The use of the term polarity has been confusing. But, it appears that the homology can be retined

As largre as the implications of this statement are, it has not been said as explicitly as this. research connections. Implied connections through thePPAR and seeking a new involvement of the Circular RNA as a super-gene family. Possible already reference. Aziz Sancar should be the one to tie circular RNA to Circadian.

Much more than this. This is understated and the references here support a more expansive assessment

Essential to fully grok. Chart out. Link to other regulatory systems

research these. the phosphofructokinase esp

and the hypoxia and cold response are connected. This may? be where. The peroxisomes are part the ER stress reponse as well.

Exercise has another known measurable benefit.. KYN alteration

So, this entire pathway, or segment, is dependent on mitochondria

Amen

Note-Cold exposure is the same pathway as hypoxia

This is the location of a few, IIRC, of the Sherpa genes. SNPs They not only have High Altitude Adaptation, but hae altered diabetic phenotyes

All of the above is great info and there are many suspects, the main current is PPARgamma. TheNrf pathways hold quite a bit of niftiness in the translation regulation, cap dependent, independent proteins and folding. Seeking some connection to, causative agent to the age related and stress related cascade hinges on mitochodria in some, (it certainly has its finger in the pie-- but so do many root level processes) Part of my diligence in the mito domain is the Anti-Streetlight effect. That is, we have looked everywhere else and, yes, tehre are constantly new revelations, but these areas of mitochondria gentics, translational regulation and defects(both-not all "errors" are errors), and ribosomal and tRNA changes have been excluded from research and thought to be mechanistis and stable non-changing variables.And now, that they are known to be ariable...muchwill have to be reevaluated

Pay attention. ER Stress, and the Integrated Stress Response as well as Unfolded Protein Response

Iinvolved in hearing loss, optic degeneration, and many familial genes.

The paraventricular axis is interesting and could relate to chronic pain. It also has some linkage to schizophrenia and possibly low latent inhibition, IIRC. yes.It is the area I thought. How very curious. The pain drug developed in the 70's was Thalidomide, a disaster in Britain as the Ramones sang about and the American doctor who stopped it recieved a Presidential medal and was then tasked with reforming our system of clinical trials that we use today. https://www.ncbi.nlm.nih.gov/pubmed/31009420

Danism: A cell in a diseased state does not respond the same way as a cell in a non-diseased state. This is essential and has many roots. Translation Regulation being the most controversial.

keep track of this sulfur molecule. It has turned up in other areas.

This could be interesting as well. Metabolic issues run through chronic illness. As do circadian dysfunctions, diabetes susceptibility,

There it is. What we would expect for an ancient system.

honestly never occurred to me.

Nice to see this kind of historical reference. the evolution of ideas by the favoritism ofone over another is dangerous juju and it has been shown many times in genetics

Ancient system. Dan-isms will be interesting. As an ancient sytem, it is likely invlved in the essential protective features of lie. Those that may have evolved in tidal pools, switching metabolisms or shutting down some systems depending upon environment.

RNA's are sugars--Both are essential, but, for instance, in the G2 Checkpoint, mRNA is firmly established to also act as a primary messenger.

The larger point of enumerating how much has changed since this paper, it that modeling systems, by definition, will have to as well. Tim is certainly well aware of all mentioned in the sidebar and more than I know. His knowledge is broader and deeper. I think there are many areas that AdderStone and Tim could potentially have in common. I was looking at his dynein work and the localization of mitochondria and adherence for anchors. In any case, by incorporating circadian messaging (melatonin (very important in the mitochondria, and/or Noctunin Circadian Rhythms and Mitochondria: Connecting the Dots.

A Robust Model for Circadian Redox Oscillations.

Mammalian Circadian Period, But Not Phase and Amplitude, Is Robust Against Redox and Metabolic Perturbations

The metabolites NADP+ and NADPH are the targets of the circadian protein Nocturnin (Curled).

Metabolic Cycles in Yeast Share Features Conserved among Circadian Rhythms.

Circadian acetylome reveals regulation of mitochondrial metabolic pathways

Mitochondrial H2O2 signaling is controlled by the concerted action of peroxiredoxin III and sulfiredoxin: Linking mitochondrial function to circadian rhythm.

Interplay between cellular redox oscillations and circadian clocks.

Study of the signaling function of sulfiredoxin and peroxiredoxin III in isolated adrenal gland: unsuitability of clonal and primary adrenocortical cells.

Mathematical modeling of circadian rhythms.

This is connected to an area Tim has a strong background in, the MAPK, p38 and the adrenocortico and PrxIII areas are essential in many areas. In short, IMHO, this is a fantastic match. It is an area of his expertise and is small enough to not need to entirely have a system modeled. Just that localized piece that is important to all.

He has a lab suitable and it can be done in yeast,

And, I thought tying Aziz in was a great idea.

There is a historical hindsight to scientific literature. One from this paper is the large amount of data of many types, and the ways in which it contradicted itself. Without the depth of insight from sequenced genomes from hundreds of species which revealed more motifs and knowing which were strongly conserved over the course of evolution, Crispr-gene editing, siglecell sequencing, and other recent techonology insights, RNA's large role and motiochondria's larger impact, it was a transition period

Today the list would include Riboswitches ( protein-less and can trigger from heat, pH, concentration of proteins, lack of protein, the same protein produced, etc). mRNA post transcription re-editing of the exons, Translation Regulation by selection of the tRNA, enhancer RNA groups, circularRNA, etc. Emerging Role of Eukaryote Ribosomes in Translational Control

Evidences suggest that according to the status, environment, development, or pathological conditions, cells produce different populations of ribosomes which differ in their ribosomal protein and/or RNA composition. Those observations gave rise to the concept of “specialized ribosomes”, which proposes that a unique ribosome composition determines the translational activity of this ribosome. The current review will present how technological advances have participated in the emergence of this concept, and to which extent the literature sustains this concept today

The view that is becoming more accepted, is that it is "often" the system acting exactly as it is designed to do. There is a set of altered pathways that purposefully reassign priorities. If in a salt/low water situation, the plant changes to a survival mode. Yes, in the worst cases something has gone wrong in the proteins of the diseased state, but, restoring a healthy state would still rescue the cell, system and organism.

While this is objectively true, it is the "Why does this mutation causes cancer now, and not before" that is the more relevant question. And, how are non-mutation laden cells induced into a tumour state?

The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity including the many cell types and states like the disease state..

The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs. https://www.google.com/search?q=Selenodiglutathione&rlz=1C1VFKB_enUS765US766&oq=Selenodiglutathione&aqs=chrome..69i57j69i61&sourceid=chrome&ie=UTF-8

True. But, we know now that riboswitches (discovered in bacteria in 2006), which were not really considered to be functional in mammalian cells, do not work in a "Pathway" at all. They are often their own switch, And, hindsight has us informed that many parts of the regulatory system are not coded proteins and operate alongside these protein actions.

Much seemed erroneous due to the determination that the non-protein coding DNA was 'junk', therby relegating 90% of the chromosomal DNA to insignificance. Crick himself made comment that this could not be true and McClintock with her "Jumping Genes" reiterated the point with many others. Today, it seems much is still attributed to "erroneuous" behavior that is codified in plants and yeast and not yet comprehensively covered in humans. Riboswitches, Ribosomal alterations for regulation, mitochondrial involverment, tRNA pieces as signaling molecules, and the diverse actions of RNA in its various forms. Riboswitches and the RNA World

Riboswitches are structured noncoding RNA domains that selectively bind metabolites and control gene expression...riboswitches reside in noncoding regions of messenger RNAs where they control transcription or translation. The characteristics of some riboswitches suggest they could be modern descendents of an ancient sensory and regulatory system that likely functioned before the emergence of enzymes and genetic factors made of protein

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

RNA is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics.

Mitochondrial Dysfunction and Damage Associated Molecular Patterns (DAMPs) in Chronic Inflammatory Diseases

Mitochondria have recently emerged as organelles which govern fundamental cellular functions including cell proliferation or differentiation, cell death, metabolism and cellular signaling that are important in innate immunity and inflammation-mediated diseases.

Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer.

mtDNA encodes for only a fraction of the proteins that are encoded within the nucleus, and therefore has typically been regarded as a lesser player in cancer biology and metastasis. Accumulating evidence, however, supports an increased role for mtDNA impacting tumor progression and metastatic susceptibility...evidence suggests that differences in mtDNA impact not only the cancer cells but also the cells within the surrounding tumor microenvironment, suggesting a broad encompassing role for mtDNA polymorphisms in regulating the disease progression. mtDNA may have profound implications in the regulation of cancer biology and metastasis.

It is certain that p53 deserves its nomer of "guardian of the cell", and that without th presence of words like tRNA, ribosomes, mRNA, translation that are the layers recently added on to the methods of action of p53 that the "disease state" was viewed as dysfunction.

This emphasises the absolute need to incorporate post-transcription and ribosomal translation regulation into the modeling sets. 40 Years of Research Put p53 in Translation

After 40 years of research, it appears more and more clearly that p53 is strongly implicated in translational regulation as well as in the control of the production and activity of the translational machinery. Translation control of specific mRNAs could provide yet unsuspected capabilities to this well-known guardian of the genome When compared to cytoplasmic mRNA steady-state levels, the significant alteration in translational efficiency accounted for about 25 to 50% of the p53-associated change in gene expression, with an equivalent increase and decrease in translation efficiency (Table 1). Overall, these studies indicate that, as expected, p53 activation is associated with a massive transcriptional reprogramming, accounting for 75–50% of p53-induced change in gene expression. However, in response to p53 activation, they showed an unexpected translational reprogramming of 25–50% of genes whose transcription and mRNA steady-state level are not altered by p53 activation.

The highest change in translation efficiency has been observed by comparing wild-type p53 and p53-null HCT-116 cells in response to serum starvation [19]. Translation is a high-consuming energy task, which is finely tuned to adapt the pool of translational machinery to the cell needs depending on the environment [74]. In response to nutriment deprivation as serum starvation, it is well established that global protein synthesis is reduced. However, repression of global protein synthesis in response to stress often co-occurs with an increase in translation of some specific mRNAs encoding proteins that are essential for cell...

It could be said, I would certainly make the point, that System Biology, by codifying the interactions, made clear that there were other actors on the stage.

In other words, without this very effort to find the "heuristic" effects of the complex systems then enabled, or even forced, the expansion of what regulatory systems are. We now face the challenge of incorporating the "'nomics" aspect of multiple data sets and reciprocal connections and causation in multiple frameworks.

Systems Biology Approaches Toward Understanding Primary Mitochondrial Diseases Multi -omics and metabolic modelling pipelines: challenges and tools for systems microbiology.

Part of the "hindsight pain" is knowing that the modularity is from bottom up. The enhancerRNA groups, the platforms and paraspeckles, the RNA groups are all congruent with modular groups. The tricky wicket is assigning "states" to them. And, that these states are not universally dual state, but can be "ratio" modulated.

or. and this is very likely. It is a riboswitch. Occams Razor is important at a cellular level. There are just too many steps. Yes there are times it is true. But, if we are discussing 'disease state motif"? No. The systems are anciect, conserved across all 3 kingdoms and even not our kingdom. This is, if I am correct, a happy thing. Much easier to model ** I wonder if applying delta rate measure (Z') using Zhang's method of reducing substrate can give further insight and even better define a reaction profile rate "acceleration" profile graph that can be used as evidence of riboswitch type, sensitivity, or distinguish by "graph" recognition a temporal basis of determination. See this work, which is examining the aaRS synthesis in looking for novel targets for tRNA modifications affecting "error" rates of codon matching. While I disagree with the premise that these are de facto "errors", and instead suggest that tthey may be Translation Regulation because these "error" mechanisms are highly conserved across kingdoms-- the potential to mediate some arms of the Integrated Stress Response, Unfolded Protein Response, Hypoxi/Cold adaptation, mechano-stress is present.

This is a double edge sword. Tinkering with something so fundemental to life is risky, but there are many anti-biotics that target this mechanism and new ones have been developed that act on the sites involved in the altered protein translation in stress response. The ones targeting Leu, or Sel may be the most interesting. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103669/

Great work. A logical mind and well reasoned. There would need to be a definition of MOTIFS, and reaction types (signaling types) that include the RNA's .

My "radio frequency tower broadcast" model is one very mportant one.<br> Riboswitches HAVE to be incorporated. And, non-membrane organelles, paraspeckles, platforms, circularRNA, whatever.

Again... WOOHOO. This is EXACTLY my thought process. And, the only way to go. You have heard me say it a thousand times. Modularity. State Dependent (motif)

The Ghost in the Machine is staring back at you. Fully understandable by current models. The old? Rubbish.

The stink of Bayesian math in science will forever irk me. It has been necessary, but the spell cast to invoke its use was because of a "ghost in the machine". It is decidedly still needed. But..... the return to the meticulous science that Tim does is essential. There is not a movement back to the benches in real ways. And.... we are at the finish line.

He is still ahead of his time here. Current models do little to account for this. A huge fault to me--recall me asking about pH? He was ahead of his time on so much and this is still not covered.

Robustness arises from having 2 GWD events. Four copies of the original regulatory system so that when one "broke", there was still another. Then, came the plasticity.

The real plasticity did not come until the nucleosome went from 2 compartments to 3 compartments. The Turtle is the last of the old, above the turlte, one sees the rapid niche specialitzation of an incredible diversity.

Every use of the word "rewire" is a call out to what was yet to come... "RNA is in control. DNA is just the hard drive."

More accurate to say that a new circuit board is activated as that section is bypassed or disabled.

On the contrary, the cell solutions are elegant and incredibly efficient with miniscule signal.<br> This is something he is later quite fluent in as he studies the migration of yeast towards pheremones.

This again was essential. His observation is spot on, and although it took som 15+ years of the Human Genome Project to get the human genome (as wrong as it was). We now have hundreds of organisms to see how evolution has used its repeating patterns. It is another perspective that simply was not available then.

Again, very much on the same page.

Good analogy. Redefined, it is quite apt. Still, it is agonizing to see the old paradigm struggle so.

Very disparate sources. Note the immediate focus on the "mutation" topic. The "environmental stress side, for instance ER is post Endoplasmic reticulum stress induces p53 cytoplasmic localization .. .p53 mRNA: an integral part of the cellular stress response | Nucleic ...

This is a novel pathway to treating all Integrated stress response diseases and may broad application to mediate the strength of response.