A model of excitation and adaptation in bacterial chemotaxis

Bacterial chemotaxis is widely studied because of its accessibility and because it incorporates processes that are important in a number of sensory systems: signal transduction, excitation, adaptation, and a change in behavior, all in response to stimuli. Quantitative data on the change in behavior are available for this system, and the major biochemical steps in the signal transduction/processing pathway have been identified. We have incorporated recent biochemical data into a mathematical model that can reproduce many of the major features of the intracellular response, including the change in the level of chemotactic proteins to step and ramp stimuli such as those used in experimental protocols. The interaction of the chemotactic proteins with the motor is not modeled, but we can estimate the degree of cooperativity needed to produce the observed gain under the assumption that the chemotactic proteins interact directly with the motor proteins.

A model for individual and collective cell movement in Dictyostelium discoideum

The cellular slime mold Dictyostelium discoideum is a widely used model system for studying a variety of basic processes in development, including cell–cell signaling, signal transduction, pattern formation, cell motility, and the movement of tissue-like aggregates of cells. Many aspects of cell motion are poorly understood, including how individual cell behavior produces the collective motion of cells observed within the mound and slug. Herein, we describe a biologically realistic model for motile D. discoideum cells that can generate active forces, that interact via surface molecules, and that can detect and respond to chemotactic signals. We model the cells as deformable viscoelastic ellipsoids and incorporate signal transduction and cell–cell signaling by using a previously developed model. The shape constraint restricts the admissible deformations but makes the simulation of a large number of interacting cells feasible. Because the model is based on known processes, the parameters can be estimated or measured experimentally. We show that this model can reproduce the observations on the chemotactic behavior of single cells, streaming during aggregation, and the collective motion of an aggregate of cells driven by a small group of pacemakers. The model predicts that the motion of two-dimensional slugs [Bonner, J. T. (1998) Proc. Natl. Acad. Sci. USA 95, 9355–9359] results from the same behaviors that are exhibited by individual cells; it is not necessary to invoke different mechanisms or behaviors. Our computational experiments also suggest previously uncharacterized phenomena that may be experimentally observable.

Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange– Nielsen Syndrome

KCNQ1 encodes KCNQ1, which belongs to a family of voltage-dependent K+ ion channel proteins. KCNQ1 associates with a regulatory subunit, KCNE1, to produce the cardiac repolarizing current, IKs. Loss-of-function mutations in the human KCNQ1 gene have been linked to Jervell and Lange–Nielsen Syndrome (JLNS), a disorder characterized by profound bilateral deafness and a cardiac phenotype. To generate a mouse model for JLNS, we created a line of transgenic mice that have a targeted disruption in the Kcnq1 gene. Behavioral analysis revealed that the Kcnq1−/− mice are deaf and exhibit a shaker/waltzer phenotype. Histological analysis of the inner ear structures of Kcnq1−/− mice revealed gross morphological anomalies because of the drastic reduction in the volume of endolymph. ECGs recorded from Kcnq1−/− mice demonstrated abnormal T- and P-wave morphologies and prolongation of the QT and JT intervals when measured in vivo, but not in isolated hearts. These changes are indicative of cardiac repolarization defects that appear to be induced by extracardiac signals. Together, these data suggest that Kcnq1−/− mice are a potentially valuable animal model of JLNS.

A general two-process model describes the hydrogen exchange behavior of RNase A in unfolding conditions.

When NMR hydrogen exchange was used previously to monitor the kinetics of RNase A unfolding, some peptide NH protons were found to show EX2 exchange (detected by base catalysis) in addition to the expected EX1 exchange, whose rate is limited by the kinetic unfolding process. In earlier work, two groups showed independently that a restricted two-process model successfully fits published hydrogen exchange rates of native RNase A in the range 0-0.7 M guanidinium chloride. We find that this model predicts properties that are very different from the observed properties of the EX2 exchange reactions of RNase A in conditions where guanidine-induced unfolding takes place. The model predicts that EX2 exchange should be too fast to measure by the technique used, whereas it is readily measurable. Possible explanations for the contradiction are considered here, and we show that removing the restriction from the earlier two-process model is sufficient to resolve the contradiction; instead of specifying that exchange caused by global unfolding occurs by the EX2 mechanism, we allow it to occur by the general mechanism, which includes both the EX1 and EX2 cases. It is logical to remove this restriction because global unfolding of RNase A is known to give rise to EX1 exchange in these unfolding conditions. Resolving the contradiction makes it possible to determine whether populated unfolding intermediates contribute to the EX2 exchange, and this question is considered elsewhere. The results and simulations indicate that moderate or high denaturant concentrations readily give rise to EX1 exchange in native proteins. Earlier studies showed that hydrogen exchange in native proteins typically occurs by the EX2 mechanism but that high temperatures or pH values above 7 may give rise to EX1 exchange. High denaturant concentrations should be added to the list of variables likely to cause EX1 exchange.