Identifying Integrative Molecular Pathways for Predictive Modeling of Infectious Disease

Schaper, Charles

doi:10.1101/835546

Cited by 2 publications

(4 citation statements)

References 25 publications

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“…As a mechanism with influence over both local and systematic physiological function, including causality of many types of dysfunction and disease, the potential association via competitive inhibition at the glucocorticoid receptor of prostaglandins and cortisol is put forth in further detail. This work supports the recent research of this lab, as described in the preprint [14], indicating for the first time that a configuration of prostaglandin E2 (PGE2) is favorable at the ligand binding domain (LBD) of glucocorticoid receptors (GR) normally occupied by cortisol. It is determined through molecular modeling, comparative analysis, and from mathematical modeling of systemic response, including the effect on producing fever.…”

Section: Introductionsupporting

confidence: 88%

“…In [14,13], a result indicates that competitive inhibition of cortisol and PGE2, in which PGE2 is externally injected via a pneumococcal vaccination, may present as fever. Thus, PGE2 from external means, which circulates via LPS and is later converted to PGE2 via COX, can interact within the hypothalamus with glucocorticoid receptors and alter the balance between thermoregulatory neurotransmitters and cortisol levels.…”

Section: Systems Regulationmentioning

confidence: 99%

“…Further correlations can be inferred from the undulation of fever characterizing disease such as brucella [5] and the rise and fall of CORT during the day and night [17] as well as respiratory systems during sleep [18,1]. Prostaglandins (PG) are a family of molecules that has received significant attention, but its association with cortisol has not been examined prior to this study (see a companion article of this lab [14] as well as the results presented herein). Prostaglandins differ from endocrine hormones, such as cortisol, since prostaglandins are produced locally in many places widely distributed throughout the human body, rather than at a single site like cortisol.…”

Section: Introductionmentioning

confidence: 99%

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Competitive Inhibition of Cortisol by Prostaglandins at the Ligand Binding Domain of Glucocorticoid Receptors

Schaper

2019

Preprint

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Here, a pathway is shown for the first time indicating competitive inhibition of cortisol by prostaglandins at the critical ligand binding domain of glucocorticoid receptors. This is significant since these materials are widely distributed: glucocorticoid receptors, cortisol and prostaglandins are found in almost every cell and tissue in the human body. In this article, a cooperative relationship is shown between cortisol and prostaglandin results during normative homeostatic conditions, and thus indicates capability of localized control, which is instructive for understanding as well as diagnosis of deviations from optimal physiological function. Moreover, as glucocorticoid receptors are nominally driven through cortisol concentration, the hypothesis developed in this manuscript indicates that the introduction of exogenous sources of prostaglandins, as associated with bacterial infection for example, might trigger dysfunctional responses, including signs and symptoms of disease like fever. The results demonstrating this association of competitive inhibition of cortisol and prostaglandins include comparative molecular modeling analyzing hydrophobic, hydrogen bonding, electrostatic and topology considerations that indicate the similarity in chemical affinity of cortisol and prostaglandin in a preferred configuration at the site of the ligand binding domain of glucocorticoid receptors. The work is useful in understanding normative physiological function as well as for developing treatments during certain diseased states.

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Section: Introductionsupporting

confidence: 88%

Section: Systems Regulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Competitive Inhibition of Cortisol by Prostaglandins at the Ligand Binding Domain of Glucocorticoid Receptors

Schaper

2019

Preprint

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“…• Identification of thermoregulation model: The model structure for thermoregulation 675 described in the supplemental preprints [4,21] was used: to evaluate the ability of the model to produce the characteristic temperature response, a model for each of the three days was determined using system identification techniques using the Matlab programming language, system identification toolbox [13]. A forcing function of a step-down in physical activity was considered as the exogenous input of physical 680 activity.…”

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confidence: 99%

Molecular Pathways Resultant in Fever due to Inhibitory Effects of Binding PGE2 to Glucocorticoid Receptors

Schaper

2020

Preprint

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5Thermoregulation is crucial to homeostasis, but the mechanisms of its dysfunction are still largely mysterious, including fever, which is generally the most disconcerting sign of a serious infection or disease. Theories on body temperature dynamics that aim to explain a fever, such as changes in an internal setpoint, have been proposed, but none can identify the fundamental molecular pathways that produce a fever. Moreover, 10 causative substances, pyrogens such as prostaglandin E2 (PGE2), have not been associated with receptors at the hypothalamus, which is responsible for autonomic control of temperature, and therefore no molecular path has been previously identified that can elucidate the causative reason for fever. Here, molecular pathways resultant in fever are identified for the first time. Based on recent developments made by this lab, 15 which has shown that PGE2 possesses similar binding affinity as the hormone cortisol (CORT) at the critical ligand binding domain (LBD) of glucocorticoid receptors (GR); mathematical modeling and a case study for validation is used to present that competitive inhibition of CORT by PGE2 as the fundamental reason for dysfunctional dynamics of body temperature, including fever. The model characterizing temperature 20 is in the form of a multivariable feedback controller comprised of a superposition of proportional and derivative terms of temperature, CORT, and PGE2 concentration at the hypothalamus thereby linking the cardiovascular, immune, and neural systems. The model constitutes a framework of linear equations that describes a closed-loop system of body temperature effects in response to infectious agents, triggering events, 25 * cschaper@transferdevices.com Graphical Abstract 65Here, the newly found association of CORT and PGE2 at the LBD is used to revisit the mathematical model of fever previously derived absent chemistry, although the model predicted its characteristics. Here, material and energy relations are added for CORT and PGE2, including the hypothalamic-pituitary-adrenal (HPA) axis, and the pathways are specified and integrated into the model to analyze temperature and fever. The model 85 is verified by comparing it to the case history of the temperature response including hypothermia and hyperthermia. Thus, a basic framework is developed for thermoregulation, which is vital to homeostasis and to understanding of basic physiology.Moreover, this study on fevers can be adapted to other signs and symptoms of disease, particularly infections. As the hypothalamus is the central controller of the autonomic 90 nervous system, disruption due to the processing of cortisol via prostaglandins, will cause misprocessing of other functions besides temperature. In a similar manner, other aspects such as fatigue and even emotional dysfunction, such as depression, may be impacted by disease through the molecular pathways described in this article. Some of these issues are described in the discussion section. 2 ResultsIt is the thesis of this article that through the competit...

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Identifying Integrative Molecular Pathways for Predictive Modeling of Infectious Disease

Cited by 2 publications

References 25 publications

Competitive Inhibition of Cortisol by Prostaglandins at the Ligand Binding Domain of Glucocorticoid Receptors

Competitive Inhibition of Cortisol by Prostaglandins at the Ligand Binding Domain of Glucocorticoid Receptors

Molecular Pathways Resultant in Fever due to Inhibitory Effects of Binding PGE2 to Glucocorticoid Receptors

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