A Peptidoglycan Fragment Triggers β-lactam Resistance in Bacillus licheniformis

To resist to β-lactam antibiotics Eubacteria either constitutively synthesize a β-lactamase or a low affinity penicillin-binding protein target, or induce its synthesis in response to the presence of antibiotic outside the cell. In Bacillus licheniformis and Staphylococcus aureus, a membrane-bound penicillin receptor (BlaR/MecR) detects the presence of β-lactam and launches a cytoplasmic signal leading to the inactivation of BlaI/MecI repressor, and the synthesis of a β-lactamase or a low affinity target. We identified a dipeptide, resulting from the peptidoglycan turnover and present in bacterial cytoplasm, which is able to directly bind to the BlaI/MecI repressor and to destabilize the BlaI/MecI-DNA complex. We propose a general model, in which the acylation of BlaR/MecR receptor and the cellular stress induced by the antibiotic, are both necessary to generate a cell wall-derived coactivator responsible for the expression of an inducible β-lactam-resistance factor. The new model proposed confirms and emphasizes the role of peptidoglycan degradation fragments in bacterial cell regulation

A Bioinformatics Filtering Strategy for Identifying Radiation Response Biomarker Candidates

The number of biomarker candidates is often much larger than the number of clinical patient data points available, which motivates the use of a rational candidate variable filtering methodology. The goal of this paper is to apply such a bioinformatics filtering process to isolate a modest number (<10) of key interacting genes and their associated single nucleotide polymorphisms involved in radiation response, and to ultimately serve as a basis for using clinical datasets to identify new biomarkers. In step 1, we surveyed the literature on genetic and protein correlates to radiation response, in vivo or in vitro, across cellular, animal, and human studies. In step 2, we analyzed two publicly available microarray datasets and identified genes in which mRNA expression changed in response to radiation. Combining results from Step 1 and Step 2, we identified 20 genes that were common to all three sources. As a final step, a curated database of protein interactions was used to generate the most statistically reliable protein interaction network among any subset of the 20 genes resulting from Steps 1 and 2, resulting in identification of a small, tightly interacting network with 7 out of 20 input genes. We further ranked the genes in terms of likely importance, based on their location within the network using a graph-based scoring function. The resulting core interacting network provides an attractive set of genes likely to be important to radiation response

Early microRNA and other non-coding RNA biomarkers for rodent non-genotoxic carcinogens

Several studies have revealed characteristic gene expression alterations after short-term treatment of rodents with non-genotoxic hepatocarcinogens. These may partly be regulated by epigenetic perturbations induced early after compound treatment. One goal of the IMI-MARCAR (bioMARkers and molecular tumour classification for non-genotoxic CARcinogenesis) consortium is to find early biomarkers for drug-induced rodent non-genotoxic carcinogenesis by using integrated molecular profiling including epigenetic parameters (mRNA, microRNA and other non-coding RNA and DNA methylation) of rodent liver in shorter term studies. MicroRNAs, as RNAs in general, are measurable with established methods and thus lend themselves as easily accessible biomarkers for both mechanistic and diagnostic investigations. A time course study with the well-characterized rodent liver tumour promoter phenobarbital in mice for total 13 weeks revealed progressive increases in hepatic expression of long non-coding RNAs and microRNAs originating from the Dlk1-Dio3 imprinted gene cluster, for which in vivo genetic dependence on constitutive androstane receptor and _-catenin could be shown with corresponding knock out and humanized mouse models. Altered expression from the Dlk1-Dio3 locus may be relevant for hepatocarcinogenicity based on recently observed associations with stem cell pluripotency in mice and various neoplasms in humans. Potential importance of this locus for rodent non-genotoxic hepatocarcinogenesis is being assessed by measuring microRNAs from this locus in mouse and rat liver after 2Ð4 weeks treatment with a selection of rodent non-genotoxic hepatocarcinogens. These studies will also include evaluations of other microRNAs suggested from 2-week rat studies and/or described in the literature as potential early biomarkers for cancer risk assessment