Drug-induced cleavage of DNA by topoisomerase II mediates the formation of chromosomal translocation breakpoints in mitoxantrone-related APL and in APL that occurs after therapy with other topoisomerase II poisons.

The effects of simultaneous expression of several efflux pumps on antibiotic resistance were investigated in Escherichia coli and Pseudomonas aeruginosa. Several combinations of efflux pumps have been studied: (i) simultaneous expression of a single-component efflux pump, which exports antibiotics into the periplasm, in combination with a multicomponent efflux pump that accomplishes efflux directly into the external medium; (ii) simultaneous expression of two single-component pumps; and (iii) simultaneous expression of two multicomponent pumps. It was found that when efflux pumps of different structural types were combined in the same cell (the first case), the observed antibiotic resistance was much higher than that conferred by each of the pumps expressed singly. Simultaneous expression of pairs of single-component or multicomponent efflux pumps (the second and third cases) did not produce strong increases in antibiotic resistance.Efflux of antibiotics out of cells is broadly recognized as a major component of bacterial resistance to many classes of antibiotics (26,28). This efflux occurs due to the activity of membrane transporter proteins, the so-called drug efflux pumps. Some efflux pumps selectively extrude specific antibiotics, while others, referred to as multidrug resistance (MDR) pumps, expel various structurally diverse antibiotics. While antibiotic-specific efflux pumps are usually encoded on transmissible plasmids and transposons, genes encoding many MDR pumps are normal constituents of bacterial chromosomes. Efflux pumps occur as either single-component or multicomponent systems. In gram-negative bacteria, single-component efflux pumps extrude their substrates into the periplasmic space (40). Examples of such single-component efflux pumps include the transposon-encoded tetracycline-and chloramphenicol-specific pumps, TetA and CmlA, respectively (2, 38), and the MDR pump MdfA, encoded in the chromosome of Escherichia coli (6). Multicomponent efflux pumps (which are found exclusively in gram-negative bacteria) traverse both inner and outer membranes. Examples include the MDR pumps AcrAB-TolC (19) and MexAB-OprM (34) from E. coli and Pseudomonas aeruginosa, respectively. Each pump contains a transporter located in the cytoplasmic membrane (as exemplified by AcrB or MexB), an outer membrane channel (TolC or OprM), and a periplasmic linker protein (AcrA or MexA), which is thought to bring into contact the other two components (42). This structural organization allows extrusion of substrates directly into the external medium, bypassing the periplasm and the outer membrane (27). The outer membrane of gram-negative bacteria serves as an efficient permeability barrier for both hydrophobic and hydrophilic antibiotics (29). Therefore, when antibiotics are extruded directly into the external medium, two independent mechanisms, efflux and low uptake through this permeability barrier, contribute to decreased intracellular accumulation of antibiotics (26).A single bacterial cell may contain multiple efflux pumps ...

Chitin is a skeletal cell wall polysaccharide of the inner cell wall of fungal pathogens. As yet, little about its role during fungus-host immune cell interactions is known. We show here that ultrapurified chitin from Candida albicans cell walls did not stimulate cytokine production directly but blocked the recognition of C. albicans by human peripheral blood mononuclear cells (PBMCs) and murine macrophages, leading to significant reductions in cytokine production. Chitin did not affect the induction of cytokines stimulated by bacterial cells or lipopolysaccharide (LPS), indicating that blocking was not due to steric masking of specific receptors. Toll-like receptor 2 (TLR2), TLR4, and Mincle (the macrophage-inducible C-type lectin) were not required for interactions with chitin. Dectin-1 was required for immune blocking but did not bind chitin directly. Cytokine stimulation was significantly reduced upon stimulation of PBMCs with heat-killed chitin-deficient C. albicans cells but not with live cells. Therefore, chitin is normally not exposed to cells of the innate immune system but is capable of influencing immune recognition by blocking dectin-1-mediated engagement with fungal cell walls.

Near edge X-ray absorption fine structure (NEXAFS) has been employed to provide insight into the chemical nature of nitrogen in deposits formed from plasmas of allylamine and propylamine. The nitrogen K-edge spectra of these materials unambiguously demonstrate the presence of significant quantities of sp or sp 2 hybridized nitrogen. This finding, in conjunction with carbon K-edge spectra, strongly indicates that there is a substantial level of dehydrogenation during the plasma polymerization process resulting in the formation of imine groups and, at high power, nitrile groups in addition to sp 3 hybridized amines. Comparison with standard polymers indicates that amide formation (following a few days exposure to atmosphere) is negligible. These findings suggest that the hydrolysis of aminated plasma polymers may be important in their long-term aging.

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