A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases

Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxy-tamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation. The PCD features were observed only at high (μM) concentrations of CQ. The use of a new synthetic coumarin-labeled chloroquine (CM-CQ) showed that these features may be associated with concentration-dependent differences in drug localization. By further using cysteine protease inhibitors z-Asp-Glu-Val-Asp-fmk (zDEVD), z-Phe-Ala-fmk (zFA), z-Phe-Phe-fmk (zFF), z-Leu-Leu-Leu-fmk (zLLL), E64d and CA-074, we were able to implicate clan CA cysteine proteases in CQ-mediated PCD. Finally, CQ induction of two CQ-resistant parasite strains, 7G8 and K1, reveals the existence of PCD features in these parasites, the extent of which was less than 3D7. The use of the chemoreversal agent verapamil implicates the parasite digestive vacuole in mediating CQ-induced PCD

(Table 1) 137Cs and 90Sr concentrations, salinity, and temperature in waters of the southeastern Baltic Sea on October 16, 2001

An analysis of variations in 137Cs and 90Sr concentrations in Baltic Sea surface waters after the accident at the Chernobyl nuclear power plant was performed. Instability of 137Cs concentrations during the short-term observations was found, when they differed 2- to 3-fold. Concentrations of 90Sr appeared to be more stable; meanwhile, their deviations sometimes exceeded ranges of experimental errors. By variations in the monthly average values of radionuclide concentrations in surface waters of the Baltic Sea in 1989-1995, no trend of water self-purification was observed. Theoretical results obtained confirmed a potential of formation and propagation of patches with increased concentrations of 137Cs in the southeastern Baltic Sea. The most reliable factor that controlled the process of self-purification of Baltic Sea water appeared to be the mean annual value of radionuclide concentration. Pronounced divergences were obtained between the measured and calculated mean annual concentrations of 137Cs and 90Sr in surface waters of the Baltic Sea in 1989-2001. These divergences are explained by potential influence of waters from the Gulf of Bothnia and by other additional supplies of radionuclides to marine environment, which were not included into mathematical models

137Cs concentrations in the southeastern Baltic Sea in 1997-2000

Variations of 137Cs concentration in the southeastern Baltic Sea were investigated over the period 1997-2000, i.e. in 11-14 years after the Chernobyl Nuclear Power Plant accident. Rate of "self-cleaning" proved to be very slow. Some results obtained in 1999 were almost the same as those measured after the accident, in 1986. Calculated results showed that "Chernobyl" caesium-137 would be "cleaned" in the Baltic Sea by 2020-2022. In 2000 average concentration had to be about 50-60 Bq/m**3. Sometimes mentioned concentrations were observed. In some cases higher concentrations averaging from 67 to 80 Bq/m**3 were registered in the southeastern Baltic Sea in 1999; and in some samples 137Cs concentrations were very high. They varied from 110 to 212 Bq/m**3. No steady correlation was observed between 137Cs concentration, salinity and temperature in surface water of the area. Distribution of radionuclide concentration sometimes depends on direction of water mass transport. Abnormally high concentrations of 137Cs in the southeastern Baltic Sea may result from additional radioactive waste discharge