo
Colemak in the house :)
Nice! I've never looked at Colemak before now. Definitely makes the right call regarding the positions of AZXCV for the keyboard shortcuts.
I'm a dvorak vim user who doesn't remap the movement keys HJKL, and it's not too bad. Colemak doesn't seem to do so well on this metric: JK (up/down) switched around and all 4 of them in the left pointer finger's domain.
Still, I would probably choose Colemak over Dvorak if I were to go do it over again.
Almost all drugs except for some newer ones are making some part of your body less efficient, though not this directly. It’s a lot easier to turn harmful machinery off than to insert useful new machinery.
That may well be, but it's hard to argue that mitochondria are harmful machinery. This is like punching a hole in your gas tank because you have a crush on the gas station attendant.
It's not about turning the whole energy-making process off, just safe ways to make it slightly less efficient since it's tuned to solve the obsolete problem of scarce calories
> It feels very weird to make drugs that make bodies less efficient. Like, if you don't need so many calories, there's a pretty easy solution!
Blame evolution for making eating a terminal goal. Making bodies less efficient might be easier than fixing this.
I've read that among a certain segment of the naturally thin population they naturally release excess calories as heat rather than storing them as fat.
I have always been on the thinner side, although I can gain weight, and I also "run hot". My appendages are frequently warmer than other people's. That could be because I have a higher core temperature or a higher peripheral temperature alone. I also have higher blood pressure so maybe there's just more convection of heat away from my core. Either way I'm shedding more heat than normal, and am more tolerant of cold temperatures and less tolerant of warm temperatures.
hm, this is interesting. i'm also on the thinner side and have been struggling to gain weight, but I definitely feel colder to the touch than average (which i always attributed to the lack of body fat to keep me warm, also im AFAB). that said, i am also more tolerant of cold temperatures than warm ones, so maybe (anecdotally ofc) there's some correlation there.
I'm thin and cold too, but I do fidget a lot - I have a tendency to twitch my leg rhythmically and such. This might contribute to excess calorie expenditure. It does seem to stop when I'm hungry, though I'm not going to claim that there's an actual energy management relationship there.
Every thin person is probably such due to a confluence of factors. I mostly attribute my thinness to the small portion sizes my mother fed me as a child.
I'm thin, tall, and cold (which could be from lower circulation due to longer limbs). I'm less tolerant of cold than of heat.
Between you and Jack C’s reply to the comment it feels like knowing somebody is tall and thin doesn’t really predict very much
Hey Jack, I would also fit this description - tall, hot, restless, need to jump in the river even in winter - and my wife (African, hates the cold, sleeps under 2 duvets) is worried about my blood pressure so we've been monitoring it over the past couple of weeks - it's definitely high and fluctuates wildly throughout the day, so I'm getting it checked out properly at the GP tomorrow. I like the idea of investing in big mitochondria though 🤣
Here's an older SSC post with something related:
https://slatestarcodex.com/2017/04/26/anorexia-and-metabolic-set-point/
The relevant quote:
> Some more evidence: people with anorexia fidget like crazy. This is the conventional wisdom among generations of psychiatrists, and has been confirmed in studies – see for example *Measurement Of Fidgeting In Patients With Anorexia Nervosa Using A Novel Shoe-Based Monitor*, which found anorexics fidget almost twice as much as healthy controls. This seems really damning to me. Consciously deciding to fidget is hard. If you don’t believe me, try to fidget as much as possible for the next two hours (the length of the study linked above) and see how well it goes. Most people just can’t do it. On the other hand, fidgeting (renamed to the more dignified “non-exercise activity thermogenesis”) is the classic strategy that the lipostat uses to maintain unconscious control over weight...
> A purely social paradigm of anorexia can’t explain the fidgeting; a biological paradigm outright predicts it.
Wow! Do you mean psychological paradigm? It's not that your conscious mind holds the mistaken belief that your fat when you're not. Or that you're attempting to control one part of your life when you can't control others. On a fundamental biological level your body thinks it's fat when it's not.
I can go on and on about the superiority of a "biological paradigm" for AN. Here are a couple tantalizing links:
* https://relative-energy.tumblr.com/post/183390573416/activity-based-anorexia-and-animal-models
* https://relative-energy.tumblr.com/post/182904564621/shan-guisingers-2003-paper-adapted-to-flee
See also this from SSC: https://slatestarcodex.com/2018/12/05/giudice-on-the-self-starvation-cycle/
> Do you mean psychological paradigm?
Rather than "social paradigm" or rather than "biological paradigm"?
I would expect the social paradigm to explain the fidgeting as nervous movement, the logic being that it's a stressful condition or stressed people tend to develop anorexia. I don't find the idea convincing without further explanation.
Anecdotally: my friend who has low body-fat and was a sports players in his youth and early twenties used to run very hot all the time. Hot to the touch. When I was fit, more fit than usual, I also felt very warm.
On the other hand, people who are thin naturally have less insulation. This might just be one of those reverse causality situations - thin people are less insulated and so lose more heat.
Worth noting: tall people apparently have higher BMI than short people, which may well be because of the square-cube law.
I've been called a space heater by my girlfriend...
First, I am disappointed that there is no "conscious uncoupling" joke in here. A missed opportunity! Second, pretty sure that instead of "all is not lost" (implying that nothing whatsoever is lost) you mean "not all is lost" (implying not everything is lost). Sincerely yours in logical pedantry,
That might be logical, but "All is not lost" is a fixed phrase, logic be damned!
https://www.macmillandictionary.com/us/dictionary/american/all-is-not-lost
Doesn’t the dictionary also allow “literally” to mean “figuratively”? So YMMV.
Modern dictionaries aim to describe language as it is commonly used, not to prescribe how it should be. I think it's wrong to say they "allow" it - they observe that it gets used that way.
You'd think that, but that's because the English have an inferior practical philosophy of language. In contrast, the motto and job of the Royal Academy of Spanish (which writes the Spanish dictionary) is "to clean, make certain, and give splendor". This is why we Spaniards can have nice things, like not having spelling bees because the correspondence between the written and the spoken word is pretty much* unambiguous.
On the danger of conflating English and logic:
https://journeys.dartmouth.edu/folklorearchive/2017/11/13/a-carton-of-milk-and-some-eggs-joke/
"All is not lost" is perfectly technically-correct if you just interpret it slightly differently - as "it is not the case that all is lost" ("is all lost?" "it is not"), rather than as "it is the case that all things are not-lost" ("what is not lost?" "all is")!
“All is not lost” I would formalize (well, quasi formalize; this is a comment section!) as (x) ~(Lx). “Not all is lost” as ~(x)(Lx). Those aren’t equivalent. Would you do it differently?
So to get into my position here in more detail:
You can interpret "all is not lost" in one of two ways, or at least two that are clear to me at a glance. One is the way you're interpreting it; the other is the way that's equivalent to your formulation of "not all is lost". Personally, I find the latter interpretation more intuitive.
To interpret "all is not lost" as "it is not the case that all is lost", logically equivalent to "not everything is lost" or "out of all things, some are not lost", I would take it as an answer to the implicit question "is all lost?", which I think is what most people tend to mean when they use the phrase. "All is not lost" under this interpretation describes a world where we were worried that all might be lost, but then found out that this isn't true, and some things still remain. I think that's the connotation the phrase is reaching for in its standard usage.
(Equivalently to that implicit question, you could also read it as a contradiction of an implied previous statement: "All is lost!" "No it's not!")
To interpret it as "nothing is lost", I would take it as an answer to the implicit question "what is not lost?", answering with "all" i.e. "out of all things, none are lost". This interpretation feels more awkward to me, linguistically speaking. It's grammatically viable but it doesn't feel like the natural way to phrase the sentiment; an ordinary English speaker, trying to express "nothing is lost", would probably use those three words.
As for "not all is lost", I think we lose something by moving to this phrasing from "all is not lost"; specifically, it muddies the connection to the implied question or statement. Sentences of the form "X is Y" negate most straightforwardly to "X is not Y" in ordinary English usage. "Not all is lost" is also a valid negation here, but in my opinion it's deemphasizing that implicit relief and instead putting more emphasis on the implication that although not all things are lost, some of them probably are. Less relieved, more foreboding.
“Sentences of the form "X is Y" negate most straightforwardly to "X is not Y" in ordinary English usage.” Not when quantifiers are involved they don’t. That was my point. If I said “all tennis players own a racquet” you would not deny that by saying “all tennis players do not own a racquet.” That would be kinda dumb. You would correctly negate it as “not all tennis players own a racquet.” Same for “all is lost”.
In my experience, in ordinary colloquial English, it absolutely is the case that people will negate "X is Y" to "X is not Y" even when you could interpret the sentence as involving a logical quantifier, because most colloquial English-speakers aren't interpreting their sentences as involving logical quantifiers; and in this case, under my preferred interpretation, the word "all" is not in fact being used as a logical quantifier.
Consider the exchange: "Brown bear, brown bear, what do you see?" "ALL", as seen in a 2014 Tumblr meme, surely a valid example of colloquial English. "All" is not functioning as a logical quantifier here; it is a noun, meaning "the totality of things". That's a perfectly normal thing for the word "all" to mean.
"[The totality of things] is lost" is a sentence containing no logical quantifiers, only a noun, being linked to an adjective. Its straightforward negation is "[the totality of things] is not lost".
Or for a slightly more reputable source, Wiktionary gives an impressively detailed list of possible senses in which the word "all" can be used, and although the first one seems to be the logical-quantifier-style usage, the only examples given of that usage involve it quantifying over a specified subject; "all tennis players", in your example, or "all my friends", "all contestants", etc. in Wiktionary's. The next usage listed is as a (pro)noun, meaning "everything", with examples such as "she knows all and sees all" or "those who think they know it all". This is the usage category into which I believe "all is not lost" falls.
All instances of translating idiomatic language word-by-word into logical notation are not useful.
In the same vein, I've always been annoyed when people write "everyone is not X" when they clearly meant "not everyone is X"...
Exactly. Or when they say “all that glitters is not gold”, implying that even gold itself does not glitter, instead of “not all that glitters is gold.”
There's some wonderful potential for Moloch tie-in with the only surefire weight loss pill involving burning from the inside
Moloch, whose cells are blazing furnaces!