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Reconstruction of in vivo time-evolving neuroendocrine dose - response properties unveils admixed deterministic and stochastic elements

Keenan, Daniel M., Alexander, Susan, Irvine, Clifford H.G., Clarke, Iaine, Scott, Chris J., Turner, Anne I., Tilbrook, A.J., Canny, B.J. and Veldhuis, Johannes D. 2004, Reconstruction of in vivo time-evolving neuroendocrine dose - response properties unveils admixed deterministic and stochastic elements, Proceedings of the national academy of sciences of the United States of America, vol. 101, no. 17, pp. 6740-6745, doi: 10.1073/pnas.0300619101.

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Title Reconstruction of in vivo time-evolving neuroendocrine dose - response properties unveils admixed deterministic and stochastic elements
Author(s) Keenan, Daniel M.
Alexander, Susan
Irvine, Clifford H.G.
Clarke, Iaine
Scott, Chris J.
Turner, Anne I.ORCID iD for Turner, Anne I. orcid.org/0000-0002-0682-2860
Tilbrook, A.J.
Canny, B.J.
Veldhuis, Johannes D.
Journal name Proceedings of the national academy of sciences of the United States of America
Volume number 101
Issue number 17
Start page 6740
End page 6745
Publisher National Academy of Sciences
Place of publication Washington, D.C.
Publication date 2004-04-27
ISSN 0027-8424
1091-6490
Summary Homeostasis in the intact organism is achieved implicitly by repeated incremental feedback (inhibitory) and feedforward (stimulatory) adjustments enforced via intermittent signal exchange. In separated systems, neurohormone signals act deterministically on target cells via quantifiable effector-response functions. On the other hand, in vivo interglandular signaling dynamics have not been estimable to date. Indeed, experimentally isolating components of an interactive network definitionally disrupts time-sensitive linkages. We implement and validate analytical reconstruction of endogenous effector-response properties via a composite model comprising (i) a deterministic basic feedback and feedforward ensemble structure; (ii) judicious statistical allowance for possible stochastic variability in individual biologically interpretable dose–response properties; and (iii) the sole data requirement of serially observed concentrations of a paired signal (input) and response (output). Application of this analytical strategy to a prototypical neuroendocrine axis in the conscious uninjected horse, sheep, and human (i) illustrates probabilistic estimation of endogenous effector dose–response properties; and (ii) unmasks statistically vivid (2- to 5-fold) random fluctuations in inferred target-gland responsivity within any given pulse train. In conclusion, balanced mathematical formalism allows one to (i) reconstruct deterministic properties of interglandular signaling in the intact mammal and (ii) quantify apparent signal-response variability over short time scales in vivo. The present proof-of-principle experiments introduce a previously undescribed means to estimate time-evolving signal-response relationships without isotope infusion or pathway disruption.
Language eng
DOI 10.1073/pnas.0300619101
Field of Research 110399 Clinical Sciences not elsewhere classified
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2004, The National Academy of Sciences of the USA
Persistent URL http://hdl.handle.net/10536/DRO/DU:30021976

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