Cellular and molecular responses to ethyl-parathion in undifferentiated SH-SY5Y cells provide neurotoxicity pathway indicators for organophosphorus impacts.

High-fidelity nonanimal screening methods are needed that can rapidly and accurately characterize organophosphorus compound (OP)-induced neurotoxicity. Herein, the efficacy of human neuroblastoma cell line (SH-SY5Y) to provide molecular and cellular responses characteristic of the OP neurotoxicity pathway was investigated in response to the OP-model compound, ethyl-parathion. Undifferentiated SH-SY5Y cells were exposed to ethyl-parathion for 30 min at 0 (control), 0.

Comparative toxicogenomics of three insensitive munitions constituents 2,4-dinitroanisole, nitroguanidine and nitrotriazolone in the soil nematode Caenorhabditis elegans.

Background: Ecotoxicological studies on the insensitive munitions formulation IMX-101 and its components 2,4-dinitroanisole (DNAN), nitroguanidine (NQ) and nitrotriazolone (NTO) in various organisms showed that DNAN was the main contributor to the overall toxicity of IMX-101 and suggested that the three compounds acted independently. These results motivated this toxicogenomics study to discern toxicological mechanisms for these compounds at the molecular level.

Methods: Here we used the soil nematode Caenorhabditis elegans, a well-characterized genomics model, as the test organism and a species-specific, transcriptome-wide 44 K-oligo probe microarray for gene expression analysis.

Reduction of vector gene expression increases foreign antigen-specific CD8+ T-cell priming.

Viral vectors have been shown to induce protective CD8(+) T-cell populations in animal models, but significant obstacles remain to their widespread use for human vaccination. One such obstacle is immunodominance, where the CD8(+) T-cell response to a vector can suppress the desired CD8(+) T-cell response to a recombinantly encoded antigen. To overcome this hurdle, we broadly reduced vector-specific gene expression.

Cross-priming utilizes antigen not available to the direct presentation pathway.

CD8+ T cells play a crucial role in protective immunity to viruses and tumours. Antiviral CD8+ T cells are initially activated by professional antigen presenting cells (pAPCs) that are directly infected by viruses (direct-priming) or following uptake of exogenous antigen transferred from virus-infected or tumour cells (cross-priming). In order to efficiently target each of these antigen-processing pathways during vaccine design, it is necessary to delineate the properties of the natural substrates for either of these antigen-processing pathways.

Regulation of T cell development by the deubiquitinating enzyme CYLD.

T cell receptor signaling is essential for the generation and maturation of T lymphocyte precursors. Here we identify the deubiquitinating enzyme CYLD as a positive regulator of proximal T cell receptor signaling in thymocytes. CYLD physically interacted with active Lck and promoted recruitment of active Lck to its substrate, Zap70.

CD8+ T cell cross-priming via transfer of proteasome substrates.

"Cross-priming" describes the activation of naïve CD8+ T cells by professional antigen-presenting cells that have acquired viral or tumor antigens from "donor" cells. Antigen transfer is believed to be mediated by donor cell-derived molecular chaperones bearing short peptide ligands generated by proteasome degradation of protein antigens. We show here that cross-priming is based on the transfer of proteasome substrates rather than peptides.