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“The formation of somites in the course of vertebrate segmentation is governed by an oscillator known as the segmentation clock, which is characterized by a period Cisplatin solubility dmso ranging from 30 min to a few hours depending on the organism. This oscillator permits the synchronized activation of segmentation genes in successive cohorts of cells in the presomitic mesoderm in response to a periodic signal emitted by the segmentation clock, thereby defining the future segments. Recent microarray experiments [Dequeant, M.L., Glynn, E., Gaudenz, K., Wahl, M., Chen, J., Mushegian, A., Pourquie, O., 2006. A complex oscillating network

of signaling genes underlies the mouse segmentation clock. Science 314, 1595-1598] indicate that the Notch, Writ and Fibroblast Growth Factor (FGF) H 89 concentration signaling pathways are involved in the mechanism of the segmentation clock. By means of computational modeling, we investigate the conditions in which sustained oscillations occur in these three signaling pathways. First we show that negative feedback mediated by the Lunatic Fringe protein

on intracellular Notch activation can give rise to periodic behavior in the Notch pathway. We then show that negative feedback exerted by Axin2 on the degradation of beta-catenin through formation of the Axin2 destruction complex can produce oscillations in the Writ pathway. Likewise, negative feedback on FGF signaling mediated by the phosphatase Selleck WH-4-023 product of the gene MKP3/Dusp6 can produce oscillatory gene expression in the FGF pathway. Coupling the Wnt, Notch and FGF oscillators through common intermediates can lead to synchronized oscillations in the three signaling pathways or to complex periodic behavior, depending on the relative periods of oscillations in the three pathways. The phase relationships between cycling genes in the three pathways depend on the nature of the coupling

between the pathways and on their relative autonomous periods. The model provides a framework for analyzing the dynamics of the segmentation clock in terms of a network of oscillating modules involving the Wnt, Notch and FGF signaling pathways. (c) 2008 Elsevier Ltd. All rights reserved.”
“Parkinson’s disease (PD) is the second most common neurodegenerative disorder with similar to 2% of people over age 65 suffering from this disease. Risk factors for PD involve interplay between still poorly defined genetic and non-genetic contributors, but appear to converge upon cellular pathways that mediate protein misfolding and oxidative stress that lead to dopaminergic neuron loss. The identification of either new or repurposed drugs that exhibit benefit in slowing the age-dependent neuronal damage that occurs in PD is a significant goal of much ongoing research. We have exploited the nematode Caenorhabditis elegans as a model system by which the neuroprotective capacity of acetaminophen could be rapidly evaluated for efficacy in attenuating dopamine (DA) neurodegeneration.