Differential stimulation of signaling pathways initiated by Edg-2 in response to lysophosphatidic acid or sphingosine-1-phosphate

Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are produced during cell activation and have multiple effects on cells. A family of seven transmembrane-spanning domain G-protein-coupled receptors, named Edg, mediate these effects of LPA and S1P. In this study, transient overexpression of Edg-2 sensitized MG63 human osteosarcoma cells to both LPA- and S1P-mediated stimulation of fibronectin matrix deposition and actin stress fiber formation. Both lipids were active in the 1-20 nM concentration range on cells transfected with Edg-2 as compared to the 10-200 nM range on mock-transfected cells. The signaling pathway for matrix deposition by Edg-2-transfected cells was Rho dependent. Overexpression of Edg-2 also caused a tenfold decrease in the concentration of either LPA or S1P that activated MAPKinase (Erkl/2) in MG63 cells. LPA- or S1P-stimulated activation of Erkl/2 was Gi dependent. These results indicate that, in MG63 cells, Edg-2 mediates actin stress fiber formation, fibronectin matrix assembly, and MAPKinase activation in response to either LPA or S1P.     

Histamine receptor-mediated signaling during development and brain function in adulthood

Histamine might have an important role in brain development. However, most studies have focused on short-term effects of histamine receptor-mediated signaling on brain function in adulthood. Little is known about the potential long-term effects of histamine receptor-mediated signaling during development on brain function in adulthood. We hypothesize that increased postsynaptic histamine receptor-mediated signaling during development has detrimental effects on brain function in adulthood. Our data support this hypothesis. In the developing mouse brain, histamine H3 receptor blockade, which increases histamine release, has detrimental sex-dependent effects on object recognition, spatial learning in the water maze, and pre-pulse inhibition in adulthood. Our data also support the hypothesis that histamine mediates the detrimental long-term sex-dependent effects of methamphetamine exposure early in life on these brain functions in adulthood. Therefore, increased efforts are warranted to carefully evaluate the effects of drugs that directly or indirectly affect histamine receptor-mediated signaling during development on cognitive function later in life.     

Lysophosphatidic acid: receptors, signaling and survival

Though the mitogenic activity of lysophosphatidic acid (LPA) has been well established through classical studies, its mechanism of action was long obscure. Recent identification and cloning of LPA-specific receptors has led to the elucidation of the G-proteins and signaling pathways through which this molecule functions. In addition to its mitogenic properties, recent reports have suggested that LPA may also promote cell survival. This review will summarize the current literature regarding LPA signaling and its role as an antiapoptotic factor.     

Comparative platelet anti-aggregant activity of D-cysteinolic acid analogues

D-Cysteinolic acid (1) analogues with an S-C-C-N skeleton showed increased platelet anti-aggregant activity in the following order: 2-aminoethanesulfonic acids, thiazolidines, 2-aminoethanethiols and 2-aminoethyl disulfides. Methyl substitutions at the 2-position potentiated the activity. Of these analogues, bis [(R)-2-aminopropyl] disulfide was the most potent inhibitor of platelet aggregation, with about 600-fold the activity of (1).     

From carrot to clinic: an overview of the retinoic acid signaling pathway

Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors.     

Retinoic acid signaling and neurogenic niche regulation in the developing peripheral nervous system of the cephalochordate amphioxus

The retinoic acid (RA) signaling pathway regulates axial patterning and neurogenesis in the developing central nervous system (CNS) of chordates, but little is known about its roles during peripheral nervous system (PNS) formation and about how these roles might have evolved. This study assesses the requirement of RA signaling for establishing a functional PNS in the cephalochordate amphioxus, the best available stand-in for the ancestral chordate condition. Pharmacological manipulation of RA signaling levels during embryogenesis reduces the ability of amphioxus larvae to respond to sensory stimulation and alters the number and distribution of ectodermal sensory neurons (ESNs) in a stage- and context-dependent manner. Using gene expression assays combined with immunohistochemistry, we show that this is because RA signaling specifically acts on a small population of soxb1c-expressing ESN progenitors, which form a neurogenic niche in the trunk ectoderm, to modulate ESN production during elongation of the larval body. Our findings reveal an important role for RA signaling in regulating neurogenic niche activity in the larval amphioxus PNS. Although only few studies have addressed this issue so far, comparable RA signaling functions have been reported for neurogenic niches in the CNS and in certain neurogenic placode derivatives of vertebrates. Accordingly, the here-described mechanism is likely a conserved feature of chordate embryonic and adult neural development.     

Investigations of receptor-mediated phagocytosis by hormone-induced (imprinted)Tetrahymena pyriformis

Receptor-mediated endocytosis byTetrahvmena pyriformis was studied using tetramethylrhodamine isothiocyanate-labeled concanavalin A (TRITC-Con A) with fluorescence and confocal microscopy. In the presence of insulin, or 24 h after insulin pretreatment (hormonal imprinting), the binding and uptake of TRITC-Con A increased when compared to controls, owing to the binding of TRITC-Con A to sugar oligomers of insulin recptors. Mannose inhibited the binding of Con A, thus demonstrating the specificity of binding. Histamine, a phagocytosis-promoting factor in mammals andTetrahymena, and galactose, did not influence the uptake of TRITC-Con A.     

Statistical analyses of freeway traffic flows

This paper concerns the exploration of statistical models for the analysis of observational freeway flow data, and the development of empirical models to capture and predict short‐term changes in traffic flow characteristics on sequences of links in a partially detectorized freeway network. A first set of analyses explores regression models for minute‐by‐minute traffic flows, taking into account time of day, day of the week, and recent upstream detector‐based flows. Day‐ and link‐specific random effects are used in a hierarchical statistical modelling framework. A second set of analyses captures day‐specific idiosyncrasies in traffic patterns by including parameters that may vary throughout the day. Model fit and short‐term predictions of flows are thus improved significantly. A third set of analyses includes recent downstream flows as additional predictors. These further improvements, though marginal in most cases, can be quite radically useful in cases of very marked breakdown of freeway flows on some links. These three modelling stages are described and developed in analyses of observational flow data from a set of links on Interstate Highway 5 (I‐5) near Seattle. Copyright © 2002 John Wiley & Sons, Ltd.     

Conditional distribution analyses of probabilistic forecasts

Probabilistic forecasts have good ‘external correspondence’ if events that are assigned probabilities close to 1 tend to occur frequently, whereas those assigned probabilities near 0 tend to occur rarely. This paper describes simple procedures for analysing external correspondence into meaningful components that might guide efforts to understand and improve forecasting performance. The procedures focus on differences between the judgements made by the forecaster when the target event occurs, as compared to when it does not. The illustrations involve a professional oddsmaker's predictions of baseball game outcomes, meteorologists' precipitation forecasts and physicians' diagnoses of pneumonia. The illustrations demonstrate the ability of the procedures to highlight important forecasting tendencies that are sometimes more difficult to discern by other means.