Using the biological taxonomy to access biological literature with PathBinderH.

UNLABELLED: PathBinderH allows users to make queries that retrieve sentences and the abstracts containing them from PubMed. Another aspect of PathBinderH is that users can specify biological taxa in order to limit searches by mentioning either the specified taxa, or their subordinate taxa, in the biological taxonomy. Although the current project requires this function only for plant taxa, the principle is extensible to the entire taxonomy. AVAILABILITY: www.plantgenomics.iastate.edu/PathBinderH. Source code and databases on request.

The mitogen-activated protein kinase p38 is necesssary for interleukin 1beta-induced monocyte chemoattractant protein 1 expression by human mesangial cells.

Mitogen-activated protein (MAP) kinases have been suggested as potential mediators for interleukin 1beta (IL-1beta)-induced gene activation. This study investigated the role of the MAP kinases p38 and ERK2 in IL-1beta-mediated expression of the chemokine MCP-1 by human mesangial cells. Phosphorylation of p38 kinase, which is necessary for activation, increased significantly after IL-1beta treatment. p38 kinase immunoprecipitated from IL-1beta-treated cells phosphorylated target substrates to a greater extent than p38 kinase from controls. SB 203580, a selective p38 kinase inhibitor, was used to examine the role of p38 kinase in MCP-1 expression. SB 203580 decreased IL-1beta-induced MCP-1 mRNA and protein levels, but did not affect MCP-1 mRNA stability. Because NF-kappaB is necessary for MCP-1 gene expression, the effect of p38 kinase inhibition on IL-1beta induction of NF-kappaB was measured. SB 203580 (up to 25 microM) had no effect on IL-1beta-induced NF-kappaB nuclear translocation or DNA binding activity. Our previous work showed that IL-1beta also activates the MAP kinase ERK2 in human mesangial cells. PD 098059, a selective inhibitor of the ERK activating kinase MEK1, had no effect on IL-1beta-induced MCP-1 mRNA or protein levels, or on IL-1beta activation of NF-kappaB. These data indicate that p38 kinase is necessary for the induction of MCP-1 expression by IL-1beta, but is not involved at the level of cytoplasmic activation of NF-kappaB. In contrast, ERK2 does not mediate IL-1beta induced MCP-1 gene expression.

Interleukin-1beta induction of mitogen-activated protein kinases in human mesangial cells. Role of oxidation.

Interleukin-1beta (IL-1beta) significantly influences renal cellular function through the induction of several gene products. The molecular mechanisms involved in gene regulation by IL-1beta are poorly understood; however, the appearance of novel tyrosine phosphoproteins in IL-1beta-treated cells suggests that IL-1beta may function through tyrosine phosphoprotein intermediates. The mitogen-activated protein (MAP) kinases are tyrosine phosphoproteins that could potentially mediate the effects of IL-1beta. Protein tyrosine phosphorylation following IL-1beta treatment may be dependent on redox changes since the IL-1beta receptor is not a protein-tyrosine kinase and oxidation has been shown to induce tyrosine phosphorylation. In this report we demonstrate that conditioning human glomerular mesangial cells with IL-1beta results in the tyrosine phosphorylation and activation of two members of the MAP kinase family, extracellular signal-regulated protein kinase 2 (ERK2) and p54 Jun-NH2-terminal kinase (JNK). This effect of IL-1beta is abrogated by pretreating cells with the antioxidants N-acetyl-L-cysteine or dithiothreitol. Furthermore, the effects of IL-1beta on ERK and JNK activation are reproduced by treating mesangial cells with membrane-permeable oxidants. IL-1beta and oxidants also cause phosphorylation and activation of the upstream ERK regulatory element MAP kinase kinase. Interestingly, IL-1beta, but not exogenous oxidants, causes phosphorylation of the upstream JNK activator, JNK kinase. These data indicate that IL-1beta activates ERK2 through an oxidation-dependent pathway. Exogenous oxidants and IL-1beta activate JNK through different upstream mechanisms; however, antioxidant inhibition of JNK activation indicates that endogenous oxidants may play a role in IL-1beta-induced JNK activation. Thus IL-1beta may affect mesangial cell function by activating MAP kinases, which can then regulate gene transcription. Furthermore, reactive oxygen species released during inflammatory glomerular injury may also affect mesangial function through a MAP kinase signal.

Modulation of IL-1-induced chemokine expression in human mesangial cells through alterations in redox status.

The effects of altering intracellular redox potential on interleukin 1 (IL-1)-induced MCP-1 gene expression by human mesangial cells were examined. Thiol containing antioxidants significantly increased cellular glutathione content while decreasing glutathione disulfide levels. These antioxidants inhibited IL-1 induction of MCP-1 mRNA expression. This correlated with a decrease in DNA binding activity of NF-kappa B, a transcription factor thought to be necessary for MCP-1 gene expression. Incubation of mesangial cells with the oxidizing agents diamide or hydrogen peroxide did not upregulate MCP-1 gene expression, and prevented IL-1 induction of MCP-1 mRNA. Oxidants appeared to inhibit the degradation of I kappa B, and the translocation of NF-kappa B to the nucleus. Non-oxidative depletion of intracellular glutathione also attenuated the effects of IL-1 on MCP-1 expression. These data indicate that the intracellular redox potential is a critical determinant of cell activation by IL-1. The observation that both oxidizing and reducing environments are inhibitory suggests that redox changes can affect the IL-1 signal transduction pathway at multiple points.

Fuzzy function approximation with ellipsoidal rules.

A fuzzy rule can have the shape of an ellipsoid in the input-output state spare of a system. Then an additive fuzzy system approximates a function by covering its graph with ellipsoidal rule patches. It averages rule patches that overlap. The best fuzzy rules cover the extrema or bumps in the function. Neural or statistical clustering systems can approximate the unknown fuzzy rules from training data. Neural systems can then both tune these rules and add rules to improve the function approximation. We use a hybrid neural system that combines unsupervised and supervised learning to find and tune the rules in the form of ellipsoids. Unsupervised competitive learning finds the first-order and second-order statistics of clusters in the training data. The covariance matrix of each cluster gives an ellipsoid centered at the vector or centroid of the data cluster. The supervised neural system learns with gradient descent. It locally minimizes the mean-squared error of the fuzzy function approximation. In the hybrid system unsupervised learning initializes the gradient descent. The hybrid system tends to give a more accurate function approximation than does the lone unsupervised or supervised system. We found a closed-form model for the optimal rules when only the centroids of the ellipsoids change. We used numerical techniques to find the optimal rules in the general case.

Activation of nuclear factor-kappa B correlates with MCP-1 expression by human mesangial cells.

Emerging evidence suggests that mesangial cell-derived monocyte chemoattractant protein-1 (MCP-1) is a potentially important mediator of glomerular monocyte infiltration. Interleukin-1 beta (IL-1) has been found in glomeruli during inflammation, and is a potent inducer of MCP-1 expression by mesangial cells. Analysis of the promoter region of the human MCP-1 gene demonstrates several putative binding sites for transcription activating factors, including recognition elements for the IL-1-inducible transcription factor, nuclear factor-kappa B (NF-kappa B). This study investigated the role of NF-kappa B in IL-1-induced MCP-1 expression by human mesangial cells. We found that treating mesangial cells with IL-1 resulted in the rapid activation (within 30 min) and nuclear translocation of NF-kappa B. NF-kappa B activation could be blocked by preventing the proteolytic degradation of I kappa B, the cytoplasmic inhibitor of NF-kappa B, with the protease inhibitor tosyl-phe-chloromethylketone (TPCK). Inhibition of NF-kappa B with TPCK correlated with a dose-dependent reduction in IL-1-induced MCP-1 mRNA levels. Conversely, raising intracellular cyclic-AMP levels, or exposing mesangial cells to herbimycin A, treatments that block IL-1-induced MCP-1 mRNA expression, significantly attenuated NF-kappa B activation. Finally, blocking the synthesis of one of the protein subunits of NF-kappa B with an antisense oligonucleotide decreased MCP-1 mRNA levels in response to IL-1. These data suggest that MCP-1 gene transcription may be mediated, in part, by the transcription factor NF-kappa B.

Plasma biotin levels in children with burns and scalds.

The plasma concentrations of biotin were measured for up to 49 days after injury in nine children with burns and scalds which involved from 12% to 50% of the surface area of the body. Biotin levels below the minimum of the control range were observed in eight of the nine injured children at some stage during the episode.