NIH research findings: mTOR

[Hip]

It seems like Bing Chat uses ChatGPT 4.0:

I read that too, but I wonder if Bing Chat uses a specific configuration of ChatGPT 4.0.

Because even in its more wordy and fluid "creative mode", Bing Chat remains very precise and only makes medical statements it can back up with reliable sources (which it always cites in its answers).

Whereas all other AI chatbots I have used often fabricate medical answers which have no apparent basis in fact.

I wonder if other versions of ChatGPT 4.0 are also this ruthlessly precise as Bing Chat.



There is also a free Android / iOS version of Bing Chat.

 

[hapl808]

I read that too, but I wonder if Bing Chat uses a specific configuration of ChatGPT 4.0.

Yes, ChatGPT 4.0 is different than Bing even though they say Bing runs ChatGPT 4.0. If you input the same question on both, the results will differ.

I don't think there's a practical free method for GPT 4.0, but Bing is the closest thing. I'm currently paying for GPT 4.0 because the chat history, context, sync'ing, etc is useful, but not sure if I'll continue. Hopefully it will continue to improve.

 

[hapl808]

I wonder if other versions of ChatGPT 4.0 are also this ruthlessly precise as Bing Chat.

If you want to compare to a Bing query, let me know and I can input something and give you the results from GPT 4.0.

With GPT 4.0 (and others), you can instruct the chatbot to be precise or less precise. Beyond the Bing mode, I can tell GPT to explain things in more detail, or to use different methods of description. A lot of it is getting used to 'talking' to the AI I think. Results can vary a lot with different prompting.

 

[Forummember9922]

FYI Avik Roy, the researcher behind the OP article/video is responsive to twitter questions.

 

[Tsukareta]

Isn't this the first animal model of chronic fatigue syndrome though ? assuming that's really what the mice are exhibiting and the research is real.

 

[Consul]

Isn't this the first animal model of chronic fatigue syndrome though ? assuming that's really what the mice are exhibiting and the research is real.

The mouse thing sounds very dubious imo. We dont even know what causes mecfs and now they supposedly have induced it into mice because they walk around less after being poisoned or something. Ehh.ok

 

[Forummember9922]

Isn't this the first animal model of chronic fatigue syndrome though ? assuming that's really what the mice are exhibiting and the research is real.

There was another cfs mouse study which showed that beta glucans treated a manmade cfs model in mice. Based on this and crossover concepts RE: Bcg vax i take beta glucans. Def not my former self but i guess ill stay on them.

 

[Forummember9922]

Not sure if relevant or how to interpret but Rapamycin lowered EBV lytic replication on a one level but increased on a different level

https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-11-110

We determined that treatment of cells with rapamycin, which is an inhibitor of mTORC1 activity, led to a reduction in the ability of B cell lines to undergo lytic replication. In contrast, EBV-positive epithelial cell lines underwent higher levels of lytic replication when treated with rapamycin.

 

[Forummember9922]

Perhaps worthy of note- Rapamycin is a Jak Stat inhibitor? (edit: technically no)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650428/

“RAPA also inhibits constitutive activation of the Jak/STAT pathway [26] …”

It also looks like EBV or proteins that it produces can influence or modulate jak stat. In which way or direction I'm unclear as i see conflicting data that appears complicated

 

[Osaca]

Perhaps worthy of note- Rapamycin is a Jak Stat inhibitor?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650428/

“RAPA also inhibits constitutive activation of the Jak/STAT pathway [26] …”

It is not, at least it is not classified as such. But it's a really good question to find out what's going on.

The paper quoted describes a very specific scenario in which "these data further support the idea that RAPA not only inhibits cell cycle progression and induces apoptosis but also acts by inhibiting IL-10 production and decreasing the tyrosine phosphorylation of the STAT proteins. This effect is specific to P-Tyr-STAT because RAPA does not inhibit serine phosphorylation of STAT3 or the overall expression of the Jak/STAT proteins in the IL-10 signaling pathway."

A JAK STAT inhibitor on the other hand inhibits the activity of one or more of the Janus kinase family of enzymes to block cytokine signalling. So mabye it can be said that Rapamycin is something like a decreaser in specific areas, rather than an inhibitor? At least that is what I understood.

It should be noted that rapamycin only partially blocks mTORC1 and does not directly inhibit mTORC2. However, second-generation ATP-competitive mTOR kinase inhibitors (TOR-KIs) efficiently block both mTOR outputs and show greater efficacy when combined with TKIs. So it seems better things could be out there. [1]

 

[Forummember9922]

It is not, at least it is not classified as such. But it's a really good questionn to find out what's going on.

The paper quoted describes a very specific scenario in which "these data further support the idea that RAPA not only inhibits cell cycle progression and induces apoptosis but also acts by inhibiting IL-10 production and decreasing the tyrosine phosphorylation of the STAT proteins. This effect is specific to P-Tyr-STAT because RAPA does not inhibit serine phosphorylation of STAT3 or the overall expression of the Jak/STAT proteins in the IL-10 signaling pathway."

A JAK STAT inhibitor on the other hand inhibits the activity of one or more of the Janus kinase family of enzymes to block cytokine signalling. So mabye it can be said that Rapamycin is something like a decreaser in specific areas, rather than an inhibitor? At least that is what I understood.

It should be noted that rapamycin only partially blocks mTORC1 and does not directly inhibit mTORC2. However, second-generation ATP-competitive mTOR kinase inhibitors (TOR-KIs) efficiently block both mTOR outputs and show greater efficacy when combined with TKIs. So it seems better things could be out there. [1]

Thank you for the correction.

 

[Osaca]

Thank you for the correction.

Maybe you can find out more about what's going on here and how it relates to EBV, it still is very mysterious to me. However, Rapamycin isn't not a JAK STAT inhibitor due to some technicality, but rather because it doesn't meet IC (inhibitory concentration) or other criterias at all. I found this website https://www.selleckchem.com/subunits/JAK1_JAK_selpan.html for existing JAK-STAT inhibitiors or those that are still in development which I found really awesome. Some of the ones in development which affect all pathways, like Cerdulatinib or SAR-20347 which has an IFNa effect, I'd never heard of before.

 

[Forummember9922]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297313/
This seems like a deep dive of how mtor and stat can intersect and or cooperate. I understood the title and date perfectly, minus the title.

 

[Violeta]

This is a list of things from selfhacked that can inhibit the mTOR pathway. Interesting to me that there are quite a few on the list that I find helpful.

• Protein restriction [21, 22]
• Calorie restriction [23]
• Ketogenic Diets [24]
• Intermittent Calorie Restriction [23]
• Exercise (inhibits mTOR in the liver and fat cells, but activates it in the brain, muscle, and heart) [25, 26]
• Cortisol/Glucocorticoids [5]
• Metformin [27]
• NAC [28]
• Resveratrol [29]
• Aspirin [30]
• Omega-3 [31]
• Extra Virgin Olive Oil [32]
• EGCG/Tea [33, 1, 34]
• Curcumin [35, 1, 36]
• R-Lipoic Acid [37]
• Caffeine [38, 39, 1]
• Fisetin (in fat cells) [40]
• Apigenin [41]
• Quercetin [42]
• Genistein [1]
• DIM [1]
• Ursolic acid [43]
• Emodin (found in Fo-Ti, Rhubarb, Aloe) [44]
• Andrographis/Andrographolide [45]
• Pomegranate/Ellagic acid [46]
• Reishi [47]
• Milk thistle/Silymarin [48]
• Oleanolic acid [49]
• Anthocyanins/Grape Seed Extract [50]
• Astragalus [51]
• Rhodiola – in cancer cells [52], salidroside activates it in muscles [53]
• Carnosine [54]
• Plumbagin(black walnut hull) [55]
• Glucagon [56]

 

[Murph]

A few years ago we had a lot of excitement and a big thread about mTOR. Although back then the idea was stimulating mTor, nor inhibiting!

https://forums.phoenixrising.me/threads/how-can-we-stimulate-mtor.49892/page-8#post-826089

mTor kept cropping up everywhere I looked, and at first that excited me. But by the end I'd sort of convinced myself that mTor is so central to cell behaviour that you'll find it in every study. A bit like how a study of cities will find people and a study of sewers will find pipes. It's definitely involved - but that observation isn't really sufficient because it's just such a major component of what you're studying.

In the thread above everyone got very excited about drugs that might stimulate mTor, but the important thing to know is exercise is supposed to turn it off via a thing called ampk. How does ampk work? When you exercise you use up ATP, turning it into AMP, and the job of ampk is to measure the ratio of atp to amp. when there's a low atp:amp ratio, ampk turns on and inhibits mTor. So, if this process was working correctly in us, pacing might be the best mTor stimulator.

This leaves us with 3 possibilities.
- Avik Roy and co are on the wrong track and mTor is too inactive, not too active. (nb they merely theorised active mTor as an explanation for the high agt13 they saw. They didn't observe active mTor directly.)
- Something is wrong with ampk such that mTor is still activated after exercise, not too inactived. This creates the autophagy problem they describe, and they are on the right track.
- mTor is fine and something else is causing the high agt13.

 

[Murph]

I'm intrigued that the scientists have active mTor as the source of the autophagy impairment. My understanding is that we would have inactive mTor.

Certainly if the whole Naviaux winter metabolism angle is right, we would have low levels of mTor activation. Hibernating animals have less mTor activation, as this squirrel study shows: https://pubmed.ncbi.nlm.nih.gov/22539739/

I strongly support their plan to make an animal model - animals models solve diseases fast. I love this picture here, i can really visualise the effect of the drug on the mice on the right.

But before treating mice with this drug that stimulates mTor and creates the problems with autophagy, i'd really like a bit more work on what is happening with ampk and mtor in patients around PEM. It would be wasteful to create an animal model that makes mice sick but doesn't have the key features of mecfs.

 

[Forummember9922]

Few studies showing that HHV6 and EBV, even HSV1 disable autophagy to give themselves an edge

https://www.hindawi.com/journals/jir/2015/546063/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248894/
https://www.tandfonline.com/doi/full/10.1080/15548627.2018.1536530
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554085/

 

[Osaca]

Few studies showing that HHV6 and EBV, even HSV1 disable autophagy to give themselves an edge

Yip and it's even worse. They don't disable autophagy, but hijack it for their own good.

That's why something like CP-COV03 looks so good even though realistically the free drug amount necessary looks currently unachievable.

 

[Consul]

I'm intrigued that the scientists have active mTor as the source of the autophagy impairment. My understanding is that we would have inactive mTor.

Well from what i understand mTor is a nutrient sensor that will try to obtain adequate resources for the cell, so if there is hypoxia going on because of the vascular dysfunction that many studies indicate it would make sense that mTor is activated. But could be more complex certainly.

 

[Rebecca under the papyrus]

Well from what i understand mTor is a nutrient sensor that will try to obtain adequate resources for the cell, so if there is hypoxia going on because of the vascular dysfunction that many studies indicate it would make sense that mTor is activated. But could be more complex certainly.

Hypoxia usually inhibits mTOR. mTOR promotes protein production and others when conditions and recources are good.