Vast Complexity of Immune Micro RNA Signals

PD MiR-155_secondary_structureImmune cells travel independently and depend on signals for their activity. Called the “wireless” brain, immune cells communicate with many other cells—neurons, astrocytes, microglia, blood vessel cells, intestinal and skin lining cells, and tissue cells. Signals help develop special capabilities, such as T cells controlling food reactions (see previous post). Signals maintain immune cells for many years as memory sentinels for particular infections. Signals tell where trouble is occurring and guide cells across difficult terrain to locations of inflammation and trauma.

Immune cell communication includes secreted molecules of all kinds and elaborate sets of information molecules in vesicles. Recently, the importance of micro RNA signals has been discovered. Research shows that immune micro RNA signals are vital for most immune functions. Micro RNA interact with all other signals such as cytokines, neurotransmitters, lipids, sugars and peptides. This post will review what is being found in these incredibly complex overlapping communication systems and the vast complexity of immune micro RNA signals.

Making New Blood Cells

Mikael Häggström wiki Hematopoiesis_simpleIn order to make various blood cells, genetic mechanisms are highly regulated, but not totally understood. All blood cells appear to come from lines originating with one stem cell called the long term haematopoietic stem cells (LT-HSC). These long-term cells reproduce themselves and make other more specific stem cells called short term stem cells (ST-HSC). Short-term stem cells make limited stem cells (called multi potent progenitors or MPP) that can make a small variety of different blood cells. These stem cells produce even more limited stem cells that make either myeloid cells (common myeloid progenitors (CMP) or lymph cells (common lymphoid progenitors or CLP).

The many different immune and blood cells are needed for different circumstances. Short or chronic stress stimulates particular cells. Long-term stem cells must survive inflammation, illness and aging. Stem cells are directed by signals of many types and epigenetic tags. Non-coding RNAs are vital signals in this process and the complexity of these signals is just now being worked out. Micro RNAs help balance the need for more long-term stem cells versus new blood cells. There are many ways that these signals operate. They affect the activation of the stem cells, their movement and the number of times they divide.

From Kelvinsong

From Kelvinsong

Micro RNAs do not code for proteins, but rather bind to specific messenger RNAs altering their function. What makes this complex is that signals from immune cells involved in inflammation change micro RNAs. They can alter how DNA makes the RNAs. They can affect how small RNAs are stabilized to maintain their functions. They can affect how they interact with the messenger RNA. Stress responses are vital in how these small micro RNAs are utilized. If these mechanisms go awry, then drastic consequences can occur, such as leukemia and autoimmune diseases.

Previous research into micro RNAs function in immune systems was based on protein transcription factors that alter DNA function directly. However, recent research shows that regulation is much more complex. One significant method of regulation involves genes that are particularly sensitive to the question of quantity—that is genes where a small change produces a major shift in the numbers of cells.

B0003644 Massed small stromal lymphocytes - colouredAnother way they are important is in choices between producing two different immune cells. This is especially the case when the choice is close and small input can have a big result. These small microRNAs appear vital for positive and negative feedback in these close call situations. Seemingly small distinctions can have major impact on disease. In fact, multiple small microRNAs can work together in these circumstances either cooperatively or the opposite. There are now a large number of microRNAs found in these regulatory networks. Research is beginning to use them as treatments.

Specific mechanisms have been discovered. But, they mostly refer to the effects of one micro RNA even when it is known that many interact. The research is just beginning.

How do MicroRNAs Work?

From OgreBot

From OgreBot

miRNAs work by altering messenger RNA and can totally change the dynamics of protein production. They are made by RNA polymerase and then cut by several enzymes that are part of the microprocessor complex. A precursor pre-miRNA is transported from the nucleus into the cytoplasm. There it is cut again into double stranded RNA by Dicer enzyme. One of these strands is taken into the large RISC complex. RISC stands for RNA-induced silencing complex. It is used by RISC to bind to messenger RNA code.

From Lonugget

From Lonugget

Each of these steps can be regulated in the immune processes producing more or less of particular microRNAs. Most of the time, microRNAs stop the function of the messenger RNA interfering with proteins. But, they can do the opposite and make more proteins.

“Micro RNA” is written as miRNA. Particular miRNAs are termed miR-xxx. This post will use this nomenclature for individual miRNAs. But, also sometimes use the general term micro RNA as well as miRNA.

Feedback Loops

A positive feedback loop starts with a transcription factor (A) producing the micro RNA that is important to make a protein. Another factor B inhibits A. But, when A inhibits (B), this increases A and produces more of one type of cell.

Negative feedback involves A which stimulates the pathway. B is crucial for more A. When A inhibits B, it inhibits more A.

Switches are systems which trigger two different genes. These systems involve at least three factors that can either stimulate or inhibit. An example is A regulating B and C and B regulating C. Such as system has at least 8 different scenarios. These can have many different results in immune function.

There are situations where the same micro RNA can have different effects, which also confuses outcomes.

Some processes involve alterations in narrow ranges of too many and too few proteins. Other processes affect the tipping point between the two forces. What complicates this is that the amount of RNAs determine whether they are utilized. Below a certain concentration they are inhibited and above a level they are saturated and ignored. These specific points are part of master regulation of whether a particular cell will be produced. Complicating this even further, there are competing types of RNAs that confuse and alter the critical threshold point.

Stem Cells

PD BOne marrowStem cells in bone marrow must produce all the necessary immune cells throughout the body. With and without stress, micro RNAs are vital in this process. One vital element is a nuclear process that binds the cap of the RNA and errors in this process create disease. These involve miR-155, let-7 and miR-21.

miR-125 has two members (a and b) and maintains stem cells in normal conditions. They stop messenger RNA that produces important proteins for cell suicide. The mechanism is very complex with many pathways involving miR-99b and let-7e. In research, more miR-125a, working in a cluster, increases cells by 10 times and involves the vital factor related to cell death and reproduction, BCL-2. This can induce leukemia of both lymphocytes and myeloid cells.

PD MiR-21_StructuremiR-125b has a different cluster of miR-99a, miR-100 and let-7c. This leads to activation of multiple very complex pathways. Two competing cytokines regulate more stem cells versus more derivative cells. These competing forces create an important switch.

miR-29a is important in bone marrow stem cells. It pushes in the direction of myeloid cells and is related to cell suicide as well.

miR-22 and miR-124 are involved in tags that are placed on DNA. These impair the start of the reproduction cell cycle in the stem cell.

miR-126 regulates the number of stem cells and can stimulate more cells without appropriate regulation of producing too many cells. Normally, a process called exhaustion will stop processes that have gone awry. This leads to stem cells causing leukemia.

Let-7 is a family of micro RNAs that are modified by tags. Complex feedback loops both positive and negative regulate how fetal cells become adult versions.

miR-193 and miR-132 are stimulated by signals from immune cells. One inhibits particular cytokines related to producing blood cells. The other targets pathways that work for and against certain cytokines. Two other micro RNAs, miR-221 and miR-222 interact in these cycles in complex ways.

miR-212 and miR-132 helps the aging stem cell work against accumulation of reactive oxygen. These are part of a cluster that is increased in aging cells. These two buffer the levels of essential proteins to combat effects of aging.

Immune Responses

From Blausen

From Blausen

Vital cells in the myeloid line include macrophages that are highly regulated by micro RNA processes. miR-155 and miR-146a are stimulated by other immune cells in both dendritic cells and macrophages. Pattern recognition receptors and many cytokines trigger NF-κB and activator protein 1 (AP-1). These inhibit miR-155 and miR-125b and stimulate let-7, which triggers other pattern receptors.

The result of this stimulation is rapid increase and then stopping, creating a pulse of activity. Antagonistic forces increase inflammation and more macrophages.

Granulocytes

B0004150 Mast cell showing histamine granulesGranulocytes are a category of white blood cells that have different compartments of molecules that are seen by microscope. The most prominent is the leukocyte, but others include eosinphils, basophils and mast cells (with histamine granules).

miR-223 dramatically affects granulocyte development. This microRNA is involved in multiple ways including a switch. One result is more of all granulocytes. Others are vital as well, miR-21, miR-130a and miR-196b.

Natural Killer Lymphocytes

T cells can produce large numbers of natural killer cells to attack microbes and cancer. miR-181 is vital for early production. These processes stimulate many cytokines including IL-4 and IL-17.

Research into micro RNA effects in platelets and red blood cells is just beginning and little is known. miR-150 increases megakaryocytes and miR-144 and miR-451 increase red blood cells impacting on several genes. miR-221 and miR-222 are increased in mast cells.

T and B Lymphocytes

From Bobologist

From Bobologist

There is a large complex literature of micro RNA effects related to lymphocytes. B-lymphocytes have multiple levels of stem cells—the pre-pro-B cells, pro-B cells and then pre-B cells. Different genetics networks produce each of these. Vital genes to produce immunoglobulin start in the pre-B cells. Newly minted B cells produce the critical receptors. Micro RNA effects are complex. At first miR-181 was thought to influence the entire process. Many different micro RNAs are being found that affect production of this sequence of cells.

miR-150 can cause cell death in pro-B cells. This microRNA inhibits a factor that can lead to cancer. This micro RNA and miR-132 have vital antagonistic roles that buffer the switch for this transition.

PD P53_pathwaysThe vital p53 stress pathway (cell death and reproduction) stimulates miR34a but inhibits pro-B to leading to pre-B through a gene that is known to cause cancer (oncogene). Another cluster miR-212 and miR-132 inhibit the previous step of pre-pro B to pro-B. Both of these mechanisms create switches. To continue concentrations must go above thresholds. A different mechanism has miR-17-92 clusters that stop cell suicide pathways and make the transition go through.

A latter step makes plasma cells from B cells by inhibiting miR-21, which can cause cancer. This transition needs miR-155 and miR-148a, which have multiple complex pathways and feedback loops.

Fetus B cell development veers towards a subclass called B1 that can not produce memory cells. Let-7 drives the transition to adult B2 cells that do have memory.

B Cell Immune Function

From Bobologist

From Bobologist

Micro RNAs are vital for the B cells antibody response. miR-142 is necessary for antibody production. miR-146a is necessary not to produce antibodies against human cells. miR-155 was the first noted to be vital in the special process B cells use to hone antibodies to make them more accurate. This process somatic hypermutation is also regulated by actions of T cells (see post). These create positive feedback. Negative feedback is created by miR-181b. Another miR-210 also causes negative feedback with defective antibodies. miR-217 interferes with DNA repair and helps cause lymphoma (cancer of lymphocytes).

T Cells

From BruceBlaus

From BruceBlaus

T cells borne in the bone marrow travel to the thymus to develop and be trained. T cells pass through training to produce vital receptors and go through a series of stages where they must pass tests of producing these receptors. Many different micro RNAs have recently been found that are vital in this training process to help get over some of the check points in T cell training. miR-181a serves as a switch combined with several complex pathways. It can impair several checkpoints.

One example occurs in the production of T helper cell 17, which is stimulated by several cytokines. A previous post showed how specific helper T cells are stimulated by food particles in order to avoid autoimmune reactions to that food (see post.) One of the main receptors works in pathways with miR-155. Another interacting pathways is triggered by miR-21 and an opposite one by miR-301, miR-23 and miR-326. All of these are counteracted by miR-20b. Smaller roles in this vital stimulation of T cells are through miR-212 and miR-132.

When T cells are triggered by material from an invading microbe, the complex process of activation occurs. This includes several other cells participating in the final decision. Once activation occurs, then the T cell becomes a powerhouse of trouble, making armies of killer cells. Very recent research shows that this process involves the interaction of multiple micro RNAs.

T cell modificationsmiR-181a affects the receptors threshold for action and encourages production of new cells. A micro RNA cluster miR-17-92 has two components in this process, miR-17 and miR-20a.

Members of this cluster independently affect multiple pathways that ultimately have the same result. miR-19b and miCR17 both help produce special T helper cells. miR-182 gives positive feedback and pushes the process further. miR-24 also helps and miR-27 inhibits through several cytokines.

Two micro RNAs produce inflammation, miR-146a and miR-155, but in antagonistic ways. They both affect specific cytokines in different ways.

Blood Cancers and Autoimmune Diseases

WC Lung_cancer_cell_largerVery complex interactions of micro RNAs are involved in multiple sclerosis, lupus, inflammatory bowel disease and blood cancers. Micro RNAs that stimulate cancers are now called oncomirs, similar to the term oncogene for a gene causing cancer. Many other micro RNAs suppress cancer through similar pathways.

miR-125b is an oncomir causing both cancers of myeloid (white blood cells) and lymphocytes. They interact with pathways in stem cells that make new cells. miR-28 suppresses lymph cancers. When miR-28 is inhibited, cancers are formed. miR-21 stimulates B lymphocyte lymphoma and inhibition of it kills the cancer. There are many other complex pathways related to micro RNA clusters that have effects on cancer.

Chronic inflammation can cause cancer. miR-155 interferes with inflammation regulation causing leukemias.

Multiple micro RNAs appear to be involved in autoimmune diseases but the mechanisms are not yet clear. Multiple different pathways involve miR-20b, miR-21, miR-212, miR-132, miR-301, miR-326 and the cluster miR-17-92. One mechanism includes miR-146a affecting B and T cell activity and miR-155 leading to arthritis against collagen molecules.

Vast Complexity of Immune Micro RNA Signals

From Agor153

From Agor153

Only 2% of DNA codes for proteins and fifty percent are jumping genes. This leaves the possibility of 48 percent of DNA making large and small non coding RNAs. This is thirty times greater than the DNA that codes for proteins. There is no way to know how much of these are important regulatory particles. But, ENCODE (Encyclopedia of genetic elements) shows it is possibly 20 percent, which is ten times greater than coding DNA.

In any case, it is clear that a vast number of different large and small RNAs are vital for all aspects of physiology. Micro RNAs with the very specific RISC mechanism for inhibition of messenger RNAs seems particularly vital. Along with all of the other regulatory signals (neurotransmitters, cytokines, proteins, lipids, sugars, peptides), regulation is vastly complex.

This complexity raises the question of where the direction is for all of this. It is absurd to think that this is the result of random processes.

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  • Roy Niles

    “This complexity raises the question of where the direction is for all of this.”

    Well if you remove the brain, the direction stops, so that has to be a clue to the answer. And since there’s reciprocal communication among all our cells in all their functional capacities, cooperative self-direction has to play an important role. We have an orchestrated system in almost every way, where the multitude of functional instruments make the music and the brain oversees the entire operation as the maestro.
    There are those who’ll argue that direction is automatically provided by the way everything is linked together, but with no meaningful communication involved, such random linkage would seem indeed to be absurd.

    • The innate immune system is the link from the epigenetic landscape to all the orchestration of reciprocal sensing and signalling. It links metabolic networks and genetic networks to the energy-dependent physiology of reproduction via RNA-mediated amino acid substitutions, which link cell type differentiation in all living genera via what is known about supercoiled DNA.

      • Roy Niles

        Such random linkage would seem indeed to be absurd.

        • Jon Lieff just placed everything known about the microRNA/messenger RNA balance into the context of feedback loops that link the epigenetic landscape to the physical landscape of DNA in all living genera.

          What links are you claiming are random and absurd?

          • Roy Niles

            The fact is that you did NOT place YOUR so-called links into the context of a feedback loop, and especially the purposeful loop that intelligently “links” the epigenetic landscape to the physical landscape of DNA, etc.
            The epigenetic landscape IS a physical landscape of intelligently constructed and adapted functions, and the claim you’ve just made that Jon Lieff has echoed the ridiculous linkanalysism that you’re pretending to be a science is laughable.

          • I do wish you’d be specific – your ideas are (I think) valid, but so what? We need the details at a category level – at least a start on them. A single system that doesn’t look like either a prayerful missive to purpose, nor like a rat’s nest of molecular interactions.
            FOR EXAMPLE, I like the idea of MASTER MOLECULES as kind of a CONTROL CENTER (or Command and Control center) to evolve as a platform. That sort of thing.

          • Roy Niles

            I’m not a biologist, I’m more of an evolution theorist and I came here to learn, and not to have someone like Kohl fill up the comments section with the unlearned and the unlearnable.
            The Master Molecules theory is a fairly old one, and I’m not aware that it’s evolutionary purposes were ever explained, or even considered.

          • ALSO jvkohl

            Okay, so I’m probably guilty of underestimating the effects of “population biology” and selection, whether in social and societal humans or in short lived high-fecund critters.
            For the rest of the solution I really think this deserves to be the focus of attention: http://jonlieffmd.com/blog/intelligent-rnas-in-the-brain
            I think this is the article that got me to look into Lieff the Gurdjieff of the mind-brain 🙂

          • Roy Niles

            I wasn’t a reader of this blog at that time.

          • Do let me know what you think. It’s going to take me a while to digest.

          • Roy Niles

            I wrote a book on what I was thinking at the time, but I use these comment sections to see what the scientifically minded public thinks today, and that I can play with a bit in the next book. Which I don’t want to preview in the comment section here.
            (Click my avatar for the name of the book, etc.)

          • Yeah? Me too! I have a backlog of half-finished interesting titles awaiting my perfection. 🙂

          • Roy Niles

            OK, so don’t click the avatar.

          • I’m on it now. You like generic silhouette?

          • Roy Niles

            They have cloud reader for Kimble on the Amazon site. Try https://read.amazon.com.

            And as to generic silhouette, I don’t care one way or the other.

          • Bump

          • Roy Niles

            in reply to your post that has become inactive, I could accuse you of self mockery as well, but for me, argument by insult is something that the other guy has to start. And it’s not an insult but a logical response to say that I doubt there’s a productive argumentor out there that can tolerate an illogical production.

          • Hmm .. Well, let me address the second part!
            If you are right, I will search “‘MASTER MOLECULES’ role evolution,” and basically draw a blank. If so, then you have spotlighted a problem, like with the “forbidden” topic of Teleology (Biologists have renamed it something or other so as not to p’ off the pin-heads, who have to be explained to explicitly that it is a valid shorthand. However, I am sure that at the human level Teleology is basically the whole idea…. Maybe. 🙂
            And the result is …
            Yeah – not much at all. Certainly no big tah-dah. Only relating to “history of molecules” – which may get us there.

          • Roy Niles

            Try teleonomy. it fits on pretty well with adaptive mutation. Or try self-agency.

          • Roy Niles

            Try to ignore the typos.

          • WHERE?

          • Roy Niles

            In this now corrected sentence above:
            Try teleonomy. It fits in pretty well with adaptive mutation.

          • Very good. Teleonomy, Adaptive mutation, and Self-agency are at 10 and 9 on the target.

          • More or less. If you’re plugged into this, could you characterize the system more broadly? I am looking for terms like “leader” or “leaderless”, chain or matrix, determiner (perhaps an outcome) and confounder (hidden commonality = cause initiating.) And finally and most importantly, are the terms Push versus Pull system.

            🙂

          • Thanks for asking. Do you want me to start from quantized energy or from hydrogen-atom transfer in DNA base pairs in solution?

            I could make comparisons along the way to quantum Darwinism, but people hate it when I do that.

          • Hmm – H transfer probably too small in the scale.
            Quantum Darwinism for sure…. But I think that’s more of a tool than an answer. I can do that. I’m looking to save all that time. 😉

          • You have no idea what I’m talking about, do you?

          • Let me get back to the site to see what’s going on. Meanwhile I actually have a different take on Quantum Darwinism – not necessarily true to the source, but as for that, I am getting that selection is ongoing and could be the universal “purpose” factor.
            As for Hydrogen transfer – that would be hard to look up so could you give a brief ?

          • Thanks for asking. Do you want me to start from quantized energy or from hydrogen-atom transfer in DNA base pairs in solution?

            I could make comparisons along the way to quantum Darwinism, but people hate it when I do that.

          • the_professeur

            Micro RNAs seem to be pre-encoded to do what they do. If the encoding is correct, the body lives well. If not, the body may live poorly or die.
            It does appear that there is some adjustments within the system as well.
            The miRNA may work Autonomously Or may be driven by some signals from the CNA. The whole thing is very interesting and still unknown.

          • I’m answering this one first.
            Hmm. I suspect that (concept or rule) has been demonstrated to need updating. Consider a look at “EPIGENETICS.” It’s another one of those damn ambiguous terms that we’re stuck with. It indicates that favorable outcomes are determiners of genetic pattern activation. Maybe I’m answering my own question? :

  • Time to move on. https://www.youtube.com/watch?v=5CN2a0Z1fQI

    See also: C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector http://science.sciencemag.org/content/early/2016/06/01/science.aaf5573

    Anyone who still wants to discuss gene-centric neo-Darwinian pseudoscientific nonsense should discuss it with Roy Niles and leave everyone else to discuss biologically-based cause and effect in intelligent conversations.

    • I smell an insult. And judging from the socio-biologically based class, I’d say it’s Mr. Dom Intolerant again.

      Quote:
      “Anyone who still wants to discuss gene-centric neo-Darwinian pseudoscientific nonsense should discuss it with Roy Niles and leave everyone else to discuss biologically-based cause and effect in intelligent conversations.”

      • Roy Niles

        More than an insult it’s an ontological switch where a neo-Darwinistic quack named Kohl has no ‘understanding’ of his own pseudo-philosophy. And in addition that quack continues to mis-understand causes and effects as being due entirely to the fact that somewhere down the chain no-one has ever found his missing link. You know, the one that’s supposedly biologically based because the devil has told our quack that a virus with a godlike presence was actually an energy thief. And all of that makes sense to him because it was supposed to.

        • LOL. All right. No guts no glory, I always say (and usually proceed to get in a lot of trouble for it.) I’m hitting the exit.

          • Roy Niles

            In the pragmatic way of thinking in terms of conceivable practical implications, every thing including confusion has a purpose, and its purpose is the first thing that we should try to note about it.

          • How is it possibly useful when it implies that reaching any universal construct of truth / reality can never be attained? That as far as humans are concerned there will always be a dominant iconization that disregards truth / reality for a personal bias or political / commercial convenient truth? Which can only imply that life is meant to overcome human limits by replacement / obsolescence of the entire humanist ideal and ultimately the species with a more divine one? I can only look forward to kicking this donut shop wisdom.

          • Roy Niles

            I didn’t say that all purposes are useful, did I? I don’t think it’s useful to come up with something like “dominant iconization” and presume that such a meaningless concept has the power to disregard anything. Or that any of this babbling “can only imply” that living things were meant to be replaced. Meant by what, if not by those living things themselves?
            You’d have us being moved to the more divine by the same deistic or theistic entity that should have fashioned us in that image to begin with.
            The hole in the donut of wisdom has mis-served your purposes.

          • WWelllll – first of all, it shows you’re reading. That’s an A for attention (sorry, not to look down, trying to make a point, and you are reading carefully.)
            But let me just say that I cannot convey to you a truth here. It’s not because the value isn’t there, but because your eyes are not in the same wavelength (something like that – I’m sure you understand the point, whether you agree or not.)

          • Roy Niles

            Everybody reads. Some of us understand what we are reading, and some of those understand when what they are reading makes no logical sense. And some of those understand that this was as much the writer’s fault as theirs, and some of those understand that this writer likely has no idea that logic was invented as a means to ascertain the truth, with those inventors at the same time realizing that the truth itself was a logical anomaly. And some of both our readers and our writers have never heard of a pragmatic philosophizer by the name of Charles Sanders Peirce and what he had to say about logic’s purposes, as well about the purposes that it was meant to serve, including the deceptive service of what some will see as abysmal ignorance. And some won’t.

          • You can better explain inventors.
            I’m going to say that you have no reason to understand, for example, the phrase “dominant iconization.” It is a fusion of two real, non-arbitrary, non-psudo (iow true) and emminently, most practical, and most sought after “truths”. Firstly, the state of polarization of all arguments between proponents of a future course and those defending the past. I cannot say this more simply – you can recognize this as the basic male-female division, or as the tendency of pundits to eviscerate the middle content for us and them direct conflict. IOW, Propaganda. But I do not need to quote another philosopher and that is not my forte’ I am not a scholastic philosopher and have a great deal of trouble when without my notes except for my favorites – so you are on your own in this space.
            Secondly, the condition of success versus failure of any grand scheme is reduced to adaptive ideas that occurs in the context the masses to adopt propaganda as a dominant means of unification of worldview, as in RE-LIGARE – the binding of religion. (The root Latin, I suppose.) Thus ICONIZATION are those ideas that are understandable and adoptable by the masses through propaganda.
            So I wonder, can you narrow down your intellectual flight to criticize my argument, now that I have explained it?

          • I’ll get back to you.
            Yes, well spoken.
            However, you are using a truth as a ‘shield of cowardice’ if you are not going to simply ask “what did you mean by -” and intend to so obfuscate any pragmatic purpose – and if that’s true (and some will do this) then my words are truer and more pragmatic – not to mention predictive.

            http://plato.stanford.edu/entr
            I have unfavorable views of rigid grammars of logic as being like attempting art by studying accounting. Of course there is a logic and there is art as well, which is a miracle. When one is learning to do miracles, and has accomplished many substantive ones of invention AND art in a fusion – one must accept that one has done something right.

            And the same is certainly true of gathering eggs of so many species as are laid over the course of such a career – and expecting them to make sense, when in fact history has already judged them.

            Fortuitously, I can quote this very philosopher in a half-accomplished approach to what I have said in fewer words (far fewer):

            (from above link)

            “By speculative grammar Peirce understood the analysis of the kinds of signs there are and the ways that they can be combined significantly. For example, under this heading he introduced three trichotomies of signs and argued for the real possibility of only certain kinds of signs. Signs are qualisigns, sinsigns, or legisigns, accordingly as they are mere qualities, individual events and states, or habits (or laws), respectively. Signs are icons, indices (also called “semes”), or symbols (sometimes called “tokens”), accordingly as they derive their significance from resemblance to their objects, a real relation (for example, of causation) with their objects, or are connected only by convention to their objects, respectively. Signs are rhematic signs (also called “sumisigns” and “rhemes”), dicisigns (also called “quasi-propositions”), or arguments (also called “suadisigns”), accordingly as they are predicational/relational in character, propositional in character, or argumentative in character. Because the three trichotomies are independent of each other, together they yield the abstract possibility that there are 27 distinct kinds of signs. Peirce argued, however, that 17 of these are logically impossible, so that finally only 10 kinds of signs are genuinely possible. In terms of these 10 kinds of signs, Peirce endeavored to construct a theory of all possible natural and conventional signs, whether simple or complex.”

          • Roy Niles

            To have a meaningful conversation, you need to at least try to be as logical, deductively and inductively, as the human thinking processes were evolved to be, even though they’ve also evolved themselves to profit from continuously illogical mistakes. You don’t need to be any more didactic in a book, however, than you have been here. You need to be a bit more pragmatic and a bit less sententious.

          • Well, I could dissect, say “droll” in part, or resolve, having investigated – but the salient part is that you are fencing with me. And I would rather find a more productive “argumentor”. And having concluded, I could construct a logical argument to cut you attempt to pieces (in an officially sanctioned way of that sport of haute couture) – but in reality I am far more vulgar than that. And I just believe in getting things done and in not causing unneeded insult and certainly the least possible harm. So, I tried.
            And I guess that’s all I have to say, other than to wish you well.

          • Epigenetics and Genetics of Viral Latency http://dx.doi.org/10.1016/j.chom.2016.04.008

            Excerpt: “…viral latency is responsible for life-long pathogenesis and mortality risk…”

            That would be the end of the story except for people like Roy Niles. He won’t recognize that it also means the nutrient energy-dependent physiology of reproduction is the key to healthy longevity.

          • Roy Niles

            I recognize that you have never seemed to understand what your oft used “virus driven energy theft” litany has to do with viral latency.

          • Please tell me the human thinking processes “evolved.” Tim Bredy’s group just linked RNA methylation to learning and memory, for comparison. If learning and memory are logically linked to thinking processes, a track record of other published works links them from ecological variation in nematodes to ecological adaptations in humans.

          • Roy Niles

            Well, yes, but then only in the special cases where variations in humans can be attributed to nematode adaptations.

          • Roy Niles

            I recognize that you have never seemed to understand what your oft used “virus driven energy theft” litany has to do with viral latency.

          • Epigenetics and Genetics of Viral Latency http://dx.doi.org/10.1016/j.chom.2016.04.008

            Excerpt: “…viral latency is responsible for life-long pathogenesis and mortality risk…”

            That would be the end of the story except for people like Roy Niles. He won’t recognize that it also means the nutrient energy-dependent physiology of reproduction is the key to healthy longevity.

      • Roy Niles

        More than an insult it’s an ontological switch where a neo-Darwinistic quack named Kohl has no ‘understanding’ of his own pseudo-philosophy. And in addition that quack continues to mis-understand causes and effects as being due entirely to the fact that somewhere down the chain no-one has ever found his missing link. You know, the one that’s supposedly biologically based because the devil has told our quack that a virus with a godlike presence was actually an energy thief. And all of that makes sense to him because it was supposed to.