A global circadian repressor controls antiphasic expression of metabolic genes in Neurospora.

The white-collar complex (WCC), the core transcription factor of the circadian clock of Neurospora, activates morning-specific expression of the transcription repressor CSP1. Newly synthesized CSP1 exists in a transient complex with the corepressor RCM1/RCO1 and the ubiquitin ligase UBR1. CSP1 is rapidly hyperphosphorylated and degraded via UBR1 and its ubiquitin conjugase RAD6.

Circadian conformational change of the Neurospora clock protein FREQUENCY triggered by clustered hyperphosphorylation of a basic domain.

In the course of a day, the Neurospora clock protein FREQUENCY (FRQ) is progressively phosphorylated at up to 113 sites and eventually degraded. Phosphorylation and degradation are crucial for circadian time keeping, but it is not known how phosphorylation of a large number of sites correlates with circadian degradation of FRQ. We show that two amphipathic motifs in FRQ interact over a long distance, bringing the positively charged N-terminal portion in spatial proximity to the negatively charged middle and C-terminal portion of FRQ.

A model for cyst lumen expansion and size regulation via fluid secretion.

Many internal epithelial organs derive from cysts, which are tissues comprised of bent epithelial cell layers enclosing a lumen. Ion accumulation in the lumen drives water influx and consequently water accumulation and cyst expansion. Lumen-size recognition is important for the regulation of organ size.

Inositol trisphosphate receptor and ion channel models based on single-channel data.

The inositol trisphosphate receptor (IPR) plays an important role in controlling the dynamics of intracellular Ca(2+). Single-channel patch-clamp recordings are a typical way to study these receptors as well as other ion channels. Methods for analyzing and using this type of data have been developed to fit Markov models of the receptor.

A kinetic model of the inositol trisphosphate receptor based on single-channel data.

In many cell types, the inositol trisphosphate receptor is one of the important components controlling intracellular calcium dynamics, and an understanding of this receptor is necessary for an understanding of calcium oscillations and waves. Based on single-channel data from the type-I inositol trisphosphate receptor, and using a Markov chain Monte Carlo approach, we show that the most complex time-dependent model that can be unambiguously determined from steady-state data is one with three closed states and one open state, and we determine how the rate constants depend on calcium. Because the transitions between these states are complex functions of calcium concentration, each model state must correspond to a group of physical states.

Markov chain Monte Carlo fitting of single-channel data from inositol trisphosphate receptors.

In many cell types, the inositol trisphosphate receptor (IPR) is one of the important components that control intracellular calcium dynamics, and an understanding of this receptor (which is also a calcium channel) is necessary for an understanding of calcium oscillations and waves. Recent advances in experimental techniques now allow for the measurement of single-channel activity of the IPR in conditions similar to its native environment, and these data can be used to determine the rate constants in Markov models of the IPR. We illustrate a parameter estimation method based on Markov chain Monte Carlo, which can be used to fit directly to single-channel data, and determining, as an intrinsic part of the fit, the times at which the IPR is opening and closing.

A mathematical model of fluid secretion from a parotid acinar cell.

Salivary fluid secretion is crucial for preventing problems such as dryness of mouth, difficulty with mastication and swallowing, as well as oral pain and dental cavities. Fluid flow is driven primarily by the transepithelial movement of chloride and sodium ions into the parotid acinus lumen. The activation of Cl(-) channels is calcium dependent, with the average elevated calcium concentration during calcium oscillations increasing the conductance of the channels, leading to an outflow of Cl(-).

A bifurcation analysis of calcium buffering.

Many mathematical models of calcium oscillations model buffering implicitly by using a rapid buffering approximation. This approximation assumes that separate time scales can be distinguished, with the buffer reactions occurring on a faster time scale than the other calcium fluxes. The rapid buffering approximation is convenient as it reduces the model to a single transport equation for calcium, but buffering is not always so fast.