PubMed Health⌕ Search

Biomedical subjects

Marcelle Kaufman

Publications and source records attributed to Marcelle Kaufman.

3 recordsLinked to original sources

Emergence of complex behaviour from simple circuit structures.

The set of (feedback) circuits of a complex system is the machinery that allows the system to be aware of the levels of its crucial constituents. Circuits can be identified without ambiguity from the elements of the Jacobian matrix of the system. There are two types of circuits: positive if they comprise an even number of negative interactions, negative if this number is odd. The two types of circuits play deeply different roles: negative circuits are required for homeostasis, with or without oscillations, positive circuits are required for multistationarity, and hence, in biology, for differentiation and memory. In non-linear systems, a circuit can positive or negative (an 'ambiguous circuit', depending on the location in phase space. Full circuits are those circuits (or unions of disjoint circuits) that imply all the variables of the system. There is a tight relation between circuits and steady states. Each full circuit, if isolated, generates steady state(s) whose nature (eigenvalues) is determined by the structure of the circuit. Multistationarity requires the presence of at least two full circuits of opposite Eisenfeld signs, or else, an ambiguous circuit. We show how a significant part of the dynamical behaviour of a system can be predicted by a mere examination of its Jacobian matrix. We also show how extremely complex dynamics can be generated by such simple logical structures as a single (full and ambiguous) circuit.

Feedback↗

A theoretical model for the regulation of Sex-lethal, a gene that controls sex determination and dosage compensation in Drosophila melanogaster.

Cell fate commitment relies upon making a choice between different developmental pathways and subsequently remembering that choice. Experimental studies have thoroughly investigated this central theme in biology for sex determination. In the somatic cells of Drosophila melanogaster, Sex-lethal (Sxl) is the master regulatory gene that specifies sexual identity. We have developed a theoretical model for the initial sex-specific regulation of Sxl expression. The model is based on the well-documented molecular details of the system and uses a stochastic formulation of transcription. Numerical simulations allow quantitative assessment of the role of different regulatory mechanisms in achieving a robust switch. We establish on a formal basis that the autoregulatory loop involved in the alternative splicing of Sxl primary transcripts generates an all-or-none bistable behavior and constitutes an efficient stabilization and memorization device. The model indicates that production of a small amount of early Sxl proteins leaves the autoregulatory loop in its off state. Numerical simulations of mutant genotypes enable us to reproduce and explain the phenotypic effects of perturbations induced in the dosage of genes whose products participate in the early Sxl promoter activation.

Animals↗

Conceptual tools for the integration of data.

We propose to start the analysis of complex systems by systematically identifying the feedback circuits that govern their dynamics. These circuits can be identified without any ambiguity by examining the Jacobian matrix of the system. They provide precious information regarding the number and nature of steady states. Logical descriptions use variables and functions that can take only a limited number of discrete values (in simple cases, only two, 0 or 1). We developed an asynchronous method with continuous time, generalized by using variables with more than two levels and logical parameters. Reverse logics is a synthetic, inductive method. It aims at proceeding rationally from the experimental facts towards models rather than from models to predictions.

Animals↗