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A set of five Bacillus subtilis promoters fused to the firefly luciferase reporter gene suitable for cell based screening is generated. The reporter cells represent novel antibiotic biosensors compatible with high throughput screening.

The NfrA protein, a putative essential oxidoreductase in the soil bacterium Bacillus subtilis, is induced under heat shock and oxidative stress conditions. In order to characterize the function of an homologous NfrA protein in Staphylococcus aureus, an nfrA deletion strain was constructed, the protein was purified, the enzymatic activity was determined, and the transcriptional regulation was investigated. The experiments revealed that NfrA is not essential in S. aureus. The purified protein oxidized NADPH but not NADH, producing NADP in the presence of flavin mononucleotide, suggesting that NfrA is an NADPH oxidase in S. aureus. In addition, the NfrA enzyme showed nitroreductase activity and weak disulfide reductase activity. Transcription was strongly induced by ethanol, diamide, and nitrofurantoin. Hydrogen peroxide induced nfrA transcription only at high concentrations. The expression of nfrA was independent of the alternative sigma factor [[sigma].sup.B]. Furthermore, the transcriptional start site was determined, which allowed identification of a PerR box homologous sequence upstream of the nfrA promoter. The observations presented here suggest that NfrA is a nonessential NADPH oxidoreductase which may play a role in the oxidative stress response of S. aureus, especially in keeping thiol-disulfide stress in balance.

YkrB has been found to be the main peptide deformylase in Bacillus subtilis and B subtilis has two functional peptide deformylases, unlike all other eubacteria thusfar studied. For the first time, biochemical and shysiological roles of two functional Def proteins derived from one organism are compared. . B subtilis has a deformylase-like gene called ykrB. Its product is much like the class II deformylase from B. stearothermophilus.

It is possible to show the presence of new symbiotic loci and signalling mechanisms through a study of the entire nucleotide sequence and gene complement of the plasmid from Rhizobium sp. NGR234. This gives the bacterium the ability to form a symbiotic relationship with leguminous plants. It can be seen that there is a high proportion of insertion and mosaic sequences, and it is possible that an Agrobacterium-like progenitor gathered symbiotic genes through transposition with other soil bacteria.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a cell surface receptor, is expressed on normal epithelial tissue and highly expressed in cancers of high unmet medical need, such as non-small cell lung, pancreatic, and colorectal cancer. CEACAM receptors undergo homo- and heterophilic interactions thereby regulating normal tissue homeostasis and angiogenesis, and in cancer, tumor invasion and metastasis. CEACAM6 expression on malignant plasma cells inhibits antitumor activity of T cells, and we hypothesize a similar function on epithelial cancer cells. The interactions between CEACAM6 and its suggested partner CEACAM1 on T cells were studied. A humanized CEACAM6-blocking antibody, BAY 1834942, was developed and characterized for its immunomodulating effects in co-culture experiments with T cells and solid cancer cells and in comparison to antibodies targeting the immune checkpoints programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and T cell immunoglobulin mucin-3 (TIM-3). The immunosuppressive activity of CEACAM6 was mediated by binding to CEACAM1 expressed by activated tumor-specific T cells. BAY 1834942 increased cytokine secretion by T cells and T cell-mediated killing of cancer cells. The in vitro efficacy of BAY 1834942 correlated with the degree of CEACAM6 expression on cancer cells, suggesting potential in guiding patient selection. BAY 1834942 was equally or more efficacious compared to blockade of PD-L1, and at least an additive efficacy was observed in combination with anti-PD-1 or anti-TIM-3 antibodies, suggesting an efficacy independent of the PD-1/PD-L1 axis. In summary, CEACAM6 blockade by BAY 1834942 reactivates the antitumor response of T cells. This warrants clinical evaluation. [ABSTRACT FROM AUTHOR]

Despite year-to-year increases in R & D budgets, the number of successful NCEs (new chemical entities) has continued to decline. Drug companies are looking into new ways to make research processes more efficient, to manage information better, and to improve collaboration among research groups. This shift from an artisan approach to an organized, streamlined discovery process is often termed the "industrialization of discovery processes." This paper presents an approach to industrializing drug discovery that involves the formal modeling of research processes at several layers of abstraction, mappings between adjacent layers, and an implementation of this hierarchy using information technology-level execution elements. This approach is applied to the assay development phase of the drug discovery process. First, a business operations model is built by identifying the business artifacts, developing models for the life cycles of these artifacts, and then creating a comprehensive model that combines these life-cycle models and their interactions. Using the concept of adaptive business objects, a solution composition model that expands on the business operations model is developed. This model is then mapped into an executable platform-specific implementation by using the IBM WebSphere® platform. Our prototype system was built and validated as a joint effort between IBM Research and Bayer HealthCare. [ABSTRACT FROM AUTHOR]