Things I’m reading or rereading and some extra bits.

I’m having big motivation issues and it’s making it harder to mentally assemble my next post so I thought I would do my reading list and share a couple of the things I want to work into the post. Hopefully this will jog things around. The stir crazy always comes back, it’s taking its time this time.

Understanding Emotions: Origins and Roles of the Amygdala.

In the last 2 years I did a binge on the amygdala in general to get a good feel for that part of the brain. It works as a “cognitive insertion point” which I think of as a place where you can draw on individual experiences to discuss a part of the brain. The amygdala receives and processes objects, and inserts direction and intensity of feelings into consciousness as well as a bunch of instructions for movement. It’s a “system 1” level structure as it requires no effort, you just feel it. A “system 2” structure is involved in effort in consciousness.

Novel Perspectives on the Development of the Amygdala in Rodents.

I finally decided to get more developmental concepts internalized. A flesh tube becomes brain parts and some of those parts migrate to make new brain parts. The amygdala is an “interface structure” and made from lots of meat that wandered in from elsewhere and sits next to things that also wandered in from elsewhere.

Development and function of the medial amygdala.

I paid particular attention to the central amygdala when I did my binge (CE or CeA). Over 90 links to articles on just that region. It’s the output subnuclei of the amygdala. The medial nucleus (ME or MeA) outputs to the CE and seems to be a junction between the senses and behavior. Stimulation of the CE produces strong salience (attention) to the point that rats will chew at an electrode that shocks them and so this nuclei features in addiction research. The ME when stimulated produces many kinds of behavior. (And in my last post I pointed out the posterior cortical nuclei seem to create feelings).

Organization of neural circuits underlying social behavior: a consideration of the medial amygdala.

Same thing but with a social behavior focus. Oxytocin discussion and how to tease apart the sensory from behavior parts of this nucleus. Since body maps are involved in movement maybe there’s a sensory body component that works with cuss words?

TRICK or TRP? What Trpc2−/− mice tell us about vomeronasal organ mediated innate behaviors.

Related to my last post. TrpC2 is a gene used in the vomeronasal organ and makes the accessory olfactory bulb severely reduced when deleted in mice. It also eliminates social aggression and effectively makes them pansexual. Female mice even scent mark like males in addition to mounting both sexes and thrusting away. The human TrpC2 is a pseudogene.

I want to post about these mice but I want to read more about a surgical counterpart, VNX mice with surgically removed vomeronasal organs.

This is an outline of how the stream of consciousness, feelings, and emotions seems to relate as a continuous looping process. And how attention can be moved around in that stream. We experience the world as continuously cycling and updating networks of neurons.

Emotions seems to come in approach-hold-withdraw kinds (or attraction/avoidance…), and fight-freeze-flight for an intensity spectrum. There is an emotional motor system that seems to govern approach and withdraw based on feeling. This feeds into what goes to the motor system proper.

What I want to do is remake this with the anatomy.

The next part came from some notes I took after reading about the structure of the autonomic nervous system. I’m trying to define and categorize all of the internal senses and feelings in preparation for finding them in the anatomy. If I missed any let me know! This should be things we all feel. It gets a bit repetitive as I’m looking at different ways of looking at the same thing, or just listing things to get them all.

Sense of Parts
Organs, muscles, bones, skin…

Sense of State
1) Sense of place in space: Proprioception
Special case: non-localized/soft/crude touch.

2) Sense of self-directed movement

Sense of Metabolic State
3) Sense of Nutritional State (hunger, specific hunger, thirst, starving…)
4) Sense of Digestive State (feeding, digesting, nausea, waste elimination)
5) Sense of Physical Integrity (Injury)
6) Sense of Chemical Integrity
Physiological (immune, O2, CO2, pH, pressure, temperature, hormonal…)
Arousal
Emotional state relative to (self, other beings, environment), feelings about.

External Senses
Smell
Vision
Hearing
Taste
Touch
Rotation
Acceleration, movement, and balance

Internal Senses
Internal parts: Introceception
Visceroception: sense of organs and muscles

Position and movement of parts: proprioception

Internal state: autonomic sense
Hunger
Specific Hunger
Thirst
Digestive distress
Waste elimination
Injury
Alertness/arousal and changes to (social hunger)
Heart rate, respiration,
O2, CO2, pH
Temperature
Immune system status
Emotional state relative to X

Looking for employment advice/inspiration.

In meat space I don’t do anything science related professionally. I wish I did. And this post is a request for employment advice. My situation seems difficult and hopefully there’s a solution. I’ve few ideas of my own for reasons I’ll explain.

What I’m doing.
Right now I’m doing janitorial work for a large auto shop. I started doing janitorial work at a medical facility while I figured out what to do with myself. That turned into figuring out my mental health which took longer than I expected, and maybe I still need what I’m doing but I want to start thinking. It’s a good job. No complaints there. There’s a tired part of me willing to just do this until I fall apart. I am in my late 40’s.

What I used to do.
Back in the 90’s and early 2000’s I worked as an undergraduate research technician. I went from entomology, to ecology and evolutionary biology, to plant genetics (actually epigenetics). I got my name into a couple of papers and even some electron microscope images into the journal Science. Things seemed promising.

But something happened in graduate school. I encountered technical problems and while my work was good, I was less efficient than I needed to be. In retrospect I was spiraling into depression and didn’t see it. I also got diagnosed with ADHD (which I knew about but haven’t fully figured out) and tourette’s syndrome (TS). I faced a choice, do I figure this out while attempting to finish a PhD or not? Given how hard it can be to do that I decided to finish with a Master’s degree in cell and molecular biology and do technical work. But this was the late 2000’s.

The financial crisis at the time made it impossible for me to land more than a couple of interviews. And I couldn’t stay unemployed for long. I decided that since I was able to do teaching assistant work I’d work on a teaching degree while working as a substitute teacher. What I got was worse depression, new PTSD learned helplessness, and anhedonia. I broke.

During this time I also became a huge brain science nerd while I figured out what the tourette’s syndrome was all about. I think I’ve done pretty good there but nothing is on paper. No track record. I went to attempt mental health technician and then just health technician and I wasn’t compatible with that. That was when the health institution I was working for offered me a janitorial position since I was struggling and willing to work otherwise. That was about 6-7 years ago.

What I want to do, and some complications.
Part of me misses the technical work. But I have almost 2 decades without using my degree. That’s a pretty big hole and I don’t know what I could do to get a chance to see how my skills are. A part of me is anxiety ridden about the possibility from previous experience. It seems like academia is out, but other than remembering that lots of those jobs were supposed to be stepping stones for others to get ahead in an academic career I don’t know how to approach it or if I want to. Private industry is similar. I feel like something would be less likely there with the gap in using my education.

Other than technical work, I don’t know. I’ve been buried in understanding why I’m the way I am with mental health and don’t know what to think about. This is complicated by part of my issue being severe life long PTSD and social anxiety and avoidance. It’s hard enough to think about and work on basic socializing. In retrospect the social avoidance hurt me professionally more than I realized. And the source of the avoidance is very early childhood combined with some social neglect. I’m working on it but I’ve little but pain in my group feelings. I can go through the motions but that only gets you so far with creative thoughts.

I do like to talk about brain science. Posting about it is hard because it’s a different social act than meat space interaction that we have an older evolutionary relationship with than symbolic marks. The process of doing videos would be as uncomfortable, and I’d need a new skill set. My recent posts are things that have been in my head for awhile that I wanted to get out, thoughts chasing each other around. There are positive feelings there but they coexist with the ever present negativity.

And I’m basically an educated amateur and would have to be able to show what I’ve learned. I could become a source of information about what terms and diagnoses mean for people somehow. There has to be a need for what I know and could learn more with direction, but for the emotional recoiling from society.

My big passion was origin of life research and I don’t think that such a thing is possible now. Those molecular biology posts were some things I am passionate about and I wanted to get all of that out of my head. Those thoughts have been chasing each other around in my head for years but given the state of academic science and the nation and my age it seems daunting.

I think that’s it for now. I’m not sure what sort of professional I should talk to or what to consider. My next step is to look at what is in demand at the state employment sites. If I think of anything else to add I will update this post. Otherwise I’ve got some ideas about a post about how feelings, emotions, and consciousness works using the amygdala as an anchor.

The human vestigal accessory olfactory systems and feelings.

I’ve spent a couple of decades reading about meat computers and I often think about where X human behavior fits best in the meat hardware. One of these bits of behavior is the very existence of things like contagious feelings, abstract feelings, cooties, bad words, profanity, vulgarity and similar.

In fact it seems inevitable that someone with tourette’s syndrome and a habitat of reading brain science would get here. Like I mentioned in the last post I don’t have that sensitivity. It was always what other people were sensitive to, and watching that very carefully, like an instinct. I think I found some things that get to this part of language via the olfactory system of all things, and a bunch of other things too. Bear with me, it’ll take some setup.

The senses and olfactory systems.

There are more than 5 senses but I’m sticking with the 5 traditional senses here. Every time we have a reaction to something we sense (think of a mosquito on your arm) that data gets processed into an object, sent to the thalamus, and then sent to the amygdala. Unless it’s the sense of smell. Olfaction is different. Olfaction gets priority access to the amygdala. This I think is related to smell as the oldest sense.

The mouse dual olfactory systems. OE: olfactory epithelium, VNO: vomeronasal organ, MOB: main olfactory bulb, AOB: accessory olfactory bulb, BAOT: bed nucleus of the accessory olfactory tract, BNST: bed nucleus of the stria terminals, MEA: medial nucleus of the amygdala, PMCo: posteriomedial cortical nucleus of the amygdala, PLCo: posterolateral cortical nucleus of the amygdala, ACo: anterior cortical nucleus of the amygdala, AON: anterior olfactory nucleus, OT: olfactory tubercle, aPC: anterior pyriform cortex, pPC: posterior pyriform cortex, LEC: lateral entorhinal cortex.

Here is a figure of the first sets of connections involving olfaction in the mouse. And most amphibians, reptiles and mammals. It’s that old, back to jawless vertebrates. I’ll be coming back to it. I adapted a figure from the following paper.

Subpopulations of Projection Neurons in the Olfactory Bulb. Imamura 2020

It’s a very ancient system. It’s also ancestrally a DUAL olfactory system. The olfactory epithelium (OE) and the main olfactory system (MOS) is one part (the green connections), and the vomeronasal organ (VNO) and the accessory olfactory system (AOS) is the other part (the red connections). You may have heard about humans and pheromone detection, if it were a thing, that’s the VNO. The VNO is a fluid pump for sampling of non-volitile substances that the OR can’t as easily sample through diffusion in air. Like hormones/pheromones, big, often non-polar molecules. Along with regular sniffing of orifices, faces and bodies in our ancestors.

The olfactory epithelium (OE) does smell in general, the VMO does non-volatile smell related to other beings including ones own kind. I’m emphasizing this because in a minority of creatures with olfactory systems, including humans, the accessory olfactory system is GONE.

The human vestigial accessory olfactory system.

We have a rudimentary VMO, there is a tiny remnant accessory olfactory nerve, and no accessory olfactory bulb (AOB). Our accessory olfactory genes are full of lots of pseudogenes (broken, mutated and not expressed). All of the vomeronasal receptors but 5 are pseudogenes, and those 5 are in the OE, not the VMO. The genomic basis of vomeronasal-mediated behaviour. Ibarra-Soria 2013

With that knowledge, one day while reading about the various behaviors the AOS seems to be able to manipulate I had a thought…what about the meat computer hardware just downstream from the AOB? Humans still have that! It occurred to me that these systems could be like feelings and behaviors cut off from olfactory control. A source of abstracted feelings and behaviors that we can use in language like abstract, non-literal language. Reminiscent of “phantom limbs” but much older.

Here’s the passage from the paper that stood out to me and gave me the thought.

“…pheromones are substances that are secreted by one individual and received by a second individual of the same species, in which they release a specific reaction, for example, a definite behavior or a developmental process” (Karlson and Lüscher 1959). Although this definition properly applies to many insect chemostimuli, it often falls short when applied to mammalian social chemosignals. Indeed, this issue has sparked some intense debate in the past (Doty 2010; Wyatt 2014).

Today, it is clear that the VNO is not exclusively dedicated to “pheromone detection.” For one, the VNO is critical for detection of predator odors, which are formally distinct from pheromones, and rather defined as “kairomones” (see below). Similarly, in snakes the VNO is important for prey detection (Halpern and Frumin 1979). Furthermore, contrary to the original definition of pheromones, many of the social chemosignals that robustly activate the AOS are not single compounds, but rather species-specific or individual-specific combinations of molecules in precise ratios (Wyatt 2009). Indeed, whereas pheromones are defined as intraspecies social signals that are “anonymous” with respect to the sender, many of the signals detected by the VNO serve to convey information about individuality (Hurst et al. 2001; Leinders-Zufall et al. 2004; Kaur et al. 2014; Ben-Shaul 2015). These include signature mixtures, which allow individuals or other social groups (e.g., families or colonies) to be recognized and distinguished. Finally, although pheromones, by strict definition, elicit a fixed and well-defined response, behavioral changes in response to many AOS signals can require learning and plasticity (Kaur et al. 2014; Xu et al. 2016), concepts that were long considered inapplicable to the AOS.

Signal Detection and Coding in the Accessory Olfactory System. Morhardt 2018

I’ll do this in order of information processing, from olfactory receptor, to olfactory bulbs, to feelings and actions related downstream brain meat.

Vomeronasal receptors, their ligands, and related feelings and behaviors.

A receptor is a protein that binds a specific molecule, its ligand. Here the ligands are odorants, and can be called vomerants for the ones that activate receptors in the VMO. There are 3 families of receptors typically found exclusively in the VMO. The interesting part is what binds them and the INNATE behavior effects that these ligands have (innate effects do not require previous experience).

Predators, and prey or food related vomerants.

Some creatures can leave scent trails that relate to preferred or safe food sources. Humans have a rich non-literal language for food and smells, things can “pass the smell test”. And humans have a language for other animals that we use as food sources, and unfortunately we treat one another as prey sometimes, grifters and “rubes” or “marks”.

Money might be in here as a “resource”. It’s not food but it has a sense of value from something.

First of all there chemicals related to predators and prey, or food in general. There is a chemical (2, 3, 5-trimethyl-3-thiazoline, TMT) from foxes that triggers freezing and flight in mice. Other predators can secrete other things too. Think about our language and how we can describe something as an external threat in a predatory sense. Rational or not. Something being “out to get you”, but not actually there at the moment.

One thing worth mentioning is how bigots, fascists and the like want to prey on other groups, but also have to spend so much time describing their prey as threats.

Conspecific” related vomerants, peers at the species level.

Many of the following observations were taken from The Accessory Olfactory System: Innately Specialized or Microcosm of Mammalian Circuitry? Holy 2018

There are chemicals produced only by male mice that trigger aggression and territorial behavior in males and females (ESP1, ESP=exocrine gland-secreting peptide, from lacrimal glands). There are chemicals only in juveniles that suppress the adult sex drive (ESP22). There are chemicals only present when a female is ready to mate (sulfated estrogens). Our language is full of non-literal uses of male and female, there has to be brain hardware for “other kind in the same species” at the least. And “other kind” can be age and sex flavored. (There is ESP36, excreted by all females tested and a subset of male mice, I’ve no idea what to make of that but it’s curious.)

None of this is prescriptive, I’m about what can and has been done with our language, there’s plenty of room for how we get individually sensitive here. Think about “think of the children/women” language, directing feelings about threat and vulnerability there. Think about language involving sex, and just how sensitive society is to it. Some wring their hands at the mere technical mention of sex organs and actions. This place also suggests chemistry in caregivers that create feelings in offspring. Mother pigs secrete a substance that reduces aggression in their offspring while they are nursing. Pheromones, binding proteins, and olfactory systems in the pig (Sus scrofa): An updated review. Sankarganesh 2022.

There are whole sets of chemicals expressed in different amounts in individuals that can determine individuals or family groups. MUPs, major urinary proteins are examples. Feelings about siblings and kin. Found in urine. Piss. Mice have dozens of MUPs, we have a single pseudogene. Why can people get “pissed off”? Unless there is brain meat for urine sensitivity.

And family groups gets us to tribal behavior, your own kind as competitors. The feelings involved in our capitalist hellscape that pit us against one another. How migrants are characterized as “taking our jobs”, when supposed job creators love elimination of jobs when they can, moving them to other places if they can spend less. Or just get rid of other humans entirely.

There is the ability to detect other species as competitors. Smell if this or that kind of animal is present but not a predator. Think competing herbivores. The way bigots compare others to vermin like a nonconspecific competitor. Rats. Mix competitor and predator feelings and maybe you get the “deep state”, an attempt to define elected political opponents as threats.

There are chemicals in feces that activate the VMO too. Hints at processing of kinds of conspecifics and digestive status. Maybe that is why things can be “shitty”.

There are chemicals that activate the VMO related to infection too. Mice can detect sick conspecifics. The feelings about disease are rampant in bigotry. Think about the homophobes that need homosexuality to be more disease ridden and their language. Think about how the homeless, disabled, or mentally ill are often treated as untouchable. And people refrain from interacting. Or the use of disease applied to migrants. Disease feelings badly applied. Sensing and avoiding sick conspecifics requires Gαi2+ vomeronasal neurons. Weiss 2023.

Meat computer downstream from the VNO.

I first got interested in some of the following regions of the brain because they are relevant to tourette’s syndrome (TS). There was a study of children and adults with TS looking at  the volume of the amygdala and hippocampus. Morphologic Features of the Amygdala and Hippocampus in Children and Adults With Tourette Syndrome. Peterson 2008

The short version is the regions I’m about to mention are larger in TS. And I point out that tics and urges are made of feelings and actions. Actions that can be denied at the cost of increasing tension. Including mental actions, obsessions. In TS at least, but the phenomenon comes to us all when it is about what we feel strongly about.

Going back to the figure I made, the MOB and AOB are the main and accessory olfactory bulbs. This is where the olfactory neurons send their signal after binding an odorant. It looks like the location of chemical identity when I read about it. It’s what is downstream from the bulbs where things get interesting. Remember, humans don’t have an accessory olfactory bulb. But we have the downstream hardware and it’s fair to think of the vestigial imprint of the accessory olfactory system. Not strictly tied to male, female, offspring, parent etc, but based on it and more plastic, changeable in humans. A computational source of feelings in the meat computer that use and abuse in thought and language. Severed from olfaction by our evolution.

PMCo.

First there is the posterior cortical amygdala (PCo), which is subdivided into posteromedial (PMCo) and posterolateral (PLCo) sections. These regions are stereotyped as olfactory regions because they are primary olfactory cortex for the olfactory system. The AOB outputs to the PMCo (red) and the MOB outputs to the PLCo (green). We still have both brain regions, though they have lots of names in the history of brain science (superficial cortical region, sCLR…).

In mice these regions are necessary and sufficient to trigger innate feelings about positive and negative feeling odors like food or predator odor. Mice with no history with foxes will avoid this odor. Activation of these regions with various manipulations in locations can create attraction or avoidance to locations. Directly making a feeling without the smell. The participation of cortical amygdala in innate, odor-driven behavior. Root 2014

In mice the PMCo is involved in social long term memory formation. If a mouse is introduced to a food through another mouse it will strongly prefer this food. This is a process called Social transmission of food preference (STFP) by the paper. It even overrides innate preferences as mice innately prefer cocoa to cinnamon and STFP will override that. The cortical amygdala consolidates a socially transmitted long-term memory. Liu 2024.

Humans still have a PMCo. It’s hard to find information about it but a brain region used by our ancestors for feelings related to predators, food, prey and others of its own kind seems like a place that could still be used for the same feelings. In all their greatness and awfulness. While we no longer go sniffing others for information we senses used with those things.

What we have managed to discover in humans is that these regions are related to detection of emotions in facial expressions and language. Emotional faces, emotion and feeling in language. Selective processing of social stimuli in the superficial amygdala. Goossens 2009. Amygdala subregions differentially respond and rapidly adapt to threatening voices. Fruhholz 2013.

In case anyone is interested the PLCo seems to contain an approach-avoidance map along its rostral-caudal (“front” to “back” -ish) axis and is interconnected with the PMCo. Control of innate olfactory valence by segregated cortical amygdala circuits. Howe 2024. I wish they also checked the PMCo but they didn’t.

MEA.

The MEA is the medial nucleus of the amygdala. Where the posterior cortical amygdala seems to generate feelings, the MEA seems to generate actions. As I read about the amygdala and its subnuclei the MEA seemed to be about “interactions with other beings” as its activation and activity relates to attack, defense, mating, offspring care,… innately. Self-grooming too which might make it about the self as a being too.

It gets direct projections from both olfactory bulbs in mice, and of course lacks AOB projections in humans. Were your MEA stimulated you would feel a powerful urge to move. Development and function of the medial amygdala. Prakash 2025.

Where you have movement you have body maps. Anatomy connections. Powerful innate anatomy feelings are a potential biological substrate for profanity/vulgarity. While the MEA is about movement, the way these words are used are often very active “fuck off/fuck you” “don’t give a shit”, pissed off”, “don’t be a dick/pussy” (oh the gendered difference there!). “Full of shit” is qualitative, a feeling. If I tried “full of fuck” that’s action oriented. So is “full of piss and vinegar”.

I still have stuff to read about though because mere mentioning of someone’s “dick”, “ass”, “pussy”, or “tits” isn’t action oriented but creates a tension, a feeling. It’s just that actions require anatomy maps so this seems a potential place for anatomy feelings. Maybe not everything the MEA does is directly action oriented and it contains or connects to body maps somewhere, and connects to the posterior cortical amygdala (related to anatomy feelings via mating in the past and such in the past) that establish feelings in anatomy without actions. These regions are interconnected. Maybe there are anatomy maps in the PCo too, but mice seem to be choosing their actions via feelings there.

How do I end something like this? I feel like there is more to say but I’ve pretty much covered the things I wanted to. The neuroanatomy of cooties and cuss words. The vestigal accessory olfactory system and human feelings.

Negative feelings about things.

I’m working on a larger piece about the accessory olfactory system and part of it has me introspective to the point of avoidance of others. So I’m going to post about it to clear my thoughts.

TRIGGER WARNINGS: profanity and the profane. This isn’t about good or bad, but about what it is and the categories it falls in. There are good and bad things here though, oh yes.

I’ve been puzzling over language and symbolic sensitivity. I have a different relationship with intensity thanks to tourette’s syndrome and language isn’t spared. When one is always intense inside the perception of intensity in language gets confusing. I’ll go straight to profanity and technical language about genitals and excretion. It never bothers me, it’s the sensitivity to others that I seem sensitive to. That negative empathy overload. I remember as a child riding my bike and just spewing out lots of forbidden words, and my father just going “I don’t think so!” like that’s a mature approach to your child. No understanding, just forbidden. And to this day I think my parents are full of shit.

There is a set of things that fall under profane that are hard to think about but important because I want to know WHY. They aren’t all popularly understood as profanity. Profanity in my experience are words of anatomy and action: fuck, shit, dick, pussy, ass, piss…

But the profane goes beyond that. The reasonable sensitivity to burning crosses and swastikas. The obsession of bigots with disgust and disease, like a homophobe that needs gay people to be more disease ridden. Or the hand-wringing and squeamishness that technical terms for reproductive anatomy brings.

Gendered language can fall in here too given the negative feeling that can be created here.

I don’t have this. What I have is an acute sensitivity to the feelings of others here for better or worse. Maybe my privilege is why I don’t have an equivalent for burning crosses and swastikas for myself, and maybe not. But it’s real and I want to write about what looks like the potential biological substrate for these things.

Right now I’m doing searches on vomerants, semiochemicals “social chemicals” that organisms make and detetect in their accessory olfactory systems, including things for predators and prey, a system we don’t have. Hopefully I have something useful to type.

Proteins related to purine biosynthic proteins, the big picture.

I want to put all of those protein domains in the previous posts into a larger context. Some of this I mentioned in previous posts in this series but they are worth mentioning again. I post a part of the big drawing to start.

Nucleotides do a set of things. I hope I have covered them all and there aren’t any things they do that I missed.

  • Nucleotides are made, in specific biochemical pathways, and separated into purine (AG) and pyrimidine (UCdT) pathways. These pathways merge with thiamine and histidine pathways.
  • Nucleotides are genomes, messenger RNAs, ribosomal, and transfer RNAs (and other associated RNAs). They base pair through polar interactions between their carbonyls (C=O) and amines (-NH3/-N=).
  • Nucleotides are the biosynthic source for other cofactors like vitamins. The output of purine biosynthesis becomes folate, flavin…
  • Nucleotides are dispensers for phosphate, and not just ATP. There are thematic differences the kinds of things ATP, GTP, and CTP dispense for.
  • Nucleotides are handles and escort molecules for cofactors including many vitamins, membrane components and some other molecules. And handles for amino acids during translation in tRNA.
  • Nucleotides along with amino acids are the substance of transcription and translation. The base pairing becomes patterns of amino acid sequence that determine protein sequence.
  • Nucleotides are signalling molecules, often when cyclized, alone and in multiples.
  • Nucleotides act as replaceable groups like in sulfur transfer and Adenylylation.

Hydrothermal systems, minerals and ocean chemistry seem to somehow expand into this.

Nucleotide biosynthesis.

First there is the variable of the biochemical pathways themselves. What was the early extent of vent chemistry generated nucleotides? Did the reactions race straight to inosine or AMP? Or did things accumulate at points like the first ring closure? Or glycine binding? Did glycine binding repeat in an early polypeptie? Maybe there was a population of 5-membered pyrrole (5-membered carbon and nitrogen ring) ring creatures that could catalyze things towards inosine?

Looking at part of the big drawing again the similarities between thiamine thiazole biosynthesis and stage 1 of purine biosynthesis are interesting. A 5-carbon chain is made from a 2C and a 3C (DXP), and it is combined with a modified glycine and sulfur. And right after purine first ring closure that molecule can be made into the second part of thiamine, AIR becomes HMP. There’s even an imine on glycine in both cases (C=N). There’s this interesting imine on aspartate in niacin biosynthesis too.

And where do the pyrimidines fit in with their ring synthesis and then attachment to ribose? Was there a point where pyrroles and pyridines (5- and 6-membered carbon and nitrogen ring) coexisted on ribose-phosphate chains? How does niacin fit in with ring creation and then ribose binding, and imine on aspartate?

And how do I think about the way the purines and pyrimidines have opposite relationships with ribose? Purines being built onto ribose and pyrimidines built and then put onto ribose. And niacin, NAD(P), built very much like pyrimidines, does that matter?

Genomes, RNA, and base pairing.

This involves interactions between strands of the same or different nucleotides. In DNA genomes and RNAs these are attractions based on polarity, but what about other interactions as one goes back? Can we count on today’s sequences being AGCU? (I believe it was once just RNA genomes) Maybe they blur down into base pairing between other 5 and 6 membered rings? Intermediates in nucleotide biosynthesis?

Was chemistry between strands a thing? Are genomes, transcription and translation just massive off-loading of functions from an ancestral molecule that did more than sit there as an information source analog? Did it make itself through chemistry it participated in as something that looked like a purine intermediate like AIR?

Nucleotides as biosynthic sources of amino acids and cofactors.

Nucleotides are the biosynthic source of the amino acid histidine, and cofactors like folate, riboflavin, and molybdenum cofactor. GTP is specifically what is dismantled for the cofactors, and ATP for histidine.

Maybe there are clues for the origin of ribose in how it is deconstructed in these things and tryptophan? PRPP is the ribose source in tryptophan, not nucleotides, but that’s part of the story too. After completing this more complicated drawing involving nucleotide metabolism I think about  being able to peel back later evolving parts of metabolism and trying to find connections to more ancient parts.

Nucleotides as phosphate dispensers.

ATP is the stereotype for dispensing phosphate for active site chemistry and molecular movement. But GTP does it too and specifically for translation and cytoskeleton proteins like microfilaments and microtubules, things that could be useful for getting around in cells or mineral systems. CTP sometimes drives cysteine attachment to make coenzyme-A and it plays a phosphate dispenser role in cell division (ParB, chromosomal partitioning), hydrolysis indicating a completed step. Otherwise all of the NTPs and dNTPs can donate phosphate to one another in interconversions.

Nucleotides as handles.

ATP acts as a handle for many cofactors like niacin, riboflavin, coenzyme-A, S-adenosyl-methionine, and thiamine. GTP and CTP acts like a handle for parts of molybdenum cofactor. All of the bases act as handles for kinds of carbohydrates ,UDP-glucose has the feel of a most ancient part, and CDP has a theme involving membrane components.

It’s interesting that deoxythimidine handles deoxycarbohydrates. A theme carried over. It makes me wonder about themes with ADP, UDP, and GDP as carbohydrate handles.

Nucleotides as the substance of transcription and translation.

This is what biology class covers. The actualized genetic code. The process where base pairing in DNA and/or RNA becomes specific amino acids joined in a polypeptide chain. Like the protein subdomains I listed for every protein on the big drawing. tRNA is another way that nucleotides are handles, but for amino acids.

Maybe it all goes to polyglycine originally. Glycine is involved in making purines, the thiamine 5-membered thiazole ring, and every other amino acid looks like a modified glycine. Which leads to another question, could other amino acids have been made right on early polyglycine? Or were they made separately like today and added to a polypeptide with glycine?

Nucleotides as signalling molecules.

Nucleotides are part of rapid intracellular communication networks as cyclized forms. Single nucleotides can be cyclized at the phosphate, or cyclic dinucleotides connected at their phosphates. And other forms with extra phosphates in different places that act as signals inside of a cell.

All that phosphate. Proteins detect specific phosphates and numbers of phosphates in specific locations in so many ways I have no problem with the idea that early biology emphasized it in protein domains. Maybe phosphate was in the very first parts of selection.

Nucleotides as replaceable chemical groups.

Here is the molybdenum cofactor part of the big drawing. Nucleotides are part of the logic of sulfur transfer to sulfur carrier proteins (red arrows and 1-3), here MoaD, 2 of which transfer sulfur to the molecule by replacing AMP (an adenylylation) added by MoaB. To a double glycine residue which is very interesting since I think things go to polyglycine somewhere in history. This also happens with ThiS in thiamine biosynthesis and I want to add that to the big drawing at some point.

This is an area that is largely unexplored by me like nucleotides as signalling molecules and nucleotides as handles outside of translation. It’s to the point where I may need a separate big drawing from everything nucleotides do in addition to the drawing that shows how they are made and what they are linked to in biosynthesis.

And that’s it for the tour of nucleotide biosynthesis, the proteins that carry it out, and their relationships with the rest of metabolism. I hope this has been interesting and others now find these origin of life puzzle pieces as interesting as I do. I may be short on answers but it’s about finding clues to how it may have happened. Being able to imagine how it could have looked given that we collectively probably won’t know for sure in our lifetimes. At least there is substance for the imagination.