Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion
Authors: Hemant Sarin
Journal: PLoS ONE (2020)
Discipline: Multidisciplinary
Keywords: Molecular diameter; Lipophilicity; Hydrophilicity; Carrier-mediated diffusion; Channel pores
Affiliations: Freelance Investigator in Translational Science and Medicine, Charleston, West Virginia, United States of America.

Abstract:  Molecular diameter, lipophilicity and hydrophilicity exclusion affinity limits exist for small molecule carrier-mediated diffusion or transport through channel pores or interaction with the cell surface glycocalyx. The molecular structure lipophilicity limit for non-specific carrier-mediated transmembrane diffusion through polarity-selective transport channels of the cell membrane is Lexternal structure ∙ Hpolar group-1 of ≥ 1.07. The cell membrane channel pore size is &gt; 0.752 and &lt; 0.758 nm based on a 3-D ellipsoid model (biphenyl), and within the molecular diameter size range 0.744 and 0.762 nm based on a 2-D elliptical model (alkanol). The adjusted van der Waals diameter (vdWD, adj; nm) for the subset of halogenated vapors is predictive of the required MAC for anesthetic potency at an initial (-) Δ Cmicro effect. The molecular structure L ∙ Hpolar group-1 for Neu5Ac is 0.080, and the L ∙ Hpolar group-1 interval range for the cell surface glycocalyx hydrophilicity barrier interaction is 0.101 (Saxitoxin, Stx; Linternal structure ∙ Hpolar group-1) - 0.092 (m-xylenediamine, Lexternal structure · Hpolar group). Differential predictive effective pressure mapping of gene activation or repression reveals that p-dioxin exposure results in activation of AhR-Erβ (Arnt)/Nrf-2, Pparδ, Errγ (LxRα), Dio3 (Dio2) and Trα limbs, and due to high affinity Dio2 and Dio3 (OH-TriCDD, Lext · H-1: 1.91-4.31) exothermy-antagonism (Δ contraction) with high affinity T4/rT3-TRα-mediated agonism (Δ expansion). co-planar PCB metabolite exposure (Lext · H-1: 1.95-3.91) results in activation of AhR (Erα/β)/Nrf2, Rev-Erbβ, Errα, Dio3 (Dio2) and Trα limbs with a Δ Cmicro contraction of 0.89 and Δ Cmicro expansion of 1.05 as compared to p-dioxin. co-, ortho-planar PCB metabolite exposure results in activation of Car/PxR, Pparα (Srebf1,-Lxrβ), Arnt (AhR-Erβ), AR, Dio1 (Dio2) and Trβ limbs with a Δ Cmicro contraction of 0.73 and Δ Cmicro expansion of 1.18 (as compared to p-dioxin). Bisphenol A exposure (Lext struct ∙ H-1: 1.08-1.12, BPA-BPE, Errγ; BPAF, Lext struct ∙ H-1: 1.23, CM Erα, β) results in increased duration at Peff for Timm8b (Peff 0.247) transcription and in indirect activation of the AhR/Nrf-2 hybrid pathway with decreased duration at Peff 0.200 (Nrf1) and increased duration at Peff 0.257 (Dffa). The Bpa/Bpaf convergent pathway Cmicro contraction-expansion response increase in the lower Peff interval is 0.040; in comparison, small molecule hormone Δ Cmicro contraction-expansion response increases in the lower Peff intervals for gene expression ≤ 0.168 (Dex· GR) ≥ 0.156 (Dht · AR), with grade of duration at Peff (min·count) of 1.33x105 (Dex/Cort) and 1.8-2.53x105 (Dht/R1881) as compared to the (-) coupled (+) Δ Cmicro Peff to 0.136 (Wnt5a, Esr2) with applied DES (1.86x106). The subtype of trans-differentiated cell as a result of an applied toxin or toxicant is predictable by delta-Cmicro determined by Peff mapping. Study findings offer additional perspective on the basis for pressure regulated gene transcription by alterations in cell micro-compliance (Δ contraction-expansion, Cmicro), and are applicable for the further predictive modeling of gene to gene transcription interactions, and small molecule modulation of cell effective pressure (Peff) and its potential. 

Retracted: Yes

PubPeer comments:
 2021 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0249385 After this article [1] was published, the corresponding author contacted PLOS ONE to request corrections. The author advised that he did not intend for [1] to be published in its current online form, and that the article should be retracted in the event that the requested revisions could not be incorporated into the published version of the article. The requested changes involve substantial revisions to the rationale, methodology, results and conclusions reported in the article text, as well as changes to Tables 3, 6, 7, 8, 10, 11, 12, and Figs 2 and 3. The PLOS ONE Editors determined that the requested revisions go beyond what is suitable for a Correction per the journalu2019s editorial standards and would instead necessitate a full re-review of an updated manuscript. In reviewing the correction request, the PLOS ONE Editors identified additional concerns with the article, including: A specific scientific rationale for the selection of representative small molecules and genes was not provided, raising questions about whether the results presented are applicable beyond the compounds studied. The methods were not described in sufficient detail to clearly relay the study design and enable other researchers to interpret the results or reproduce the analyses. The article did not report adequate validation of the in silico model to support the reported claims about gene transcription regulation. In light of these additional issues, the PLOS ONE Editors determined that the published article does not meet the journalu2019s publication criteria and there are concerns about the validity of the reported results and conclusions. Based on the outcome of the editorial assessment and in line with the authoru2019s request, the PLOS ONE Editors retract this article. We regret that the concerns about this work were not addressed prior to the articleu2019s publication. In response to the retraction decision, HS expressed an intention to address the above issues in a future submission of this work. Reference 1.Sarin H (2020) Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion. PLoS ONE 15(10): e0236446. https: doi.org 10.1371 journal.pone.0236446 pmid:33021979 , 
 Copy pasted from https: retractionwatch.com 2021 04 06 an-author-asked-for-multiple-corrections-to-a-paper-plos-one-decided-to-retract-it  (....) A doctor with the same name as the author, Hemant Sarin, lost his medical license in Maryland in 2019, after failing to submit a criminal background check, according to public documents issued by that stateu2019s board of physicians. The revocation was for one year, but Sarinu2019s medical license is still listed as u201crevokedu201d in that state. The Hemant Sarin who lost his Maryland medical license lists an address in Charleston, which matches the location given in the PLOS ONE paper. The author Sarin is also an ambassador for an organization called Future Science, and gives his affiliation as u201cfreelance investigatoru201d with an M.D. earned in 1999, a year that matches the medical board records for Hemant Sarinu2019s license in California, Maryland and other states. (......) ,