Studies of heavy metal sorption by Trenton Channel (Detroit River) sediments

Sediment resuspension plays a dominant physical role in downstream transport of sediment-bound, or in-place pollutants. During resuspension, however, numerous sorption reactions may alter contaminant phase distributions. Previous field resuspension studies on heavily contaminated sediments (Theis et al., 1988, J. Great Lakes Res. 14, 216) showed parallel trends in metal partitioning with pH and time for each of 7 metals (Cd, Co, Cr, Cu, Ni, Pb, Zn), when pH was < 7.5 during resuspension. To improve our ability to interpret follow-up laboratory partitioning experiments using sediments from the field sites, we conducted an evaluation of sediment sample storage as a potential factor leading to field-laboratory partitioning differences. Although metal sorption observed in the laboratory differed substantially from that observed in the field, sample storage effects, reported as holding time and changes in solid phase metal fractionation, gave minimal support for the hypothesis that sample storage caused the differences. It appears, rather, than our in vitro batch equilibrium systems incompletely replicated those attributes of a sediment-water system that are relevant to adsorption and desorption of heavy metals during a resuspension event. Accordingly, we conclude that a general improvement in the understanding of contaminant partitioning would result if future studies would assign greater importance to evaluating the effects of relevant physical phenomena on partitioning (e.g. particle interaction and shear stress), in addition to such widely studied chemical determinants as pH, time, and metal species.     

Importance of mitochondrial transmembrane processes in human mitochondriopathies

In a substantial group of subjects suspected to have a mitochondriopathy no defect in the mitochondrial energy metabolism (pyruvate dehydrogenase complex or respiratory chain complexes) can be demonstrated. At least in some of these subjects it seems justified to consider a defect in one of the proteins which mediate the transport of several ions and substrates across the mitochondrial membranes. Of particular interest are proteins which are directly involved in the process of oxidative phosphorylation, such as the adenine nucleotide translocator (ANT) and the phosphate carrier (PiC). However, defects in transmembrane ion transporters also may induce impaired energy metabolism probably as a result of osmotic disturbances within the mitochondrial matrix. In this respect, the voltage-dependent anion channel (VDAC) and other ion channels have to be taken into consideration. Here we review the still incomplete knowledge of the occurrence of ANT, PiC, VDAC, cation channels, and a few substrate carriers in human tissues, as well as their possible role in pathology.     

A new series of potent oxindole inhibitors of CDK2

A novel series of oxindole-type inhibitors of CDK2 that have heteroatom substituted alkynyl moieties at their C-4 position is described. These novel 4-alkynyl-substituted inhibitors have superior potency relative to their parent compound in free enzyme and in cell based assays. The crystal structure of CDK2 in complex with one of these analogues was determined and gives insight to their increased potency. The biochemical evaluation of a representative derivative is also described.     

Synthesis of potent oxindole CDK2 inhibitors

A series of oxindole CDK2 inhibitors was synthesized. These novel analogues have a saturated monosubstituted cyclic moiety at their C-4 position that mimics the ribofuranoside of ATP. This substitution afforded agents with increased potency relative to the parent indolinone and nanomolar range IC(50) against the CDK2 enzyme and two cancer cell lines.     

Modeling as a tool to manage ecosystems under multiple stresses: an application to Lake Ontario

Present-day ecosystem management involves understanding of the synergistic effect of multiple stressors on multiple and frequently nebulous management end-points. An example is the simultaneous management of nutrient load reductions and salmon stocking in Lake Ontario. In this study, a simple whole-lake annual time scale model was developed to assess the relationship between these two stressors and various ecosystem responses. The model was used to explore the utility of some possible management end-points for ecosystem health. In historical simulations, production per stocked fish and salmon survival appeared to be good indicators, while nutrient recycling rate and average ecosystem-wide food limitation were found to be fairly unresponsive to the two stressors. The model was further used to predict long term averages of salmon biomass and selected health indicators at various sustained loading and stocking rates. Salmon biomass increased with stocking rate at all stocking rates examined, but the rate of increase declined somewhat at high stocking rates. The response of salmon biomass to nutrient loading appeared to be approximately sigmoidal i.e. there was a nutrient threshold below which fish biomass could not be sustained and another nutrient threshold above which salmon biomass either remained constant or even decreased. The response to either stressor was found to be modified by the value of the other stressor, illustrating the importance of ecosystem-level models for aquatic ecosystem management.     

Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model

Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent.