Creating biophysically constrained viral latency (1)

Caption: Contemporary analyses of cell metabolism have called out three metabolites: ATP, NADH, and acetyl-CoA, as sentinel molecules whose accumulation represent much of the purpose of the catabolic arms of metabolism and then drive many anabolic pathways. Such analyses largely leave out how and why ATP, NADH, and acetyl-CoA (Figure 1) at the molecular level play such central roles. Yet, without those insights into why cells accumulate them and how the enabling properties of these key metabolites power much of cell metabolism, the underlying molecular logic remains mysterious. Four other metabolites, S-adenosylmethionine, carbamoyl phosphate, UDP-glucose, and Δ2-isopentenyl-PP play similar roles in using group transfer chemistry to drive otherwise unfavorable biosynthetic equilibria. This review provides the underlying chemical logic to remind how these seven key molecules function as mobile packets of cellular currencies for phosphoryl transfers (ATP), acyl transfers (acetyl-CoA, carbamoyl-P), methyl transfers (SAM), prenyl transfers (IPP), glucosyl transfers (UDP-glucose), and electron and ADP-ribosyl transfers (NAD(P)H/NAD(P)+) to drive metabolic transformations in and across most primary pathways. The eighth key metabolite is molecular oxygen (O2), thermodynamically activated for reduction by one electron path, leaving it kinetically stable to the vast majority of organic cellular metabolites.

For an example of the anti-entropic energy-dependent RNA-mediated complexity of cell metabolism and cell type differentiation, see: Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation

Topical application of sulforaphane-rich extracts of 3-day-old broccoli sprouts up-regulated phase 2 enzymes in the mouse and human skin, protected against UVR-induced inflammation and edema in mice, and reduced susceptibility to erythema arising from narrow-band 311-nm UVR in humans.

See also: Skin microbiota–host interactions

The skin is a complex and dynamic ecosystem that is inhabited by bacteria, archaea, fungi and viruses. These microbes—collectively referred to as the skin microbiota—are fundamental to skin physiology and immunity. Interactions between skin microbes and the host can fall anywhere along the continuum between mutualism and pathogenicity. In this Review, we highlight how host–microbe interactions depend heavily on context, including the state of immune activation, host genetic predisposition, barrier status, microbe localization, and microbe–microbe interactions. We focus on how context shapes the complex dialogue between skin microbes and the host, and the consequences of this dialogue for health and disease.‏

Study: Vitamin B3 might help against skin cancer

Nicotinamide, an amide form of vitamin B3, boosts cellular energy and regulates poly-ADP-ribose-polymerase 1, an enzyme with important roles in DNA repair and the expression of inflammatory cytokines. Nicotinamide shows promise for the treatment of a wide range of dermatological conditions, including autoimmune blistering disorders, acne, rosacea, ageing skin and atopic dermatitis. In particular, recent studies have also shown it to be a potential agent for reducing actinic keratoses and preventing skin cancers.

Nicotinamide: Mechanism of action and indications in dermatology

The existing clinical data and literature on nicotinamide suggests that it is an inexpensive, safe drug with beneficial effects as an adjunct in many dermatological diseases because of its anti-inflammatory, anti-oxidant, barrier repair and protective effects. It can be used both as a topical and oral drug without any major adverse effects.

For the link from topical application that protects human skin from excess UVR-induced inflammation to diet-driven protection from cancer, see also: Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention

The engineered commensal Escherichia coli bound specifically to the heparan sulphate proteoglycan on colorectal cancer cells and secreted the enzyme myrosinase to transform host-ingested glucosinolates—natural components of cruciferous vegetables—to sulphoraphane, an organic small molecule with known anticancer activity. The engineered microbes coupled with glucosinolates resulted in >95% proliferation inhibition of murine, human and colorectal adenocarcinoma cell lines in vitro. We also show that murine models of colorectal carcinoma fed with the engineered microbes and the cruciferous vegetable diet displayed significant tumour regression and reduced tumour occurrence.

Reported as: With these special bacteria, a broccoli a day can keep the cancer doctor away

For comparison, see: Sulforaphane-Induced Cell Cycle Arrest and Senescence are accompanied by DNA Hypomethylation and Changes in microRNA Profile in Breast Cancer Cells

Rarely does anyone see an example of how conserved across-kingdom molecular mechanisms protect all organized genomes from the virus-driven degradation of messenger RNA that links mutations to all pathology.

So far as I know, evolutionary biologists still claim that energy-dependent protection emerged so that species could evolve their increasing organismal complexity over-the-weekend.

See for comparison: Tuning the dynamic range of bacterial promoters regulated by ligand-inducible transcription factors

This work enables predictable control over the dynamic range of regulatory components.

Article excerpt:

1) Because the lac and tet systems evolved separately, the promoters that respond to LacI and TetR are tuned to transcribe downstream genes at rates appropriate to their original setting.

2) We also developed a thermodynamic model that predicted the contribution of free energy of binding to the overall transcriptional initiation rate, which we measured in a fluorescence-based plate reader experiment.

The two excerpts can be linked to the overwhelming amount of pseudoscientific nonsense touted by neo-Darwinian theorists via the example of the energy-dependent pheromone-controlled weekend resurrection of the bacterial flagellum in P. fluorescens, which fluoresces with exposure to UV light.

Evolutionary resurrection of flagellar motility via rewiring of the nitrogen regulation system

The energy-dependent fixation of two RNA-mediated amino acid substitutions was reported in the context of how evolution “rewired” the nitrogen regulation system over-the-weekend via two mutations.

From the Editor’s Summary
Losing and then regaining flagella

The ability to adapt to changes in the function of gene regulators, as opposed to structural genes, is a crucial aspect of evolutionary change. Taylor et al. mutated a central regulator for the formation of flagella in the bacterium Pseudomonas fluorescens. They then put the mutated flagella-free bacteria under strong selection pressure to regain mobility. The mutated bacteria regained the lost flagella, and motility, within 4 days. Two stereotypical mutations diverted an evolutionarily related regulator that normally controls nitrogen uptake to control flagella biosynthesis. The mutations increased the levels of the co-opted regulator, then altered its specificity for the flagella pathway.

The ability to adapt to ecological variation via the de novo creation of amino acids should not be placed back into the context of neo-Darwinian nonsense about mutations and evolution. The neo-Darwinists have failed to link mutations to beneficial changes in behavior. In bacteria and in humans the behavior is biophysically constrained in the context of viral latency via energy-dependent changes in microRNAs and autophagy.