A Dominant-Negative Approach That Prevents Diphthamide Formation Confers Resistance to Pseudomonas Exotoxin A and Diphtheria Toxin

Diphtheria toxin (DT), Pseudomonas aeruginosa Exotoxin A (ETA) and cholix toxin from Vibrio cholerae share the same mechanism of toxicity; these enzymes ADP-rybosylate elongation factor-2 (EF-2) on a modified histidine residue called diphthamide, leading to a block in protein synthesis. Mutant Chinese hamster ovary cells that are defective in the formation of diphthamide have no distinct phenotype except their resistance to DT and ETA. These observations led us to predict that a strategy that prevents the formation of diphthamide to confer DT and ETA resistance is likely to be safe. It is well documented that Dph1 and Dph2 are involved in the first biochemical step of diphthamide formation and that these two proteins interact with each other. We hypothesized that we could block diphthamide formation with a dominant negative mutant of either Dph1 or Dph2. We report in this study the first cellular-targeted strategy that protects against DT and ETA toxicity. We have generated Dph2(C-), a dominant-negative mutant of Dph2, that could block very efficiently the formation of diphthamide. Cells expressing Dph2(C-) were 1000-fold more resistant to DT than parental cells, and a similar protection against Pseudomonas exotoxin A was also obtained. The targeting of a cellular component with this approach should have a reduced risk of generating resistance as it is commonly seen with antibiotic treatments

Carrier induced magnetic interaction in the diluted magnetic semiconductor PbSnMnTe

Low-temperature AC susceptibility and specific heat measurements have been performed to study the influence of the concentration of charge carriers on the ferromagnetic phase transition of Pb1-x-y SnyMnxTe for various compositions (0.005⩽x⩽0.1, 0.4⩽y⩽1.0). A critical carrier density above which a ferromagnetic transition can take place is observed. This behavior is also reflected in the Curie-Weiss temperature T obtained from high-temperature susceptibility data. A simple modified RKKY mechanism for semiconductors is proposed in which carriers from two valence bands located in different regions of the Brillouin zone contribute. The effect of a finite mean free path of the carriers is taken into account. This model gives excellent agreement with the data is obtained without the use of a fitting paramete

Magnetic Behavior of Diluted Magnetic Semiconductors

The magnetic characteristics of Diluted Magnetic Semiconductors are reviewed and related to the exchange interactions and mechanisms. The relevance of the long-range interactions in II–VI DMS is emphasized. An analytical expression for the radial dependence is derived from the freezing temperature and compared with theoretical predictions. The magnetic properties of Fe-DMS are summarized and interpreted on the basis of the dominant crystal field splitting effects. Recent studies on IV–VI Mn DMS are presented with the emphasis on the new phenomena of carrier induced ferromagnetism