Excerpt: They claim to have found novel autoregulatory feedback loops that link changes in microRNAs to the alternative splicing factors SRSF1 and SRSF2.  Ectopic expression of SRSF1 can automagically repress the level of multiple microRNAs and SRSF2 can automagically upregulate miRNA expression.

The fact that a peer-reviewed work published in 2018 links autoregulatory feedback loops to automagically altered gene expression and apoptosis via alternative splicings of pre-mRNAs suggests it is time for all serious scientists to retire. The magic of pseudoscientists has prevailed for more than 2 decades.

See for comparison: In clinical trial, cream reduces squamous cell carcinoma risk

Results of a new randomized, double-blinded, controlled clinical trial in veterans showed a 75 percent reduction in the risk of needing surgery to treat a squamous cell carcinoma for a year after applying a skin cream for up to four weeks.

How Fluorouracil Works: (with my emphasis)

The ability of chemotherapy to kill cancer cells depends on its ability to halt cell division. Usually, the drugs work by damaging the RNA or DNA that tells the cell how to copy itself in division. If the cells are unable to divide, they die. The faster the cells are dividing, the more likely it is that chemotherapy will kill the cells, causing the tumor to shrink. They also induce cell suicide (self-death or apoptosis).

Chemotherapy drugs that affect cells only when they are dividing are called cell-cycle specific. Chemotherapy drugs that affect cells when they are at rest are called cell-cycle non-specific. The scheduling of chemotherapy is set based on the type of cells, rate at which they divide, and the time at which a given drug is likely to be effective. This is why chemotherapy is typically given in cycles.

Chemotherapy is most effective at killing cells that are rapidly dividing. Unfortunately, chemotherapy does not know the difference between the cancerous cells and the normal cells. The “normal” cells will grow back and be healthy but in the meantime, side effects occur. The “normal” cells most commonly affected by chemotherapy are the blood cells, the cells in the mouth, stomach and bowel, and the hair follicles; resulting in low blood counts, mouth sores, nausea, diarrhea, and/or hair loss. Different drugs may affect different parts of the body.

Fluoruracil belongs to the category of chemotherapy called antimetabolites. Antimetabolites are very similar to normal substances within the cell. When the cells incorporate these substances into the cellular metabolism, they are unable to divide. Antimetabolites are cell-cycle specific. They attack cells at very specific phases in the cycle. Antimetabolites are classified according to the substances with which they interfere. Fluoruracil is classified as a pyrimidine analog because it interferes with DNA and RNA synthesis by mimicking the building blocks necessary for synthesis.

The term antimetabolites is confusing. Metabolism is enzyme-dependent. Cell type differentiation is energy-dependent and the creation of microRNA links ATP to the creation of enzymes that metabolize food to the species-specific pheromones.

Pheromones biophysically constrain viral latency. That is how they prevent all pathology in the context of metabolism. Enzyme-dependent cycles of metabolism are the key to healthy longevity. Simply put, pheromones prevent the transgenerational epigenetic inheritance of nearly all viruses that have not been biophysically constrained by food energy-dependent metabolism.

Hardin, Hall and Rosbash (1990) put that fact into the perspective of Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. The feedback loops are food energy-dependent and biophysically constrained by naturally occurring RNA interference (i.e., natural selection for energy-dependent codon optimality). The feedback links the metabolism of food to pheromone-controlled biophysically constrained viral latency.
 

Rosbash shared the 2017 Nobel Prize in Chemistry, which attests to the fact that all serious scientists probably know how to prevent or to effectively treat cancer as a disorder of cyclic changes in the chemistry of energy-dependent RNA mediated cell type differentiation. Prevention should include limiting exposure to nutrient stress and/or social stress because stress alters microRNA-mediated alternative splicings that link food energy to the biophyiscally constrained chemistry of protein folding.

See: Microrna-mediated regulation of splicing factors SRSF1, SRSF2 and hnRNP A1 in context of their alternatively spliced 3’UTRs

The microRNAs targeting SRSF1 and SRSF2 are involved in a regulatory feedback loop. microRNAs miR-183-5p and miR-200c-3p that target SRSF2, affect the expression of genes involved in apoptotic regulation.

They claim to have found novel autoregulatory feedback loops that link changes in microRNAs to the alternative splicing factors SRSF1 and SRSF2.  Ectopic expression of SRSF1 can automagically repress the level of multiple microRNAs and SRSF2 can automagically upregulate miRNA expression.

The fact that a peer-reviewed work published in 2018 links autoregulatory feedback loops to automagically altered gene expression and apoptosis via alternative splicings of pre-mRNAs suggests it is time for all serious scientists to retire. The magic of pseudoscientists has prevailed for more than 2 decades.

See for comparison:

From Fertilization to Adult Sexual Behavior (1996)

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 [model organisms.]

See also:

Feedback loops link odor and pheromone signaling with reproduction (2005)

The feedback loops are food energy-dependent and biophysically constrained by the pheromone-controlled physiology of reproduction in species from microbes to humans.

Sarcasm alert: The treatment of automagically dysregulated apoptosis should probably begin with a change in diet.

Changes in diet have been linked from the energy-dependent creation of enzymes that specifically link an energy-dependent base pair change to microRNA-mediated DNA repair via fixation of an RNA-mediated amino acid substitution. The substitutions are linked to energy-dependent cell type differentiation and healthy longevity without the magic.

Just add food energy or the virus-driven theft of quantized energy to eliminate the term autoregulatory and you could prevent or effectively treat all virus-driven pathology. 

Energy-dependent RNA interference links the enzyme-dependent metabolism of food and drugs to cell type differentiation via feedback loops that link pheromones to biophysically constrained viral latency.

Do not claim to have a logical philosophy if you cannot link the creation of the sun’s anti-entropic virucidal energy to every aspect of the biophysically constrained pheromone-controlled physiology of reproduction in species from microbes to human by starting with the obvious need to control viral replication in the ocean and linking the control to healthy longevity in modern human populations via fixation of RNA-mediated amino acid substitutions in all differentiated cell types.

See also: Metabolic Labeling and Profiling of Transfer RNAs Using Macroarrays

Transfer RNAs (tRNA) are abundant short non-coding RNA species that are typically 76 to 90 nucleotides in length. tRNAs are directly responsible for protein synthesis by translating codons in mRNA into amino acid sequences.

See also: Molecular mechanism of promoter opening by RNA polymerase III

RNA polymerase III (Pol III) and transcription factor IIIB (TFIIIB) assemble together on different promoter types to initiate the transcription of small, structured RNAs.

Nothing happens without the energy-dependent creation of the enzymes and the biophysically constrained viral latency that links the creation of G protein-coupled receptors to the functional structure of supercoiled DNA. The claims about molecular mechanisms of promoter opening appear to be deliberate attempts to obfuscate cause and effect.

Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

Female sex and history of prior pregnancies are associated with favorable melanoma outcomes. Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on melanocytes. Selective GPER activation in primary melanocytes and melanoma cells induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemically delivered GPER agonist was well tolerated, and cooperated with immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against tumor rechallenge. GPER may be a useful, pharmacologically accessible target for melanoma.

Sex-specific cell type differentiation links yeasts to primates via the nutrient-dependent pheromone-controlled physiology of reproduction that links the food energy-dependent structure and function of enzymes and G protein-coupled receptors to the biophysically constrained Structure and dynamics of GPCR signaling complexes, which are required to biophysically constrain viral latency in the context of effect of androgens and estrogens on difference in the cell type of males and females.

Any focus on G protein-coupled estrogen receptors compared to G protein-coupled androgen receptors  should be viewed with suspicion in the context of what has been known to all serious scientists about hormones and behavior since our Hormones and Behavior review of RNA-mediated cell type differentiation. From Fertilization to Adult Sexual Behavior (1996)

Simply put, the alternative splicings of pre-mRNAs, which are now called microRNAs, biophysically constrain energy-dependent viral latency and prevents the transgenerational epigenetic inheritance of nearly all virus-driven pathology until excess nutrient stress or social stress takes its toll on the innate immune system.

Eventually, our food energy-dependent RNA-mediated DNA repair fails, and the accumulation of viral microRNAs predicts the failure of cell type differentiation in the tissues that are required to sustain our physical health and mental health.

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