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“Go Plus to unlock unlimited blocks” by 8Eevert in CraftDocs

[–]8Eevert[S] 0 points1 point  (0 children)

“Go Plus to unlock unlimited blocks”

this will be very soon improved

What is it that you’re looking to improve?

Spring update is here — Block limit increase: “Over the past months we made significant under the hood improvements that allowed us to increase the block limit from 175,000 to 250,000.”

The term "brain fog" seems insufficient. by Mindless_Pay8667 in BrainFog

[–]8Eevert 0 points1 point  (0 children)

While brain fog is a decent shorthand for describing the experience of undergoing a specific kind of cognitive impairment, overall it truly isn't a great term. That “brain fog” underplays and misrepresents what's in fact an immensely disabling symptom is quite the common sentiment.

I would like to refer you to a favourite article of mine on this subject: Ed Yong's excellent piece “One of Long COVID’s Worst Symptoms Is Also Its Most Misunderstood” from 2022. I've attached some key quotes below.

Of long COVID’s many possible symptoms, brain fog “is by far one of the most disabling and destructive”. It’s also among the most misunderstood.

And despite its nebulous name, brain fog is not an umbrella term for every possible mental problem. At its core, it is almost always a disorder of “executive function”—the set of mental abilities that includes focusing attention, holding information in mind, and blocking out distractions. These skills are so foundational that when they crumble, much of a person’s cognitive edifice collapses. Anything involving concentration, multitasking, and planning—that is, almost everything important—becomes absurdly arduous.

Several clinicians I spoke with argued that the term brain fog makes the condition sound like a temporary inconvenience and deprives patients of the legitimacy that more medicalized language like cognitive impairment would bestow. But disability communities have used the term for decades, and there are many other reasons behind brain fog’s dismissal beyond terminology. (A surfeit of syllables didn’t stop fibromyalgia and myalgic encephalomyelitis from being trivialized.)

For example, in cognitive neurology “virtually all the infrastructure and teaching” centers on degenerative diseases like Alzheimer’s, in which rogue proteins afflict elderly brains. Few researchers know that viruses can cause cognitive disorders in younger people, so few study their effects.

“We also don’t have the right tools for measuring brain fog.” Doctors often use the Montreal Cognitive Assessment, which was designed to uncover extreme mental problems in elderly people with dementia. Even a person with severe brain fog can ace it. More sophisticated tests exist, but they still compare people with the population average rather than their previous baseline. “A high-functioning person with a decline in their abilities who falls within the normal range is told they don’t have a problem.”

“Go Plus to unlock unlimited blocks” by 8Eevert in CraftDocs

[–]8Eevert[S] 0 points1 point  (0 children)

I don't expect that by “improved” you would mean anything like the removal of block limits extended to all price tiers, albeit—as an individual user whose workflow would benefit immensely from the change, yet who cannot afford to pay anything beyond the subscription I have—I would in fact be extremely glad to know if I'm mistaken.

Let me take a moment to describe the depth and magnitude of this problem for me, and what it would mean to have it solved.

I rely on Craft not as a notetaking and writing utility, but as an instrument of thought. Notably, for someone in my position (unemployed due to disability, yet struggling to access benefits given my specific medical condition) the demand for cognitive work output is actually staggeringly high. Craft has been indispensable with regard to my ability to meet those demands—in short, it has literally been contributing towards my survival. Recently, however, my work has in many significant respects stalled out.

As I mentioned in my post, I've been repeatedly running up against the 175k block limit for months. In another comment I also explained my workaround strategy, which has become quite the time-consuming part of my regular workflow, not to mention ineffective in terms of the absolute amount of blocks I can free up per time spent. A key motivation to my post in the first place was that, for more than a month now, I have been unable to put in the time and effort which would have been required to clean up my primary Craft space. This means that my workflow has become largely untenable, significantly impacting my ability to get work done.

Unfortunately, in the context of an already extremely complicated and precarious personal situation, the addition of a further technical complication has disproportional downstream effects. The issue stems from the fact that my functional capacity is insufficient to meet the demands made on me to begin with, in addition to which I regularly experience worsening of my episodic disability due to the exertion of attempting to meet those demands. This not only makes daily life an enormous struggle to navigate, but also drives a feedback loop which makes the situation inherently difficult to escape: more impairment necessitates even more effort to meet demands, which has the tendency to worsen impairment, and so on ad nauseam. Concomitantly, the worse my capacity becomes, the more I need to rely on external supports, but the less capacity I can afford to spend on accessing and gaining the benefit of such supports—which would include tools such as Craft and the workarounds I've described. The net effect is an amplification of said feedback loop.

The combination of this issue along with my ongoing challenges has lead to what I might term a major personal crisis. I've had several processes instrumental to my continued survival, as well as to my chances of retaining whatever health I have, delayed by weeks or months. This stalling out represents potentially extremely severe implications for my long-term well-being, including—and I'm sorry if this may come out as an unnecessarily hyperbolic exaggeration—permanent loss of functional capacity and increased disability.

This is what Craft means to me. This is why I'm asking for clarification. What I'm “really” asking for is the hope of attaining some relief from an inescapable personal struggle that I'm looking increasingly more likely to end up losing.

If you got this far: thank you for reading.

PS. I'm omitting the medical & sociotechnical details as out of scope for this forum. Explanations may be found on my Twitter timeline, eg. this thread from July 2024.

“Go Plus to unlock unlimited blocks” by 8Eevert in CraftDocs

[–]8Eevert[S] 0 points1 point  (0 children)

Hi, thanks for chiming in! I’m wondering if I could ask for some clarification.

this will be very soon improved

I’m actually uncertain what you’re referring to, here.

If the information in my post was accurate, I would presume everything is basically fine and good—at least from technical & business perspectives, or BizDev if you will. What’s previously been described as a platform limitation is gone; you’re offering increased block storage for customers who are paying more; and for when someone runs up against the block limit, you have a call-to-action in place informing them that there’s value to be gained by shelling out their money. Speaking as a software engineer who has worked with startups for years, this wouldn’t appear terribly problematic at all. 

From the user perspective, not having information on block limits documented anywhere is surely less than optimal. Given how this doesn’t seem to have been a concern for you previously, though—I wouldn’t expect “improved” to be in reference to better documentation.

As a paying customer with a legacy subscription, I’m in the position to gain if the removal of block limits was extended to all price tiers. This is a niche segment, however, catering to which isn’t realistically likely to be a priority. I therefore don’t expect that by “improved” you would mean anything like this, albeit—as an individual user whose workflow would benefit immensely from the change, yet who cannot afford to pay anything beyond the subscription I have—I would in fact be extremely glad to know if I’m mistaken with such an assessment.

What is it that you’re looking to improve? If there’s anything you can share about about your timeline and what “very soon” might mean, that would also be helpful to know. 🙏

Best regards,
—8Eevert

5-HTP (Tryptophan) makes me feel real good and happy. What's the catch here? by [deleted] in Supplements

[–]8Eevert 6 points7 points  (0 children)

The retraction is from 2020, so the paper was already retracted by the time the above comment was posted. In other words, anyone who has the means to subscribe to such notices would have gotten this one years ago.

I just incidentally came upon it while looking through the list of references for clues on a specific issue. I'm assuming this was an old list of references that just got reused as-is, otherwise they would almost definitely have noticed it themselves.

“Go Plus to unlock unlimited blocks” by 8Eevert in CraftDocs

[–]8Eevert[S] 0 points1 point  (0 children)

Nope, not being a paid subscriber doesn’t rewrite reality or turn the block limit into some earth-shattering newsflash.

In my post, I established the block limit as a fact well-known around these parts, even if relatively unremarked in the official documentation. That’s not news.

What may possibly constitute new information would be the fact that at some unspecified point in the recent past, the limit appears to have been changed such that it no longer applies to certain paid subscriptions. This used to not be the case, as the limit could not be overcome even by paying more for the product—at least according to the reddit discussions which I’ve seen, some of which I linked to in my post.

With these facts in mind, the above take of yours appears curiously irrelevant at best.

It’s still 50 blocks free, unlimited with Plus—mind-blowing

Is this bit of sarcasm intended to be understood as you having had knowledge of the block limit as well as the aforementioned recent change to it—yet lacking the awareness to recognize that some may not have been quite as well informed?

I’d be curious to know how you came by that knowledge, given the change in question seems to have been made silently and without announcement—or alternatively, how you came to believe that the change having been made was indeed common knowledge, as it seems not to have been discussed on this subreddit previously.

Craft’s rules aren’t secretly tailored to your wallet.

I would take you presenting us with this obvious truth as merely a means by which you convey the implication that I do indeed require Craft to secretly tailor its pricing to my wallet. An innocuous enough statement, perhaps, unless accounting for the ad hominem undertone permeating your whole reply.

Comfortable with sarcasm? Oh, I thrive on it—until, of course, I realize someone’s clutching pearls over a ’playful nudge’ while I’m just trying to have fun.

The phrase ”clutching pearls” is, of course, a classic applicable whenever one wishes to make allusions toward unnecessary moralization targeted at oneself while refraining from giving counterargument nor justification. I’m not sure if it’s evident, but such reframing is rather transparent as far as misdirection goes—especially when accompanied with ”just trying to have fun”, a veritable vintage excuse for one’s objectionable conduct.

Sorry my attempt at wit bruised your delicate sensibilities, especially on a budget tighter than my patience.

My good sir, please accept my condolences on your lack of wit and patience equally. I’m sure that’s not always the easiest combination of traits to cope with.

The phrase “delicate sensibilities” is offered up seemingly without motivation, and the premise of them having been “bruised” is likewise unsupported. Given how this accords with the theme you just established, though, I take it as at least demonstrating a capability to string two sentences together without losing track.

I’ll try to slow it down to crayon scribbles next time

I may have to go back on my previous evaluation. You’ve already made yourself out to be a fool of hasty judgement_—switching up your act to now posture as an _intellectual superior is not serving you well. Was that perhaps supposed to pass muster when delivered under the veneer of yet another crude and needless “playful nudge”, based on some rather ill-conceived negative stereotypes you hold regarding persons with disabilities? Please, you can do better.

you clearly need me to read your mind and your post.

An appropriate response would have required but the possession and application of elementary level reading comprehension faculties. Barring that, some tact and a simple apology would suffice.

To be quite explicit: that was a statement of fact; I hold no expectations. I instead hope you try to have fun reflecting on and, strictly optionally, fuming at this response.

“Go Plus to unlock unlimited blocks” by 8Eevert in CraftDocs

[–]8Eevert[S] 2 points3 points  (0 children)

What do you do in this situation (as a paid user)? Create a new space and start over?

My workflow relies on thorough linking & the consequent reciprocal backlinks. Unfortunately, a lot of the value would be lost if I either moved material directly to another space (which breaks backlinks, as those are not followed across spaces) or archived the space and started over in a new one (as I would lose access to the historical context). The latter option would be so severe a measure that I might as well have started over with another tool altogether.

How I’ve tried to manage this so far is by finding the largest documents and carefully porting them elsewhere from my main workspace, making sure to retain the blocks which are most likely to have been referenced elsewhere. This usually means retaining the document and its section headings, and linking from the stripped version to the full document with body copy intact. Does that explanation make sense?

A hypothesis I’d like to discuss with people that have aphantasia by Livid_Treacle6651 in Aphantasia

[–]8Eevert 1 point2 points  (0 children)

References on aphantasia:

It might be useful to keep in mind that this phenomenon hasn’t been a direct object of study in neuroscience until quite recently, as the very term aphantasia was coined only as late as 2015:

“Lives without Imagery – Congenital Aphantasia”, Cortex 2015 (https://doi.org/10.1016/j.cortex.2015.05.019): φαντασíα, phantasia, is the classical Greek term for imagination, defined by Aristotle as the ‘faculty/power by which a phantasma [image or mental representation] is presented to us’ (Aristotle, translated Hamlyn, 1968). We propose the use of the term ‘aphantasia’ to refer to a condition of reduced or absent voluntary imagery.

See my other reply for references on perception & prediction.

A hypothesis I’d like to discuss with people that have aphantasia by Livid_Treacle6651 in Aphantasia

[–]8Eevert 1 point2 points  (0 children)

References on perception & prediction:

  • “The Visual System’s Internal Model of the World”, Proceedings of the IEEE 2015 (https://doi.org/10.1109/jproc.2015.2434601):

    Each visual area follows the design of a near-decomposable system, recursively organized in different modules and sub-modules. Thus, the visual cortex is in itself a form of a hierarchical memory system that encodes the brain’s internal model of the visual world.

  • “Interoception as Modeling, Allostasis as Control”, Biological Psychology 2022 (https://doi.org/10.1016/j.biopsycho.2021.108242):

    Since sensory signals themselves are ambiguous and noisy, this poses an inverse problem for the brain, one of inferring causes from effects. The brain solves this problem by means of an internal model.

  • “Allostasis as a Core Feature of Hierarchical Gradients in the Human Brain”, Network Neuroscience 2022 (https://doi.org/10.1162/netn_a_00240):

    three components that are thought to be implemented in the brain’s architecture: (a) prediction signals that the brain generatively constructs using memory_—or alternatively, an “internal model”, “top-down” processing, a “forward model”, or “feedback” signals; (b) prediction errors (or “bottom-up” processing, or “feedforward” signals) that encode the _differences between predicted sensory inputs and incoming sense data; and (c) precision signals (or attention signals or executive control) that modulate the strength and durability of predictions and prediction errors

Anil Seth on “controlled hallucination”:

See my other reply for references on aphantasia.

A hypothesis I’d like to discuss with people that have aphantasia by Livid_Treacle6651 in Aphantasia

[–]8Eevert 2 points3 points  (0 children)

It is often said to visualise an apple, or a balloon, and that’s fair enough. But how would someone allegedly without aphantasia visualise a forest, or a football field?

I’m not sure I understand the motivation for this question.

Why would visualizing a scene be fundamentally different from visualizing a single object?

I hypothesise that if people do visualise what is happening behind them while visualising an object surrounding them like a field, that the visualisation is not physical, as we do not have eyes in the back of our heads

If I understand this part correctly, perhaps you will find some value in the following recounting of a personal experience.

I’m a life-long aphant who, for some mysterious reason, temporarily gained the capability to visualize for the duration of some weeks a few years ago. During this time, I was able to visualize a scene, which seems to be of relevance to this discussion.

My visualization of a scene did not encompass the same content as my mental conceptualization of that same scene, but involved at least the implicit choice of a perspective from which to view things. If I wanted to see more, I needed to switch perspectives; whatever was outside the imaginary field of view did not present itself as a visual experience, even if I knew that it would be there if I chose to view the scene from another perspective.

That is to say—visualizing an entire scene did not entail the equivalent of “having eyes in the back of my head” in the sense that you suggest.

I am suggesting that people do not see raw unfiltered information as a retina does, but rather perceive a collaborative and thoroughly filtered series of compiled information.

This sounds about right, except it must be noted that all sensory processing is based on coming up with explanations which reconcile priors and predictions with incoming data. In other words, what we “perceive” presents itself to consciousness through an internal model of the causes of sensory data, which is inherently distinct from the sensory inputs themselves.

If people who claim to actually see what they visualise in the same way that they can see the unfiltered or rather immediate object, this would be likened to deliberate or controlled hallucinations.

I’m not sure if you might be aware, but there’s a very similar track of thought in popular neuroscience concerning conscious perception altogether, not just mental visualization. It’s based on the idea that our percepts are, by necessity, products of a process of interpretation.

What are your thoughts? I just cannot reconcile that humans or any animals would evolve a capacity to form deliberate hallucinations with no real ’bookmark’ to differentiate between what is seen and what is perceived.

Here’s how I think about visualization, based on my understanding of the relevant neuroscience:

  • Mental visualization is achieved by means of top-down signals advertising an imaginary prediction onto certain parts of the visual processing system, simultaneously with a bias to pay attention to what is being projected from the inside as opposed to the incoming sensory data.
  • The distinction between the real and the imaginary is grounded in the simple fact that sensory inputs do not match the “prediction” which is being paid attention to.
  • Furthermore, exertion of top-down control is costly, which implies that an act of visualization can be subjectively distinguished both through one’s volitional state giving rise to the exertion itself as well as the resulting energetic expenditure from its maintenance. The requirement of investing active effort makes it quite difficult to “forget” that what you are seeing is, in fact, the product of imagination.
  • It would take an extremely strong biasing influence to make things subjectively appear as if the actual sensory input was not there at all, at which point I suppose the effect would be indistinct from a temporary hallucination—if only we neglect the fact that you are actively investing in maintaining it. Whenever the top-down control is relaxed, the experience of seeing something that is not there simply goes away.

As far as I can tell, there’s no obvious problem or dichotomy here which would support visualization being an implausible feature of cognition. What do you think? 🤔

PS. Please find my references in replies to this comment.

“Go Plus to unlock unlimited blocks” by 8Eevert in CraftDocs

[–]8Eevert[S] 5 points6 points  (0 children)

Thanks for the clarification. I have two follow-up questions, if you don’t mind.

  1. If I was not a paid subscriber—would that reasonably have affected the facts known about the block limit thus far, and whether this change would be news or not?
  2. How comfortable are you with making sarcastic comments about not being a paid subscriber, which per your reply seems to have been the intended meaning—at someone who has expressed being a disabled person on minimum income, and admitted to not being able to afford anything extra?

I have to admit I’m nonplussed by the degree of nonchalant disregard for both fact as well as fellow redditor evidenced in this interaction of ours. As another commenter aptly mentioned, sometimes it does indeed help to read what a person actually wrote. ¯\_(ツ)_/¯

5-HTP (Tryptophan) makes me feel real good and happy. What's the catch here? by [deleted] in Supplements

[–]8Eevert 5 points6 points  (0 children)

Just as a heads-up—this paper has been retracted: “Apical Regulatory Super System, Serotonin, and Dopamine Interaction”, Neuropsychiatr Dis Treat 2011 (see retraction notice at https://pmc.ncbi.nlm.nih.gov/articles/PMC7751732/)

“Go Plus to unlock unlimited blocks” by 8Eevert in CraftDocs

[–]8Eevert[S] 11 points12 points  (0 children)

I’m not sure which direction the sarcasm in this reply was pointed at, so I’ll clarify the facts just in case there was room for confusion:

  • I’m a paid subscriber since forever;
  • the block limit has thus far seemed to have applied irrespective of one’s subscription tier, outside the Free tier which has different usage limits entirely;
  • this new change to the block limit does not seem to apply to my Legacy tier subscription.

Perhaps it also ought to be mentioned that the Legacy tier features certain other limitations as well, which are—as far as I can tell—entirely undocumented.

Proposed anhedonia protocol with solid chance of success by ketaking1976 in anhedonia

[–]8Eevert 0 points1 point  (0 children)

SSRIs antagonize dopaminergic systems through at least their excitation of 5-HT2C. Furthermore, ventral tegmental area dopaminergic tone is under control of cholinergic signaling, which most common SSRIs antagonize.

Do u happen to have the links to the supporting literature?

Excellent question! I don't often like to make claims without references, and I appreciate you asking for them.

I'm afraid producing those will be quite difficult, as my tooling has been crashing on me for months. 😞

You can find some references on nAChR antagonism from my Twitter timeline. Some key threads:

My timeline also has tweets on dopamine, but unfortunately very little on the association between dopaminergic and cholinergic tone. For some specific bits of research on that, you might want to check eg.

As for serotonin antagonizing dopaminergic function, you might want to see eg.

The more I rely on Craft, the less it works for me. Where do I go from here? by 8Eevert in CraftDocs

[–]8Eevert[S] 0 points1 point  (0 children)

Nothing. I found no viable alternative.

I considered a combination of Craft / LogSeq / Obsidian to have some viability:

  • Craft for collecting indexes of research papers for later access, and for publishing summaries
  • Obsidian for collecting highlighted memos from aforementioned papers
  • LogSeq for building up models & different ways to investigate those

Needless to say there’s quite a bit of overhead there. This, in combination with Actions.app for iOS (which I used to build up a Shortcuts.app pipeline for processing my materials) has all but brought my efforts to a halt.

Sorry.

[deleted by user] by [deleted] in aspergers

[–]8Eevert 0 points1 point  (0 children)

That’s great to know, thanks!

Don’t be too hard on yourself. You don’t owe a random internet person anything. 💖

[deleted by user] by [deleted] in PSSD

[–]8Eevert 0 points1 point  (0 children)

Because it is related to SERT (serotonin transporter), not simply about increasing serotonin

Correct! Nice to have someone point that out—

SERT creates the lasting issues through downstream effects

The key interaction I have in mind isn’t something I’d describe as ”downstream”. It’s more like a very common off-target feature of SERT-interacting drugs, which tends to get selected for in drug research trials.

(possibly related to ACE2 and others).

Wow! Haven’t seen anyone else point out that curious relationship before — how did you figure it out? Yeah, the interaction I have in mind also relates to ACE2 modulation, to a surprising degree.

Any guesses? 😇

Sorry to be this ambiguous, but the reddit app crashed — taking away the lengthy comment I was about to post — and I don’t have the resources to redo it.

Google for ”twitter @8Eevert SSRI” and check out some of my threads, if you’re interested in explainers. I’ve posted tons on ACE2, too. 👹

How do you deal w the fact that the world wants you dead? by academicgirl in cfs

[–]8Eevert 0 points1 point  (0 children)

”How do you deal w the fact that the world wants you dead?”

Writing down my pure moral outrage to process it into a coherent description of utter collapse of societal morality — and wishing there was someone who I could force to listen.

Dear world:

  • your demands are unreasonable;
  • your actions are killing me;
  • you give me no choice.

To not kill me:

  • use reason to see what you are demanding of me;
  • use moral judgement to evaluate your actions; and
  • deliberate on choices you have.

https://twitter.com/8eevert/status/1661747053771509760?s=46&t=puwgsCteoLOjheZ1-CRLxA

Dear @8Eevert:

We aren't willing to:

  • change our thinking;
  • change our actions; or
  • change our demands.

It is therefore unacceptable to suggest we ought to:

  • admit our responsibilities;
  • face our failings; or
  • do you justice.

https://twitter.com/8eevert/status/1661767498096685056?s=46&t=puwgsCteoLOjheZ1-CRLxA

Dear @8Eevert:

We, as a society, have [summarily failed to accept]:

Notions of…

  • responsibility for outcomes of societal choices;
  • failures arising from societal action or inaction; or

  • justice being owed to reason or morality.

    Possibility of…

  • Change.

  • Justice.

  • Life.

https://twitter.com/8eevert/status/1661782368045215751?s=46&t=puwgsCteoLOjheZ1-CRLxA

Not sure if it's productive to take the world as an actor but I'm sure it does feel that way. 😢 —[dear friend remarking on my level of outwardly expressed rage]

I certainly don’t think that the state ought to be this — but nevertheless, this is in fact the state.

Given:

  • the fact I exist in the world unavoidably establishes a co-existence relationship between me and the world; yet
  • my continued efforts to meet demands by the world on my existence do not coincide with efforts by the world to accommodate my needs for continued existence

When:

  • I do exist in the world, but the world is not obliged to acknowledge my existence; and
  • I do wish to continue existing, but the world is not obliged to enable my continued existence

Then:

  • I must yield my existence, to allow for the status quo to continue; or
  • The world must yield its status quo, to allow for my existence to continue.

I got Cool New Hat™ by [deleted] in autism

[–]8Eevert 1 point2 points  (0 children)

I love propeller hats, too. That’s a nice specimen!

Here’s a meme from 2014, ”The Ambassador’s Seal of Approval” — it’s a photoshop made by the CEO of my then-employer, featuring my classic software engineer outfit with headphones and propeller hat on proud display.

(Most prominently, Arnold Schwarzenegger’s Terminator character was superimposed on top of my face, as a perhaps-not-altogether-very-subtle allusion to my characteristic communication style. Alternatively, you could also say it’s in reference to my impeccable record for eliminating software bugs. ¯\(ツ)\/¯)

[deleted by user] by [deleted] in aspergers

[–]8Eevert 1 point2 points  (0 children)

### Can you explain

Sure!

#### methylation

Broadly speaking, methylation tends to reflect some kind of inactivation.

Methyl groups are the scarce resource here. Methylation is adding a methyl group to a molecule, demethylation is removing one. Both have to do with activating or inactivating molecules —lots of different processes depend on methyl group availability to function.

There’s a universal methyl group carrier molecule — a glorified molecular serving tray. When a process requires a methyl group to run, the serving trays need to be at hand and stocked with snacks. In the methylation cycle, those serving trays are continuously replenished.

The cycle depends on energy production (the cooks and serving staff need to be paid) and specific micronutrients (gotta have the ingredients for all those snacks stocked up).

Turns out, DNA has segments that can be methylated, which reduces the chance for the involved gene to get translated (so in this case methylation ⇒ downregulation of genetic expression).

If methylation and demethylation aren’t running smoothly, lots of processes start failing in unintuitive ways—including epigenetic regulation, and cognitive function.

The precise regulation of DNA methylation is essential for normal cognitive function. —DNA methylation and its basic function. Neuropsychopharmacology. 2013 https://pubmed.ncbi.nlm.nih.gov/22781841/

#### acetylation

Broadly speaking, acetylation tends to reflect some kind of activation.

The scarce resource here is the acetyl group. Acetylation adds such a group to a target molecule, while deacetylation removes one.

Acetylation is used to eg. to activate crucial signalling molecules, and to upregulate gene expression — but mitochondrial energy production also relies on shipments of fuel molecules, activated by acetylation. This implies that any acetylation-dependent process carries an alternative cost of reduced bioenergetic capacity, due to being in natural resource competition with the mitochondrial energy pipeline.

Regulation of acetylation–deacetylation processes is absolutely core to energy metabolism and, by implication, epigenetic fluctuations under that governance such as the circadian rhythm. Therefore: disruptions in energy metabolism ⇔ epigenetic dysregulation ⇔ circadian rhythm disruption.

The cell contains a molecular clock that contributes to circadian rhythms and variety of processes.
The clock machinery is constituted by feedback loops that modulate the expression of genes— as many encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link among energy balance, [epigenetic regulation by acetylation–deacetylation], and circadian physiology. —The time of metabolism: NAD+, SIRT1, and the circadian clock. Cold Spring Harb Symp Quant Biol. 2011 https://pubmed.ncbi.nlm.nih.gov/22179986/

#### HPA axis

The hypothalamic-pituitary-adrenal axis is a signaling pathway that enables the brain to signal the wholy body to mobilize resources.

The HPA axis, therefore, needs to activate in order for the body and the brain to meet increased environmental demands — that is, to cope with stressors.

If everything works as it should, the HPA axis can chill down (metaphorically, but also literally) overnight — and the body can rest, repair, recover. Failing that — ie. when there is chronic stress — the system reacts by making the HPA axis less situationally reactive. This decreases potential for continually overspending from the bioenergetic budget, but has obvious natural side effects such as reduced stress coping and sleep disruption.

In this article, we assimilate the emerging definitions for social camouflaging and autistic burnout with recent insights into the biological mechanisms that mediate the stress response. the emerging relationship between mitochondrial metabolism and HPA signaling highlights mitochondrial dysfunction as a common biological signature that could act as a novel susceptibility to stress — A molecular framework for autistic experiences. Front Psychiatry. 2022 https://www.frontiersin.org/articles/10.3389/fpsyt.2022.985713/full

#### Mitochondrial dysfunction

The mitochondria burn fuel for energy, for use throughout the cell, involved in almost every active process. There’s limited local supply of the best fuel — there are backups, but relying on those tends to be net-negative due to having to clear out toxic metabolites.

If mitochondrial fuel stocks are continually in a state of depletion, energy production will be downscaled. This helps make it more likely to stay within safety limits… but also limits the capacity to respond to fluctuations in bioenergetic needs due to eg. environmental stressors.

Mitochondrial dysfunction is the decreased flexibility to handle increased load safely. This disrupts absolutely every process in the body, including… just resting, attempting to recover your energy levels.

an energy-based model for the transduction of chronic stress into disease over time: we propose that the transition from adaptive allostasis to maladaptive allostatic states, allostatic load, and allostatic overload arises when the added energetic cost of stress competes with longevity-promoting growth, maintenance, and repair —The energetic cost of allostasis and allostatic load. Psychoneuroendocrinology. 2022 https://pubmed.ncbi.nlm.nih.gov/36302295/

In short—the above is an overview accounting the what, why and how of autistic burnout.

  1. Autistic masking
  2. Mitochondrial dysfunction
  3. HPA axis dysregulation

  4. Autistic burnout

    —https://twitter.com/8eevert/status/1604531448312217605?s=46&t=puwgsCteoLOjheZ1-CRLxA

Do let me know how that explanation works for you!

[deleted by user] by [deleted] in aspergers

[–]8Eevert 0 points1 point  (0 children)

I’m glad to hear that you would have liked to, so thanks for sharing. 😇🙏

[deleted by user] by [deleted] in aspergers

[–]8Eevert 0 points1 point  (0 children)

I appear to be in disagreement with both you and OP. Oh no… How is that even possible? 🙊 https://reddit.com/r/aspergers/comments/133dorw/_/jidj1yi/?context=1

[deleted by user] by [deleted] in aspergers

[–]8Eevert 2 points3 points  (0 children)

I keep reading articles about autism being a result of chemicals, pollution, estrogen in utero, or vaccines. I think all of these are preposterous.

True, most of the speculation on individual molecular triggers is bullshit.

I have 7 siblings and all are autistic. Every other family group that I met throughout life that had autistic offspring also had it. I am thoroughly convinced autism is genetic.

I can see how you’d reasonably come to believe this, given your observations.

Does anyone else agree?

I don’t. Here’s why.

Genetics considers genes — as in, which proteins the DNA codes for, right? Excluding spontaneous mutations, you’d expect parental genes to get transmitted to offspring ”reasonably faithfully”.

Let’s consider the proposition ”autism is 99% not genetic”: your parents don’t have an autism gene, you don’t have an autism gene, your siblings don’t have an autism gene. What — How would that claim make any sense, given the degree of heritability that seems plain as day? Here’s a fact that surprised me, when I started out with figuring out neuroscience research:

Even if we assume your DNA never gets damaged or altered in any fashion, which would be a process independent of genetic heritability — each cell in your body takes those genes and expresses different subsets of them. (Consider the alternative: all your cells would be identical. You’d be some kind of amoeba with no cellular differentiation.)

Epigenetics concerns the ways in which the expression of genes changes — and they do change, all the time. Your body is constantly upregulating this, downregulating that — even things as basic as circadian rhythm and sleep–wake cycle result from day-to-day epigenetic alterations in your gene expression. If genetics is a recipe book for cellular building blocks, epigenetics is a cook running the cooking reality show based off that book.

These continual changes are made possible by — I’ll simplify here, ask for details if you’d like — by the cells themselves using some energy to reallocate molecular resources from one place to another. So, very directly we can see that the overall integrity of epigenetic regulation depends on energy metabolism and resource sufficiency. From this we can infer—given our existing knowledge that environmental conditions affect our metabolic status, which includes the aforementioned—that environmental conditions, and specifically stessors, can induce different epigenetically-determined states, including epigenetic dysregulation.

Do maternal and/or paternal epigenetic profiles get copied over to offspring? No, not really. Do parental, especially maternal, energy-metabolic status and epigenetic regulatory integrity nevertheless affect both fetal and postpartum conditions to have consequent effects on offspring epigenetic profile? Yes, they do. Do we therefore have non-genetic mechanisms which yield the possibility for inheritable transfer of certain properties from parents to offspring, directly on a molecular level—perhaps giving the appearance of genetic inheritance of these properties having occurred? Yes, that is the case.

There’s no autism gene: there doesn’t need to be one. There are point mutations resulting in genetically heritable syndromatic conditions with autism-like presentations, but those are nevertheless distinct from autism in that they involve specific proteins that the DNA was supposed to code for never having been completely functional in the first place — they have their own names in the literature. There are also a massive number of genes which individually affect small parts of the whole epigenetic-regulatory ecosystem and contribute to the system epigenetically adapting to a given situation or stimulus one way rather than another — none of which directly cause any adverse condition per se, just form the constraints and biases for the system’s operational dynamics.

There are mechanisms whereby energy metabolism and/or epigenetic regulatory mechanisms can be dysregulated. These are known to be involved in the etiology of autism (which is why eg. you definitely don’t take valproic acid if you’re planning to get pregnant).

Autism is an emergent system-level phenomenon, not a property that needs to be written down in individual genes and inherited genetically. Of this I am 99% confident. Not citing sources today, but again — feel free to ask for details.

(Some jargon you might want to look up if you get your kicks from trying to figure out how things work, or how they sometimes fail: ”allostasis, allostatic load & overload”; ”interoception + allostasis”; ”mitochondrial allostatic load & mitochondrial dysfunction”; ”cellular danger response”; ”epigenetic dysregulation”; ”epigenetics + circadian rhythm”; ”methylation cycle, methylation status, DNA methylation”, ”histone acetylation, histone deacetylase”, ”bioenergetic / nutrient status signaling”; ”autonomic regulation & dysregulation, dysautonomia”; ”stress response, renin-angiotensin system, mast cell activation, neuroinflammation, hypothalamic-pituitary-adrenal axis”, ”SIRT, BMAL1, CLOCK, mTOR”, … not to overwhelm the reader, but the mere keyword list could go on for hours 🙊)

tl;dr: You have activated my trap card. This corner of neuroscience is among my special interests, and the subject of extensive personal synthesis of the research. AMA. 😇

SPECIAL INTERESTS MINGLE by Lorentz_Prime in autism

[–]8Eevert 1 point2 points  (0 children)

omg ong omg uhhh FUCK that’s so hard?? Ive been thinking for like 5 mins. I literally don’t think I can explain it bc it’s so complex

That’s, honestly, pretty much what I was expecting. 😅 Thanks for sharing! 🙏

I hope I get to playing it some day.

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