Global identifiability of nonlinear models of biological systems.

A prerequisite for well-posedness of parameter estimation of biological and physiological systems is a priori global identifiability, a property which concerns uniqueness of the solution for the unknown model parameters. Assessing a priori global identifiability is particularly difficult for nonlinear dynamic models. Various approaches have been proposed in the literature but no solution exists in the general case. In this paper, we present a new algorithm for testing global identifiability of nonlinear dynamic models, based on differential algebra. The characteristic set associated to the dynamic equations is calculated in an efficient way and computer algebra techniques are used to solve the resulting set of nonlinear algebraic equations. The algorithm is capable of handling many features arising in biological system models, including zero initial conditions and time-varying parameters. Examples of usage of the algorithm for analyzing a priori global identifiability of nonlinear models of biological and physiological systems are presented.

Global identifiability of linear compartmental models--a computer algebra algorithm.

A priori global identifiability deals with the uniqueness of the solution for the unknown parameters of a model and is, thus, a prerequisite for parameter estimation of biological dynamic models. Global identifiability is however difficult to test, since it requires solving a system of algebraic nonlinear equations which increases both in nonlinearity degree and number of terms and unknowns with increasing model order. In this paper, a computer algebra tool, GLOBI (GLOBal Identifiability) is presented, which combines the topological transfer function method with the Buchberger algorithm, to test global identifiability of linear compartmental models. GLOBI allows for the automatic testing of a priori global identifiability of general structure compartmental models from general multi input-multi output experiments. Examples of usage of GLOBI to analyze a priori global identifiability of some complex biological compartmental models are provided.

Application of a novel chemiluminescence-based DNA detection method to single-vector and multiplex DNA sequencing.

A chemiluminescent DNA detection method is described and its application shown for both single-vector and multiplex DNA sequencing using the standard dideoxy chain-termination process. This recently developed detection method, which utilizes the light emitted by an enzyme-catalyzed dioxetane reaction, is highly sensitive and affords significant advantages in safety and speed over the traditional radioactive labeling method. When adapted to a multiplex strategy, this chemiluminescent detection method constitutes a safe, simple and rapid method for increasing the throughput of DNA sequencing procedures.

Preprocorticotropin releasing hormone: cDNA sequence and in vitro processing.

Human corticotropin releasing hormone (hCRH) is expressed in both hypothalamus and placenta. Its expression in placenta increases markedly in the latter part of gestation. We have isolated and characterized a human placental CRH cDNA clone and performed in vitro translation of sense-strand hCRH cRNA synthesized from this cDNA and co-translational processing of the resulting preproCRH peptide. Sequence analysis of the cDNA confirms the exon-intron junctions predicted from the gene sequence and establishes the presence of at least two sites of transcription initiation of the human CRH gene in placenta. The translated preproCRH gene product contains a hydrophobic, functional signal sequence which suggests that placental CRH peptide is capable of being secreted. These structural features of the preproCRH mRNA and peptide may help to understand the regulation of placental CRH observed during human gestation.