5th-6th Sept 2018 Dublin, Ireland

The eternal significance of microRNAs (8)

Use of definitions in attempts to explain any aspect of species-specific biophysically constrained cell type differentiation and aging has been replaced by the use of model systems of biological processes.  Biological processes can be compared to so-called “evolutionary processes” to show that only biological processes need to be considered in the context of Darwin’s “conditions of life” or answers to the the question  What is Life? Schrödinger (1944).
K. L. Mettinger et al. (eds.), Exosomes, Stem Cells and MicroRNA, Advances in Experimental Medicine and Biology 1056, https://doi.org/10.1007/978-3-319-74470-4_6

This volume provides insight into the pivotal roles of stem cells, exosomes and other microvesicles in biofunction and molecular mechanisms and their therapeutic potential in translational nanomedicine. It further highlights evidence from recent studies as to how stem cell derived exosomes and microRNAs may restore and maintain tissue homeostasis, enable cells to recover critical cellular functions and begin repair regeneration.

Chapter 2 The Emerging Roles of microRNAs in Stem Cell Aging

involved in many biological processes such as developmental timing, differentiation, cell death, stem cell proliferation and differentiation, immune response, aging and cancer. Accumulating studies in recent years suggest that miRNAs play crucial roles in stem cell division and differentiation. In the present chapter, we present a brief overview of these studies and discuss their contributions toward our understanding of the importance of miRNAs in normal and aged stem cell function in various model systems.

Chapter 6  MicroRNAs, Regulatory Messengers Inside and Outside Cancer Cells

…like hormones, miRNAs can be secreted and regulate gene expression in recipient cells. Altered expression levels of miRNAs in cancer cells determine the acquisition of fundamental biological capabilities (hallmarks of cancer) responsible for the development and progression of the disease.

Model systems link the energy-dependent creation of microRNAs from microRNA biogenesis to the regulation of all cancer hallmarks. The virus-driven degradation of messenger RNA has been linked to all cancers and all other pathology in species from microbes to humans. Natural selection for energy-dependent codon optimality has been linked to healthy longevity.
See: Codon identity regulates mRNA stability and translation efficiency during the maternal-to-zygotic transition
See for comparison:  The Neutral Theory in Light of Natural Selection May 2, 2018

…50 years after its introduction by Kimura. We argue that the neutral theory was supported by unreliable theoretical and empirical evidence from the beginning, and that in light of modern, genome-scale data, we can firmly reject its universality. The ubiquity of adaptive variation both within and between species means that a more comprehensive theory of molecular evolution must be sought.

The ubiquity of adaptive variation attests to the facts about how the creation of quantized energy is linked to biophysically constrained viral latency. Adaptive variation links energy-dependent changes from angstroms to ecosystems in all living genera  via the physiology of their food energy-dependent pheromone-controlled reproduction.

For comparison to mRNA stability during the maternal-to-zygotic transition, see: Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

The energy-dependent molecular mechanisms of recombination clearly link microRNA biogenesis to the stability of organized genomes during the life histories of all genera. Serious scientists object to the use of definitions in attempts to explain any aspect of species-specific biophysically constrained cell type differentiation.

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

…it is tiresome to raise the same objections repeatedly, wondering why researchers have not fulfilled some of the basic requirements for establishing the occurrence of an autophagic process.

 

Cytosis can be used to teach everything from base editing to RNA editing to everyone over age 10. They will learn how to link the creation of energy to biophysically constrained viral latency via the physiology of pheromone-controlled reproduction.

The eternal significance of microRNAs (2)

Summary: What is known for sure, however, is that biological processes called “nature” are not simplistic. Neither is the entity called “the environment.” The two separate worlds overlap and intertwine so only a single interactive one exists. Yes, it may be simpler to look at each singly, but one does so at intellectual peril.
The Immune Landscape of Cancer (2018)

Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes.

More than 725 collaborators linked the anti-entropic virucidal energy of sunlight  from  the energy-dependent creation of microRNAs and biophysically constrained viral latency to cell type differentiation via autophagy.
See for comparison: From Fertilization to Adult Sexual Behavior (1996)

What is known for sure, however, is that biological processes called “nature” are not simplistic. Neither is the entity called “the environment.” The two separate worlds overlap and intertwine so only a single interactive one exists. Yes, it may be simpler to look at each singly, but one does so at intellectual peril.

Richard P. Feynman placed the intellectual peril into the context of food energy and human idiocy.
See:

See also: The Translation Machinery Is Immune from miRNA Perturbations: A Cell-Based Probabilistic Approach

Mature microRNAs (miRNAs) are non-coding RNA that regulate most human genes through base-pairing with their targets.

Base-pairing is energy-dependent and biophysically constrained. See: Structural diversity of supercoiled DNA and the parody: All About that Base (Meghan Trainor Parody) 12/10/14
Others now appear to be following on the heels of the late Eshel Ben-Jacob’s works, which showed that the “stochastic nature of miRNA action” is light energy-dependent and biophysically constrained by the physiology of pheromone-controlled reproduction in species from microbes to humans.
See: MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination
MicroRNA-based regulation is obviously the key to biophysically constrained viral latency in the context of everything known about the eternal significance of microRNAs.
See also: microRNA 
The quantized energy-dependent differential expression of microRNAs has been linked to healthy longevity or from virus-driven energy theft to all pathology in more than 71,000 indexed published works.
Serious scientists now know that John McCain’s glioblastoma can probably be effectively treated with the microRNA-mediated immunotherapy that led to the remission of Jimmy Carter’s brain cancer.
See: John McCain’s brain cancer prognosis is ‘not very good,’ medical expert says
The reporters touch on the likely link from melanoma to brain cancer via microRNAs, and then dismiss it.
See for comparison: Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene
Would you like to target the regulation of your cell death genes?
See: The Remarkable Cancer Treatment That Helped Jimmy Carter Combat Brain Tumor

…his doctors have said he no longer needs cancer treatment thanks in part to a groundbreaking new kind of medication that trains the immune system to fight cancer tumors.

Anyone who is interested in learning how to prevent all diseases of the body and the brain (e.g., suicide prevention) may want to select the following link. Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis.
The Warburg Effect links virus-driven energy theft to all pathology in the context of sympatric speciation, which is food energy-dependent and controlled by feedback loops that link the food energy to the pheromone-controlled physiology of reproduction.
Unfortunately, the Warburg effect is commonly used to explain mutation-driven evolution outside the context of the food energy that is required for sympatric speciation. Biologically uninformed theorists continue to display what Feynman referred to as human idiocy — as if no one on Earth can stop them.
But see: Cytosis. You could learn that the cure for all pathology is food energy-dependent and microRNA-mediated in the context of biophysically constrained viral latency.
See also: Substitutions Near the Receptor Binding Site Determine Major Antigenic Change During Influenza Virus Evolution
Anyone who makes claims about “viral evolution”  should be forced to explain why they have not learned how fixation of RNA-mediated amino acid substitutions have been linked to healthy longevity.

Editor’s summary: Five antigenic sites in the virus surface hemagglutinin protein, which together comprise 131 amino acid positions, are thought to determine the full scope of antigenic drift of influenza A virus. Koel et al. (p. 976) show that major antigenic change can be caused by single amino acid substitutions.

See also: Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity

Brain gene expression profiling studies of suicide and depression using oligonucleotide microarrays have often failed to distinguish these two phenotypes. Moreover, next generation sequencing approaches are more accurate in quantifying gene expression and can detect alternative splicing.

Who doesn’t want others to know that our 1996 Hormones and Behavior review of RNA-mediated cell type differentiation included a section on “molecular epigenetics” and alternative splicing? See: From Fertilization to Adult Sexual Behavior

human-evolution

Vietnam Veterans and others with glioblastoma

The Agent Orange Widows Club

After their husbands died of an aggressive brain cancer, the widows of Vietnam veterans have found one another as they fight the VA for benefits.

See also: Vietnam Veterans with Glioblastoma Multiforme Stage 4 Brain Cancer
This post was removed:

Targeting NF-κB in glioblastoma: A therapeutic approach

This is the level of complexity that the VA needs to understand and link to the treatment of this aggressive cancer, which is obviously caused by virus-driven energy theft. When the VA understands that, the treatment will open the floodgates of litigation for all the pathology in every veteran who ever served overseas and failed to adapt to the viruses encountered during the stressful conditions of war.

“…we used the NBD peptide, a peptide corresponding to the NEMO binding domain that specifically inhibits the induction of NF-κB activity (15). The NBD peptide has been used previously to inhibit inflammation in animal models such as acute inflammation in carrageenan-induced mouse paw edema and collagen-induced arthritis (31) or Duchenne muscular dystrophy (13). One of our main reasons for choosing the NBD peptide to treat GBM is the reported ability of NBD to enter into the CNS and exert an effect on NF-κB activation in a mouse model of Parkinson’s disease (14). Indeed, our results show that NBD treatment of mice with GBM significantly extended their survival, probably as a result of the specific inhibition of NF-κB not only in the tumor cells but also in the tumor microenvironment.”

My conclusion: Even if the VA understands what all serious scientists have learned about energy-dependent biophysically constrained biologically-based cause and effect, liberal academics will continue to try to prevent dissemination of accurate information. The facts about virus-driven energy theft compared to nutrient energy-dependent ecological adaptation refute every aspect of neo-Darwinian nonsense that is still being taught to your children and grandchildren if they are attending public schools.

Grady was the first person to get the treatment dripped through a tube into a space in the brain where spinal fluid is made, sending it down the path the cancer traveled to his spine.

This makes me wonder how Jimmy Carter’s brain cancer was cured. So far as I know, the cure must link genetically engineered cell type differentiation from viral latency in the cells dripped into the brain to the natural information processing.

Natural information processing can then link natural selection for energy-dependent codon optimality from base pair changes to RNA-mediated amino acid substitutions that stabilize the supercoiled DNA of all living genera, and prevent the accumulation of virus-caused mutations.

See for instance: DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma.

CAR is the acronymn for chimeric antigen receptor. See for an example of how CAR-T cell treatment must link energy-dependent changes in the microRNA/messenger RNA balance of the mouse model organism to vial latency via the anti-EGFRvIII chimeric antigen receptor.

Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts

CONCLUSION:
These results warrant the development of novel CAR-T-cell strategies that incorporate miR-17-92 to improve therapeutic potency, especially in patients with GBM [glioblastoma].

Targeting NF-κB in glioblastoma: A therapeutic approach (revisited)

We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM.

See also: MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

Now that treatment is based on what was learned about virus-driven energy theft in the mouse model organism, how much longer will it be before viruses are linked to all pathology via changes in the microRNA/messenger RNA balance that clearly link virus-driven messenger RNA degradation to tissue-type specific pathology in all cells of all living genera?

See also: A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance

Reported as: Scientists uncover new way to defeat therapy-resistant prostate cancer

In addition to IκBα/NF-κB, the signaling circuit includes the microRNA miR-196b-3p, Meis2 and PPP3CC. While miR-196b-3p promotes tumor development, Meis2, which is an essential developmental gene in mammals, can disrupt the circuit when overexpressed. The protein PPP3CC can inhibit NF-κB activity in prostate cancer cells.

The likelihood that all signaling circuits include either nutrient energy-dependent microRNAs, which are linked to healthy longevity or viral microRNAs that are linked from virus-driven energy theft to pathology peaked at the time that more than 50,000 published works had reported on differences in microRNAs that linked hydrogen-atom transfer in DNA base pairs in solution to healthy longevity or to all pathology. (May 2016)

See for comparison: microRNA. On December 29, 2016 there were more than 56,600 published works.

rp_levels-of-organization.jpg

Energy-dependent sensory maps (1996-2016)

Developmental broadening of inhibitory sensory maps

My summary: They help to detail how olfactory input causes the energy-dependent de novo creation of sensory maps, which are representations of the external world. The experience-dependent representations link chemotaxis and phototaxis to biophysically constrained behavior. The representations are systematically organized in brain structures throughout development. Simply put, the maps are links from the epigenetic landscape to the physical landscape of supercoiled DNA in organized genomes.
By investigating how ongoing neurogenesis in the mouse olfactory bulb is linked to existing circuitry, they found differences between excitatory and inhibitory neuronal networks. This led them to compare functional responses of both maturing and established granule cells. They confirmed previously observed refinement of excitatory maps but also found that inhibitory sensory maps became broader during experience-dependent maturation.
Abstract conclusion:

These data describe the development of an inhibitory sensory map as a network, highlighting the differences from previously described excitatory maps.

Summary: Energy-dependent RNA methylation links RNA-directed DNA methylation from learning and memory to the stability of the sensory maps.
See this report from 2005: Feedback loops link odor and pheromone signaling with reproduction

At least 10,000 neurons in 26 different brain areas appear to transmit signals directly to GnRH neurons. Among these are areas involved in odor and pheromone processing, sexual behavior, arousal, reward, and other functions. This suggests that GnRH neurons are poised to modulate reproductive physiology and behavior in accordance with the overall state of the animal.

See also:

…noradrenergic, dopaminergic, serotoninergic, and opiotergic pathways; inhibitory neurotransmitters (e.g., gamma aminobutyric acid) and excitatory amino acids (e.g., glutamic and aspartic acids); and other brain peptides including pineal secretions (melatonin) and corticotrophin releasing hormone, and the complex interactions among them are subtle but functional species-specific influences on the electrochemical transmission of neuronal signals that the hypothalamus translates to the chemical signal GnRH. Puberty: ontogeny, neuroendocrinology, physiology & disorders (1992, p. 1164)

–as cited in Kohl (2006) The Mind’s Eyes: Human pheromones, neuroscience, and male sexual preferences (author’s copy) and in Handbook of the Evolution of Human Sexuality (2007, p. 350)
Pseudoscientists have ignored the fact that energy-dependent autophagy links the innate immune system to the de novo creation of G protein-coupled receptors (GPCRs). For example, achiral glycine in position 6 of the GnRH decapeptide links energy-dependent excitatory and inhibitory neuronal networks to supercoiled DNA, which protects all organized genomes from virus-driven energy theft and genomic entropy.
See for comparison: Novel candidate genes underlying extreme trophic specialization in Caribbean pupfishes

This greater phenotypic distance is primarily due to the large jaws of scale-eaters (Fig. S1B). Orr’s extension of Fisher’s geometric model predicts that de novo mutations with a large effect on phenotypic variation are more likely to be fixed during adaptation toward distant phenotypic optima than nearby optima (Orr 1998; Orr 2005). Based on this model, we predict more large-effect variants mediated the transition from generalist to scale-eater due to the greater phenotypic distance across the fitness valley separating these species.

Reported as: Jawing away: Bahama pupfish study identifies candidate genes driving food-niches

…each, through subtle jaw size differences, has carved out its own food niche —- all within the last 10,000 years. They specialize by their jaw size and food—algae, snails or quick-striking scale-eaters —- that like Darwin’s finches, reflect differences in seed choices by the size and shape of their beaks.

They claim their ridiculous theory of greater phenotypic difference extends to a model of how fixed de novo mutations predict what happened during 10,000 years of evolution in three variants of one vertebrate species. Their ridiculous theory can be compared to the works of serious scientists who have linked energy-dependent changes from angstroms to ecosystems in all living genera via food odors and pheromones.
For a comparison to energy-dependent changes in amino acid substitutions among three primate species, see: Nothing in Biology Makes Any Sense Except in the Light of Evolution (1973)

…the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla (p. 127).”

Dobzhansky (1973) included more information on the importance of these nutrient energy-dependent RNA-mediated amino acid substitutions. He wrote:

Cytochrome C is an enzyme that plays an important role in the metabolism of aerobic cells. It is found in the most diverse organisms, from man to molds.

E. Margoliash, W. M. Fitch, and others have compared the amino acid sequences in cytochrome C in different branches of the living world. Most significant similarities as well as differences have been brought to light. The cytochrome C of different orders of mammals and birds differ in 2 to 17 amino acids, classes of vertebrates in 7 to 38, and vertebrates and insects in 23 to 41; and animals differ from yeasts and molds in 56 to 72 amino acids. Fitch and Margoliash prefer to express their findings in what are called “minimal mutational distances.” It has been mentioned above that different amino acids are coded by different triplets of nucleotides in DNA of the genes; this code is now known.

Dobzhansky (1973) may have knowingly linked light-induced energy-dependent changes in enzymes from Schrodinger’s claims about the anti-entropic energy of sunlight to selection for codon optimality via the “minimal mutational distances” reported in the context of Fitch and Margoliash (1967). But Dobzhansky reported the energy-dependent differences in the context of a model of links from energy-dependent changes in single nucleotide polymorphsims to amino acid substitutions. That fact should cause all pseudoscientists to wonder why Dobzhansky (1973) framed his review of cell type differentiation as an example of the need to start with an anti-entropic energy source.
Why did he choose this title: Nothing in Biology Makes Any Sense Except in the Light of Evolution Did he know that sunlight is the energy source for all biodiversity, or was he guessing?
See also my comments on: Combating Evolution to Fight Disease
For comparison to everything now known about energy-dependent RNA-mediated amino acid substitutions and cell type differentiation, Fitch and Margoliash (1967) determined the minimal mutation distance between two cytochromes in the context of a definition, which was linked from what they thought would be

“…the minimal number of nucleotides that would need to be altered in order for the gene for one cytochrome to code for the other. This distance is determined by a computer making a pair-wise comparison of homologous amino acids (8).”

Simply put, first they dismissed the need for an anti-entropic energy source. Then they took de Vries definition of “mutation” and linked energy-dependent changes in RNA-mediated amino acid substitutions to morphological phenotypes. They failed to link the energy-dependent changes in RNA-mediated amino acid substitutions to the physiology of reproduction, which is the only way to link the energy-dependent changes in morphology to changes in behavior.
If others had not linked the changes to reproductive sexual behavior, Linda Buck, who is the co-author of Feedback loops link odor and pheromone signaling with reproduction might never have linked every aspect of energy-dependent cell type differentiation to odors and pheromones. See for example: From Fertilization to Adult Sexual Behavior.

Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans…

All serious scientists now know that the 2004 Nobel Laureate in Physiology or Medicine, Linda Buck clearly linked energy-dependent autophagy from substitution of achiral glycine in GnRH to all vertebrate biodiversity. With co-authors, she integrated what is known about the nutrient energy-dependent pheromone-controlled physiology of excitatory and inhibitory metabolic and genetic networks reproduction in yeast to non-human primates and humans.
If there is any experimental evidence that supports claims about 10,000 years of evolution and trophic specialization in Caribbean pupfishes or any other species, I have not seen it. All experimental evidence supports Dobzhansky’s claims and the claims of all others who have linked the anti-entropic virucidal energy of the sun to healthy longevity and also linked virus-driven energy theft to all pathology.
See also: Vietnam Veterans and others with glioblastoma