Biomedical subjects

Karen M Page

Publications and source records attributed to Karen M Page.

11 recordsLinked to original sources

PubMed2007

Generalized, switch-like competitive heterodimerization networks.

High-dimensional switches have been proposed as a way to model cellular differentiation, particularly in the context of basic Helix-Loop-Helix (bHLH) competitive heterodimerization networks. A previous study derived a simple rule showing how many elements can be co-expressed, depending on the rate of competition within the network. A limitation to that rule, however, is that many biochemical parameters were considered to be identical. Here, we derive a generalized rule. This in turns allows one to study more ways in which these networks could be regulated, linking intrinsic cellular differentiation determinants to extracellular cues.

Basic Helix-Loop-Helix Proteins↗

PubMed2006

The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression.

The mouse mutant ducky and its allele ducky(2J) represent a model for absence epilepsy characterized by spike-wave seizures and cerebellar ataxia. These mice have mutations in Cacna2d2, which encodes the alpha2delta-2 calcium channel subunit. Of relevance to the ataxic phenotype, alpha2delta-2 mRNA is strongly expressed in cerebellar Purkinje cells (PCs). The Cacna2d2(du2J) mutation results in a 2 bp deletion in the coding region and a complete loss of alpha2delta-2 protein. Here we show that du(2J)/du(2J) mice have a 30% reduction in somatic calcium current and a marked fall in the spontaneous PC firing rate at 22 degrees C, accompanied by a decrease in firing regularity, which is not affected by blocking synaptic input to PCs. At 34 degrees C, du(2J)/du(2J) PCs show no spontaneous intrinsic activity. Du(2J)/du(2J) mice also have alterations in the cerebellar expression of several genes related to PC function. At postnatal day 21, there is an elevation of tyrosine hydroxylase mRNA and a reduction in tenascin-C gene expression. Although du(2J)/+ mice have a marked reduction in alpha2delta-2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tyrosine hydroxylase gene expression. However, du(2J)/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in alpha2delta-2. A hypothesis for future study is that effects on gene expression occur as a result of a reduction in somatic calcium currents, whereas effects on PC firing occur as a long-term result of loss of alpha2delta-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.

Animals↗

PubMed2006

Stochastic models of receptor oligomerization by bivalent ligand.

In this paper, we develop stochastic models of receptor binding by a bivalent ligand. A detailed kinetic study allows us to analyse the role of cross-linking in cell activation by receptor oligomerization. We show how oligomer formation could act to buffer intracellular signalling against stochastic fluctuations. In addition, we put forward the hypothesis that formation of long linear oligomers increases the range of ligand concentration to which the cell is responsive, whereas formation of closed oligomers increases ligand concentration specificity. Thus, different physiological functions requiring different degrees of specificity to ligand concentration would favour formation of oligomers with different lengths and geometries. Furthermore, provided that ligand concentration specificity is taken as a design principle, our model enables us to estimate parameters, such as the minimum proportion of receptors, that must engage in oligomer formation in order to trigger a cellular response.

Computer Simulation↗

PubMed2005

Mathematical models of the fate of lymphoma B cells after antigen receptor ligation with specific antibodies.

We formulate models of the mechanism(s) by which B cell lymphoma cells stimulated with an antibody specific to the B cell receptor (IgM) become quiescent or apoptotic. In particular, we aim to reproduce experimental results by Marches et al. according to which the fate of the targeted cells (Daudi) depends on the levels of expression of p21(Waf1) (p21) cell-cycle inhibitor. A simple model is formulated in which the basic ingredients are p21 and caspase activity, and their mutual inhibition. We show that this model does not reproduce the experimental results and that further refinement is needed. A second model successfully reproduces the experimental observations, for a given set of parameter values, indicating a critical role for Myc in the fate decision process. We use bifurcation analysis and objective sensitivity analysis to assess the robustness of our results. Importantly, this analysis yields experimentally testable predictions on the role of Myc, which could have therapeutic implications.

Apoptosis↗

PubMed2004

Dominant-negative calcium channel suppression by truncated constructs involves a kinase implicated in the unfolded protein response.

Expression of the calcium channel Ca(V)2.2 is markedly suppressed by coexpression with truncated constructs of Ca(V)2.2. Furthermore, a two-domain construct of Ca(V)2.1 mimicking an episodic ataxia-2 mutation strongly inhibited Ca(V)2.1 currents. We have now determined the specificity of this effect, identified a potential mechanism, and have shown that such constructs also inhibit endogenous calcium currents when transfected into neuronal cell lines. Suppression of calcium channel expression requires interaction between truncated and full-length channels, because there is inter-subfamily specificity. Although there is marked cross-suppression within the Ca(V)2 calcium channel family, there is no cross-suppression between Ca(V)2 and Ca(V)3 channels. The mechanism involves activation of a component of the unfolded protein response, the endoplasmic reticulum resident RNA-dependent kinase (PERK), because it is inhibited by expression of dominant-negative constructs of this kinase. Activation of PERK has been shown previously to cause translational arrest, which has the potential to result in a generalized effect on protein synthesis. In agreement with this, coexpression of the truncated domain I of Ca(V)2.2, together with full-length Ca(V)2.2, reduced the level not only of Ca(V)2.2 protein but also the coexpressed alpha2delta-2. Thapsigargin, which globally activates the unfolded protein response, very markedly suppressed Ca(V)2.2 currents and also reduced the expression level of both Ca(V)2.2 and alpha2delta-2 protein. We propose that voltage-gated calcium channels represent a class of difficult-to-fold transmembrane proteins, in this case misfolding is induced by interaction with a truncated cognate Ca(V) channel. This may represent a mechanism of pathology in episodic ataxia-2.

Animals↗

PubMed2004

Language learning: how much evidence does a child need in order to learn to speak grammatically?

In order to learn grammar from a finite amount of evidence, children must begin with in-built expectations of what is grammatical. They clearly are not born, however, with fully developed grammars. Thus early language development involves refinement of the grammar hypothesis until a target grammar is learnt. Here we address the question of how much evidence is required for this refinement process, by considering two standard learning algorithms and a third algorithm which is presumably as efficient as a child for some value of its memory capacity. We reformulate this algorithm in the context of Chomsky's 'principles and parameters' and show that it is possible to bound the amount of evidence required to almost certainly speak almost grammatically.

Algorithms↗

PubMed2002

Unifying evolutionary dynamics.

Darwinian evolution is based on three fundamental principles, reproduction, mutation and selection, which describe how populations change over time and how new forms evolve out of old ones. There are numerous mathematical descriptions of the resulting evolutionary dynamics. In this paper, we show that apparently very different formulations are part of a single unified framework. At the center of this framework is the equivalence between the replicator-mutator equation and the Price equation. From these equations, we obtain as special cases adaptive dynamics, evolutionary game dynamics, the Lotka-Volterra equation of ecology and the quasispecies equation of molecular evolution.

Animals↗

PubMed2002

Module dynamics of the GnRH signal transduction network.

We analyse computational modules of a frequency decoding signal transduction network. The gonadotropin releasing hormone (GnRH) signal transduction network mediates the biosynthesis and release of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH). The pulsatile pattern of GnRH production by the hypothalamus has a critical influence on the release and synthesis of gonadotropins in the pituitary. In humans, slower pulses lead to the expression of the beta-subunit of the LH protein and cause anovulation and amenorrhea. Higher frequency pulses lead to expression of the alpha subunit and a hypogonadal state. The frequency sensitivity is a consequence of the structure of the GnRH signal transduction network. We analyse individual components of this network, organized into three network architectures, and describe the frequency-decoding capabilities of each of these modules. We find that these modules are comparable to simple circuit elements, some of which integrate and others which perform as frequency sensitive filters. We propose that the cell computes by exploiting variation in the time scales of protein activation (phosphorylation) and gene expression.

Animals↗

PubMed2002

The novel product of a five-exon stargazin-related gene abolishes Ca(V)2.2 calcium channel expression.

We have cloned and characterized a new member of the voltage-dependent Ca(2+) channel gamma subunit family, with a novel gene structure and striking properties. Unlike the genes of other potential gamma subunits identified by their homology to the stargazin gene, CACNG7 is a five-, and not four-exon gene whose mRNA encodes a protein we have designated gamma(7). Expression of human gamma(7) has been localized specifically to brain. N-type current through Ca(V)2.2 channels was almost abolished when co-expressed transiently with gamma(7) in either Xenopus oocytes or COS-7 cells. Furthermore, immunocytochemistry and western blots show that gamma(7) has this effect by causing a large reduction in expression of Ca(V)2.2 rather than by interfering with trafficking or biophysical properties of the channel. No effect of transiently expressed gamma(7) was observed on pre-existing endogenous N-type calcium channels in sympathetic neurones. Low homology to the stargazin-like gamma subunits, different gene structure and the unique functional properties of gamma(7) imply that it represents a distinct subdivision of the family of proteins identified by their structural and sequence homology to stargazin.

Amino Acid Sequence↗

PubMed2002

Empathy leads to fairness.

In the Ultimatum Game, two players are asked to split a prize. The first player, the proposer, makes an offer of how to split the prize. The second player, the responder, either accepts the offer, in which case the prize is split as agreed, or rejects it, in which case neither player receives anything. The rational strategy suggested by classical game theory is for the proposer to offer the smallest possible positive share and for the responder to accept. Humans do not play this way, however, and instead tend to offer 50% of the prize and to reject offers below 20%. Here we study the Ultimatum Game in an evolutionary context and show that empathy can lead to the evolution of fairness. Empathy means that individuals make offers which they themselves would be prepared to accept.

Biological Evolution↗

PubMed2001

The ducky mutation in Cacna2d2 results in altered Purkinje cell morphology and is associated with the expression of a truncated alpha 2 delta-2 protein with abnormal function.

The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and cerebellar ataxia. A mutation in Cacna2d2, the gene encoding the alpha 2 delta-2 voltage-dependent calcium channel accessory subunit, has been found to underlie the ducky phenotype. The alpha 2 delta-2 mRNA is strongly expressed in cerebellar Purkinje cells. We show that du/du mice have abnormalities in their Purkinje cell dendritic tree. The mutation in alpha 2 delta-2 results in the introduction of a premature stop codon and predicts the expression of a truncated protein encoded by the first three exons of Cacna2d2, followed by 8 novel amino acids. We show that both mRNA and protein corresponding to this predicted transcript are expressed in du/du cerebellum and present in Purkinje cells. Whereas the alpha 2 delta-2 subunit increased the peak current density of the Ca(V)2.1/beta(4) channel combination when co-expressed in vitro, co-expression with the truncated mutant alpha 2 delta-2 protein reduced current density, indicating that it may contribute to the du phenotype.

Alleles↗