Absence of stable intermediates on the folding pathway of barnase

Barnase is one of the few protein models that has been studied extensively for protein folding. Previous studies led to the conclusion that barnase folds through a very stable submillisecond intermediate (≈3 kcal/mol). The structure of this intermediate was characterized intensively by using a protein engineering approach. This intermediate has now been reexamined with three direct and independent methods. (i) Hydrogen exchange experiments show very small protection factors (≈2) for the putative intermediate, indicating a stability of ≈0.0 kcal/mol. (ii) Denaturant-dependent unfolding of the putative intermediate is noncooperative and indicates a stability less than 0.0 kcal/mol. (iii) The logarithm of the unfolding rate constant of native barnase vs. denaturant concentrations is not linear. Together with the measured rate (“I” to N), this nonlinear behavior accounts for almost all of the protein stability, leaving only about 0.3 kcal/mol that could be attributed to the rapidly formed intermediate. Other observations previously interpreted to support the presence of an intermediate are now known to have alternative explanations. These results cast doubts on the previous conclusions on the nature of the early folding state in barnase and therefore should have important implications in understanding the early folding events of barnase and other proteins in general.

Self-organized defensive behavior in honeybees

We investigated the defensive behavior of honeybees under controlled experimental conditions. During an attack on two identical targets, the spatial distribution of stings varied as a function of the total number of stings, evincing the classic “pitchfork bifurcation” phenomenon of nonlinear dynamics. The experimental results support a model of defensive behavior based on a self-organizing mechanism. The model helps to explain several of the characteristic features of the honeybee defensive response: (i) the ability of the colony to localize and focus its attack, (ii) the strong variability between different hives in the intensity of attack, as well as (iii) the variability observed within the same hive, and (iv) the ability of the colony to amplify small differences between the targets.

Nonlinear-dynamical arrhythmia control in humans

Nonlinear-dynamical control techniques, also known as chaos control, have been used with great success to control a wide range of physical systems. Such techniques have been used to control the behavior of in vitro excitable biological tissue, suggesting their potential for clinical utility. However, the feasibility of using such techniques to control physiological processes has not been demonstrated in humans. Here we show that nonlinear-dynamical control can modulate human cardiac electrophysiological dynamics by rapidly stabilizing an unstable target rhythm. Specifically, in 52/54 control attempts in five patients, we successfully terminated pacing-induced period-2 atrioventricular-nodal conduction alternans by stabilizing the underlying unstable steady-state conduction. This proof-of-concept demonstration shows that nonlinear-dynamical control techniques are clinically feasible and provides a foundation for developing such techniques for more complex forms of clinical arrhythmia.

Linear and nonlinear pathways of spectral information transmission in the cochlear nucleus

At the level of the cochlear nucleus (CN), the auditory pathway divides into several parallel circuits, each of which provides a different representation of the acoustic signal. Here, the representation of the power spectrum of an acoustic signal is analyzed for two CN principal cells—chopper neurons of the ventral CN and type IV neurons of the dorsal CN. The analysis is based on a weighting function model that relates the discharge rate of a neuron to first- and second-order transformations of the power spectrum. In chopper neurons, the transformation of spectral level into rate is a linear (i.e., first-order) or nearly linear function. This transformation is a predominantly excitatory process involving multiple frequency components, centered in a narrow frequency range about best frequency, that usually are processed independently of each other. In contrast, type IV neurons encode spectral information linearly only near threshold. At higher stimulus levels, these neurons are strongly inhibited by spectral notches, a behavior that cannot be explained by level transformations of first- or second-order. Type IV weighting functions reveal complex excitatory and inhibitory interactions that involve frequency components spanning a wider range than that seen in choppers. These findings suggest that chopper and type IV neurons form parallel pathways of spectral information transmission that are governed by two different mechanisms. Although choppers use a predominantly linear mechanism to transmit tonotopic representations of spectra, type IV neurons use highly nonlinear processes to signal the presence of wide-band spectral features.