(p)ppGpp is at the core of global bacterial regulation as it controls growth, the most important aspect of life. It would therefore be expected that at least across a species the intrinsic (basal) levels of (p)ppGpp would be reasonably constant. On the other hand, the historical contingency driven by the selective pressures on bacterial populations vary widely resulting in broad genetic polymorphism. Given that (p)ppGpp controls the expression of many genes including those involved in the bacterial response to environmental challenges, it is not surprising that the intrinsic levels of (p)ppGpp would also vary considerably. In fact, null mutations or less severe genetic polymorphisms in genes associated with (p)ppGpp synthesis and hydrolysis are common. Such variation can be observed in laboratory strains, in natural isolates as well as in evolution experiments. High (p)ppGpp levels result in low growth rate and high tolerance to environmental stresses. Other aspects such as virulence and antimicrobial resistance are also influenced by the intrinsic levels of (p)ppGpp. A case in point is the production of Shiga toxin by certainE. colistrains which is inversely correlated to (p)ppGpp basal level. Conversely, (p)ppGpp concentration is positively correlated to increased tolerance to different antibiotics such as beta-lactams, vancomycin, and others. Here we review the variations in intrinsic (p)ppGpp levels and its consequences across theE. colispecies.

Background The goal of this study was to evaluate outcomes in children with relapsed, molecularly characterized intracranial ependymoma treated with or without craniospinal irradiation (CSI) as part of a course of repeat radiation therapy (re-RT). Methods This was a retrospective cohort study of 31 children. Patients with distant relapse received CSI as part of re-RT. For patients with locally recurrent ependymoma, those treated before 2012 were re-irradiated with focal re-RT. In 2012, institutional practice changed to offer CSI, followed by boost re-RT to the site of resected or gross disease. Results Median follow-up was 5.5 years. Of 9 patients with distant relapse after initial RT, 2-year freedom from progression (FFP) and overall survival (OS) were 12.5% and 62.5%, respectively. There were 22 patients with local failure after initial RT. In these patients, use of CSI during re-RT was associated with improvement in 5-year FFP (83.3% with CSI vs 15.2% with focal re-RT only, P = 0.030). In the subgroup of patients with infratentorial primary disease, CSI during re-RT also improved 5-year FFP (100% with CSI, 10.0% with focal re-RT only, P = 0.036). Twenty-three patients had known molecular status; all had posterior fossa group A tumors (n = 17) or tumors with a RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A) fusion (n = 6). No patient developed radiation necrosis after fractionated re-RT, though almost all survivors required assistance throughout formal schooling. Five out of 10 long-term survivors have not developed neuroendocrine deficits. Conclusions Re-irradiation with CSI is a safe and effective treatment for children with locally recurrent ependymoma and improves disease control compared with focal re-irradiation, with the benefit most apparent for those with infratentorial primary tumors.