Starting University Again

[danishispsychic]

yoga. specifically Gentle , Hatha 1, Restorative , Nidra . no vinyasa, power yoga , hot yoga. Pranayama breath work. Epsom Salt Baths.

 

[Wolf]

The Methylene Blue + Sarcosine combo definitely works. Though I'd take breaks (especially from the MB). That's all I got for you.

Sarcosine is not that far from RP stuff. Sure it has some correlations with cancers (so you take breaks), but it's been thought to work through glycine reuptake inhibition (though I bet it does more than that).

Some people on Longecity noticed that taking high dose of B2 before sleep increased their thinking the next day. I'm not sure it's very physiological use of it, but it didn't hurt me badly when I tried.

Why the break from the MB?

 

[Terma]

Why the break from the MB?

It's prudent notably because MB's half life is very long. It's both mine and Ray Peat's policy to cycle and take breaks, but especially for drugs with long half-lives, imo. It's a good default.

As to specific effects, hammering down NOS enzymes - iNOS notably - may affect the immune system negatively when exposed to pathogens. I'd be most careful in winter. If you're fairly healthy already you might not get any problem (pure guess), but you're not me.

On the other hand, Sarcosine has a very short half-live of a few hours, so (if you ever) you have to dose often. But that means it doesn't carry on into the night, and overall it worries me less than constant hammering the body with MB.

You might even notice it subjectively, that being on MB alone for many days, you start to feel off. It does that to me. It might be its effects on serotonin and catecholamines, or the constant nNOS antagonism in neurons. Or other. [maybe: lowering of eNOS and blood flow in the brain]

 

[Travis]

It's prudent notably because MB's half life is very long. It's both mine and Ray Peat's policy to cycle and take breaks, but especially for drugs with long half-lives, imo. It's a good default.

As to specific effects, hammering down NOS enzymes - iNOS notably - may affect the immune system negatively when exposed to pathogens. I'd be most careful in winter. If you're fairly healthy already you might not get any problem (pure guess), but you're not me.

On the other hand, Sarcosine has a very short half-live of a few hours, so (if you ever) you have to dose often. But that means it doesn't carry on into the night, and overall it worries me less than constant hammering the body with MB.

You might even notice it subjectively, that being on MB alone for many days, you start to feel off. It does that to me. It might be its effects on serotonin and catecholamines, or the constant nNOS antagonism in neurons. Or other. [maybe: lowering of eNOS and blood flow in the brain]

How do you suppose it lowers nitric oxide?

 

[LUH 3417]

yoga. specifically Gentle , Hatha 1, Restorative , Nidra . no vinyasa, power yoga , hot yoga. Pranayama breath work. Epsom Salt Baths.

Do you think hot yoga is too stressful?

 

[michael94]

id go to university again if money wasnt an issue

 

[Terma]

How do you suppose it lowers nitric oxide?

Wait, do you mean you don't think the molecule should do that? I thought that was 75% of the reason to take it.

I can get why you'd think it might not because of:
Methylene Blue Is a Guanylate Cyclase Inhibitor That Does Not Interfere with Nitric Oxide Synthesis
but if you look at the bottom:

This letter was sent to Dr. Joshua Manghelli, who responds in this manner:

To the Editor:

Dr. Evora is indeed correct that methylene blue inhibits guanylate cyclase1; however, there are data to support the contention that it inhibits nitric oxide synthase as well.2 We believe that the figure should be adjusted to include the inhibition of both enzymes.

and you follow the references from there.

There could be a dosage issue but I would defer to haidut on that.

 

[Travis]

Wait, do you mean you don't think the molecule should do that? I thought that was 75% of the reason to take it.

I can get why you'd think it might not because of:
Methylene Blue Is a Guanylate Cyclase Inhibitor That Does Not Interfere with Nitric Oxide Synthesis
but if you look at the bottom:

and you follow the references from there.

There could be a dosage issue but I would defer to haidut on that.

I think it probably does, and I'm not doubting that, but its classic use in in vitro cell studies and enzymology appears to be for increasing superoxide. I have actually come across this use being used is many studies on pain and anesthesia, as superoxide appears involved in these. [I have three studies bookmarked proving that nitrous oxide is also produced from nNOS.] Now if methylene blue increases superoxide, it can be though to lower nitric oxide via the spontaneous formation of peroxynitrite:

Ȯ₂⁻ + ṄO ⟶ ONOO⁻​

This came up about a week ago—when 'Mr. Smart' was arguing just for sport—because iron overload, which should reliably increase superoxide, has been shown to lower the nitric oxide concentration. Since iNOS expression was not effected, I had taken this to mean that more nitric oxide had become converted into peroxynitrite on account of increased superoxide.

And just to make sure I had been remembering things correctly, I had just typed in 'methylene blue superoxide' into GoogleScholar. The second result is as follows:

Wolin, Micheal. "Methylene blue inhibits vasodilation of skeletal muscle arterioles to acetylcholine and nitric oxide via the extracellular generation of superoxide anion." Journal of Pharmacology and Experimental Therapeutics (1990)

'The inhibition of vasodilation to acetylcholine or nitric oxide by methylene blue was completely prevented by suffusion of superoxide dismutase, but not affected by suffusion of catalase. Based on the current conceptualization of the mechanism of action of these vasodilator agents in isolated larger blood vessels, methylene blue appears to inhibit responses in this skeletal muscle microcirculatory preparation through the extracellular generation of superoxide anion and not via a direct interaction with guanylate cyclase.' ―Wolin​

So, perhaps we ought to take this idea seriously. I think the equation below is more like an equilibrium:

Ȯ₂⁻ + ṄO ⇌ ONOO⁻​

Where the concentration of any one species depends on all others. I think it would be fairly easy to find the equilibrium constant online to get an idea of how much peroxynitrite is formed from given concentrations of ṄO and Ȯ₂⁻. Peroxynitrite is actually more reactive than the others, and does has a proclivity for adducting-with tyrosine residues—pulling it out of solution and shifting the equilibria to the right.

 

[Travis]

This is interesting because peroxynitrite is the other substrate for cyclooxygenase other than the lipid, either arachidonic (20∶4ω−6) or eicosapentaenoic (20∶5ω−3) acid. Studies indicate that it is the peroxy group of peroxynitrite (ONOO⁻) that forms the endoperoxide bridge of prostaglandin H, the precursor of all others. As you know: prostaglandin E₂ can cause pain when injected, one way of linking superoxide and nitric oxide to pain.

Landino, Lisa. "Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis." Proceedings of the National Academy of Sciences (1996)

'Peroxynitrite activates the cyclooxygenase activities of constitutive and inducible prostaglandin endoperoxide synthases by serving as a substrate for the enzymes’ peroxidase activities. Activation of purified enzyme is induced by direct addition of peroxynitrite or by in situ generation of peroxynitrite from NO coupling to superoxide anion. Superoxide dismutase completely inhibits cyclooxygenase activation in systems where peroxynitrite is generated in situ from superoxide.' ―Landino​

There are a few more studies that seem to indicate that total prostaglandin formation is proportional to peroxynitrite.

 

[Terma]

Wolin, Micheal. "Methylene blue inhibits vasodilation of skeletal muscle arterioles to acetylcholine and nitric oxide via the extracellular generation of superoxide anion." Journal of Pharmacology and Experimental Therapeutics (1990)

'The inhibition of vasodilation to acetylcholine or nitric oxide by methylene blue was completely prevented by suffusion of superoxide dismutase, but not affected by suffusion of catalase. Based on the current conceptualization of the mechanism of action of these vasodilator agents in isolated larger blood vessels, methylene blue appears to inhibit responses in this skeletal muscle microcirculatory preparation through the extracellular generation of superoxide anion and not via a direct interaction with guanylate cyclase.' ―Wolin​

So, perhaps we ought to take this idea seriously. I think the equation below is more like an equilibrium:

Ah ok. I've never heard of some of this. Peroxynitrite is something I'd feared greatly in other context and would never consider it could possibly be involved in a two-way equilibrium. I was going to suggest hydrogen peroxide until that line about catalase, which is thoroughly discounted.

Thanks bringing it up, as it does cast doubt on various things I believed about MB, and O2- generation is not to be discarded! I wonder if this ties into its dose-dependent responses at all.

I have a marvelously hard time following the Discussion in that article, requires to have followed much of their other experiments; just looking up terms such as cremaster produced surprises. It does cast some doubt on the ability of MB to reach or exert its inhibitory effects in specific tissues. That appears important, since it's generally assumed on forums that MB inhibits NO activity in blanket fashion. I don't have much doubt it should inhibit iNOS-derived effects in macrophages, but now I do wonder if it will affect nNOS in neurons adequately (which by the way produces hydrogen peroxide directly or indirectly, which complicates potential therapies already), which is critical in context of combining it with Sarcosine.

The only clue to go on I see is the fact they believe the O2- is generated extracellularly. Or believed in 1990, anyway, already dated...

(There are some other very interesting links from that article I'd never heard of, although they're beside the point; this will take some time to digest:
An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation
Identification of a 54-kDa mitochondrial acetaminophen-binding protein as aldehyde dehydrogenase. - PubMed - NCBI
https://www.researchgate.net/public..._function_as_an_O2_sensor_in_pulmonary_artery
)

 

[Travis]

The only clue to go on I see is the fact they believe the O2- is generated extracellularly. Or believed in 1990, anyway, already dated...

I know that superoxide certainly is generated extracellularly by neutrophil NADPH oxidase, a granular enzyme secreted along with myeloperoxidase at targets. The neutrophil appears to be the immune cell that creates the most reactive small molecules extracellularly, with the macrophage of course creating the most intracellularly. The natural killer cells just release proteins such as perforin and the proteolytic granzyme—as do T cells. The neutrophil is is indisputably the most effective cell against yeast.

Yet eosinonphils appear more effective against helminths, and also secrete myeloperoxidase and NADPH oxidase. The eosinophil neurotoxin can plausibly explain some symptoms of eosinophilia, and the eosonophil's basic protein—another degranulation product—has high affinity for a muscarinic acetylcholine receptor. Could this be the mechanism that instigated the coughing seen in eosinophilic asthma? or the contraction needed for parasite expulsion?

Mitochondrial scientists are confident that superoxide is generated near the mitochondria, and also wherever free iron is found. As a molecule that will fluoresce red light, similar to singlet oxygen (¹O₂), you might think that heme could actually collect this and use it for energy. The microtubule scientist Guenter Albrecht-Buehler suspects that heme could be analogous to chlorophyll, both in structure and also in function. Suppose that instead of the porphyrin–Mg²⁺ complex absorbing UV light, as in the case of chlorophyll, it absorbs ¹O₂ light when complexed with iron. Heme's central iron atom is well-known to bind O₂ in both hemoglobin and countless enzymes, and can apparently raise its' electrons from the triplet into the singlet state. This process would be expected to emit red light.

I consider peroxynitrite to be important because nitric oxide and superoxide are often found in close proximity, and also because it is a non-lipid substrate of cyclooxygenase. Here's is an article by a chemist, followed by a short one by a biochemist, if anyone is interested:

Koppenol, W. H. "Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide." Chemical research in toxicology (1992)

'Superoxide is formed by a variety of organelles and cells (see ref 19 for review). Stimulation of neutrophils and macrophages increases the rate of production of nitric oxide and superoxide, and the formation of peroxynitrite appears to proceed quantitatively in activated rat alveolar macrophages. Peroxynitrite carries out reactions that can harm cells: it initiates lipid peroxidation and reacts with sulfhydryls and methionine, and it may play a role in reperfusion injury...' ―Koppenol

Squadrito, Giuseppe L. "The formation of peroxynitrite in vivo from nitric oxide and superoxide." Chemico-biological interactions (1995)

'A number of lines of evidence indicate that peroxynitrite is indeed formed in vivo. For example, superoxide can diminish the effects of nitric oxide by diverting it to form peroxynitrite. For this reason, superoxide scavengers such as SOD and thiols can enhance the biological activity of NO. (In fact, this may be a raison d’etre for mammalian SOD).' ―Squadrito

'Similarly, NO can capture superoxide and divert its effects, even to the extent of acting as an antioxidant. A number of systems are now known in which the presence of nitric oxide can alter, or even protect against, the effects of superoxide and superoxide-derived reactive oxygen species. Independent evidence for the existence of peroxynitrite in vivo derives from the demonstration by Beckman et al. using immunohistochemical techniques, that nitrotyrosine residues are present in atherosclerotic human coronary arteries. This appears to be convincing evidence for peroxynitrite formation in arterial plaques, since tyrosine is nitrated by peroxynitrite, but not by nitric oxide itself.' ―Squadrito

'Malinski et al. report a maximal concentration of NO of 450 nM at the endothelial cell surface after stimulation with bradykinin and up to 4 μM during middle cerebral artery occlusion in the rat. The values of 450 nM and 4 μM would imply that under these conditions, NO reacts with O₂⁻ 150 and 1300 times faster than O₂⁻ decays by all other pathways. Clearly, under these conditions the formation of peroxynitrite is expected. Thus, when the approach of Saran and Bors is combined with the newer value for the rate constant for the reaction of NO with O₂⁻ determined by Huie et al., we conclude that it is likely that peroxynitrite is formed in vivo.' ―Squadrito
​

 

[danishispsychic]

Do you think hot yoga is too stressful?

Gosh- Some people lurrrrve it. For me- it is really stressful in the Bikram form. If you are doing any of the more gentle yoga in a heated room- I think THAT can be really beneficial . The combo of super heat and super strenuous for me if kind of a wipe out.

 

[LUH 3417]

Gosh- Some people lurrrrve it. For me- it is really stressful in the Bikram form. If you are doing any of the more gentle yoga in a heated room- I think THAT can be really beneficial . The combo of super heat and super strenuous for me if kind of a wipe out.

I never did bikram but I did hot power yoga which is similar. I think I destroyed my adrenals doing that for a year. Now I do a hot class once in a while but it’s mostly slow and gentle. The only standing poses are warrior 1, 2 and tree. Was curious as to why you wrote hot yoga, and I agree with you.

 

[danishispsychic]

I never did bikram but I did hot power yoga which is similar. I think I destroyed my adrenals doing that for a year. Now I do a hot class once in a while but it’s mostly slow and gentle. The only standing poses are warrior 1, 2 and tree. Was curious as to why you wrote hot yoga, and I agree with you.

I just think with yoga that a classic practice is best with all asana . Really knowing all the classic asana , doing floor work, inversions and a balanced practice that is level appropriate is key. " Power Yoga " is not really Yoga in my opinion. In terms of lowering cortisol, a really balanced practice of about 90 mins that included a long nice Savasana with an Epsom Salt bath after works wonders.

 

[LUH 3417]

I just think with yoga that a classic practice is best with all asana . Really knowing all the classic asana , doing floor work, inversions and a balanced practice that is level appropriate is key. " Power Yoga " is not really Yoga in my opinion. In terms of lowering cortisol, a really balanced practice of about 90 mins that included a long nice Savasana with an Epsom Salt bath after works wonders.

Thanks for the tip

 

[zewe]

Hey I used to get good grades in math related courses, without really stressing. That changed in my recent course. Biggest thing I learned is in the past I got free overview and structure of reading material from really good teachers. Recently though with Hubris that just showing up to class is enough. Some teacher can't provide the structure during class, they may be new to it, so you may have to make it yourself

Don't fall behind, make sure you are up to date on homework and theories, the rest will come. You should read the material at level that lets you ask competent questions in lectures, or so the teacher can look you in the eye while explaining, and you not pretending to understand, but actually do understand. Make him be the examination subject..
Do something like Anki: try to make a plan, so you see through your notes 3 times total, night after lecture, before assignments, before the next lecture, are there notes you can take to really condense the learned material into shortcuts, you can adjust accordingly, stuff like that. always maintain an overview of course material, and where you are at.
Do the assignments no matter how easy/boring/complex they seem, it's there to solidify the knowledge.

No supplement helped long term, You just gotta do it. Good luck

I LOVE this answer!!

@Wolf: my answer would be to take notes.
Take notes during your lectures; take notes of your reading assignments.

And, [I foresee a few groans] do not take notes on your laptop! Write them out by hand; you'll learn and retain more.

Computers are changing humans cognitively and it's not necessarily for
the better.

Yes, handwriting is slower and more cumbersome than typing but it forces your brain to work harder. This is a totally different type of cognitive processing as opposed to typing.

You will listen, digest and process the information for better comprehension and retention.

When typing, you may produce a word for word record of the lecture but you won't process much of the meaning of its content.

 

[Amazoniac]

id go to university again if money wasnt an issue

Your message on the other thread reminded me to ask you if you don't make the mindings: why?
a) Missing the social aspect
b) Grew up being conditioned on what to do and now feels a and drift after leaving the macadamia
c) Humiliate freshman
d and less important) Learn from experienced gurus