*The CI is significantly different from 1,

*The CI is significantly different from 1, find more by one-sample t-test, indicating a significant change in the ability of the mutant strain

to reside or propagate in mice with respect to the wild type. Effect of double mutation of genes forming hubs on growth, stress adaptation and virulence of S. Typhimurium S. Typhimurium shows a high degree of redundancy in metabolic reactions [18], and based on this we decided to test for interactions between gene-products of genes that formed hubs. Twenty-three different double deletion mutants were constructed (Table 3). No difference between wild type and mutated strains was observed during growth at the different temperatures, pH and NaCl concentrations, while the resistance

towards H2O2 was affected for eight of the double knockout mutants (Table 3). This decreased resistance was more often observed when the mutated genes were MLN0128 environmental hubs. From the eight affected double mutants, four of them included the wraB environmental hub and three of them were deficient in cbpA, which is also an environmental hub. Two of the double mutants deficient in osmC (environmental hub), ychN (functional hub) and yajD (functional hub) also exhibit a decreased resistance towards H2O2. (Table 3). Five double mutants were also assessed for virulence. The competition indexes (CI) of these strains are listed check details in Table 4. The ability of the mutants Dichloromethane dehalogenase to propagate in mice was enhanced in one case and reduced in two: The wraB/ychN double mutant strain had a significantly increased CI of 1.9, while the values of the CI for the wraB/osmC and the cbpA/dcoC double mutants were significantly reduced

to 0.7 and 0.4, respectively. Discussion We have detected a high degree of overlapping in the stress responses of S. Typhimurium at the transcriptional level towards heat, oxidative, acid and osmotic stresses. Such overlap could help explain the cross resistances in stress adaptation so often reported in literature [19, 20]. Previous work in Salmonella has demonstrated that increased and cross resistance can be caused by hysteresis or memory, i.e. genes involved in resistance and induced during a stressful condition remain induced after the condition ceases [10], and a recent study in E. coli has demonstrated that cross-stress protection also can arise in short time due to genetic mutations [6]. Thus it may be that both memory in gene expression and short time evolution by adaptive mutations contribute to the phenomena of cross resistance. Our network analysis revealed that the nodes degree distribution followed the power law for both transcriptional and functional (genome scale) networks.

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