Alterations of brain network activity are observable in Alzheimer's disease (AD) together with the occurrence of mild cognitive impairment, before overt pathology. However, in humans as well in AD mouse models, identification of early biomarkers of network dysfunction is still at its beginning. We performed in vivo recordings of local field potential activity in the dentate gyrus of PS2APP mice expressing the human amyloid precursor protein (APP) Swedish mutation and the presenilin-2 (PS2) N141I. From a frequency-domain analysis, we uncovered network hyper-synchronicity as early as 3 months, when intracellular accumulation of amyloid beta was also observable. In addition, at 6 months of age, we identified network hyperactivity in the beta/gamma frequency bands, along with increased theta-beta and theta-gamma phase-amplitude cross-frequency coupling, in coincidence with the histopathological traits of the disease. Although hyperactivity and hypersynchronicity were respectively detected in mice expressing the PS2-N141I or the APP Swedish mutant alone, the increase in cross-frequency coupling specifically characterized the 6-month-old PS2APP mice, just before the surge of the cognitive decline.

Klebsiella pneumoniae MirM7 is a wild-type strain which grows as cocci at pH 7 and above and as rods at pH 6.5 and below. Cultures of this strain and an auxotrophic derivative, MirM7b, have been found to undergo spontaneous lysis after purification from possible contaminating viruses. Lysates always contained two phages, FR2 and AP3, most often at high titers. FR2 and AP3 plated with the same efficiency on both MirM7b and K59 (another K. pneumoniae strain sensitive to FR2 and AP3) and lysogenized 45 and 54% of the K59-infected cells, respectively. These findings raise the possibility that MirM7b is lysogenic for FR2 and AP3, although nonimmune to their superinfection. The fact that mitomycin C and N-methyl-N'-nitro-N-nitrosoguanidine can induce phages FR2 and AP3 from MirM7b confirmed this possibility. When MirM7b was infected with FR2, several strains immune to FR2 and AP3, which were all rod shaped, were obtained. Furthermore, 19 derivatives, rod shaped at all pH's, have been isolated from MirM7b. They were all immune to both FR2 and AP3. From mating experiments between the MirM7b donor derivative, strain M720, and either K59 or MirCV5, a rod-shaped MirM7b derivative cured from the prophages, cysteine recombinants were obtained which were most often (80%) immune to FR2 and AP3. Nonimmune and still lysogenic recombinants were obtained by mating M720 with a rod-shaped immune MirM7b derivative; the majority of the nonimmune strains maintained the rod shape. Five coccus-shaped recombinants were also isolated; they were nonimmune to superinfection. Several physiological properties of strain MirM7b and the other nonimmune coccal recombinants have been studied in comparison with those of the rod-shaped immune derivatives. All of the coccal strains have shown several alterations with respect to the rods. The role of possible derepressed prophage genes in the various physiological alterations of MirM7 is discussed, and the analogies between this system and those of vertebrate cells transformed by proviruses are stressed.

The pH-conditional morphology mutant of Klebsiella pneumoniae strain MirM7 grows as cocci at pH 7 and as rods at pH 5.8. The mutant has a high-level mecillinam resistance (50% lethal dose > 200 ,ug/ml) in both forms. When broth cultures of the rod-shaped mutant were grown with 0.7 ,ug of mecillinam per ml, cells assumed a round shape and continued to divide at a higher rate than the untreated control. A MirM7 rod-shaped revertant (MirA12), when treated with the same antibiotic concentration, changed to coccal shape and stopped dividing. The penicillin-binding proteins (PBPs) of strains MirA12 and MirM7 were analyzed. K. pneumoniae had six major PBPs quite similar to those of Escherichia coli. No differences were seen in the PBPs of MirM7 cocci and rods and MirA12 cells. In particular, PBP2 was found to be prepent and similar in MirM7 rods and cocci and MirA12 cells. We suggest that in gram-negative rods, a control mechanism exists which prevents further septation in the absence of lateral cell wall elongation. The unique behavior of MirM7 is due to the fact that the control mechanism is not active in this strain. This model allows us to explain the preservation of shape in bacterial rods under various conditions of growth and the mechanism of bacterial killing by mecillinam.

Mir M7 is a spontaneous morphologically conditional mutant of Klebsiella pneumoniae which grows as round cells (cocci) at pH 7 and as normal rods at pH 5.8. We studied the rates of peptidoglycan synthesis of cocci and rods growing at pH values of 7 and 5.8, respectively. It was found that exponentially growing cocci produced a reduced amount of peptidoglycan per cell, compared with rods. Moreover, a shift of cocci to the permissive pH (5.8) caused an increase in the rate of peptidoglycan synthesis, whereas the reverse shift of rods to pH 7 determined a twofold reduction in the rate of [3H]diaminopimelic acid incorporation. During synchronous growth at pH 7, the rate of peptidoglycan synthesis after cell division decreased with time and rose before and during the first division. The susceptibilities of rods and cocci to ,B-lactam antibiotics were also studied. It was found that cocci were more sensitive both to penicillin G and to cephalexin than were rods, but they showed a high level of resistance to mecillinam. The peculiar behavior of this mutant was interpreted as supporting the existence in bacterial rods of two different sites for peptidoglycan synthesis: one responsible for lateral wall elongation and one responsible for septum formation. In Mir M7, shape damage is described as dependent on the specific inhibition, at the nonpermissive pH, of the site for lateral wall extension.

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