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Robert George's prescription to make business moral ('Making Business Moral,' October 2008) is really a call for businesses to support the formation of moral people and therefore ensure an honest [...]

Nifurtimox and benznidazole are the front-line drugs used to treat Chagas disease, the most important parasitic infection in the Americas. These agents function as prodrugs and must be activated within the parasite to have trypanocidal effects. Despite >40 years of research, the mechanism(s) of action and resistance have remained elusive. Here, we report that in trypanosomes, both drugs are activated by a NADH-dependent, mitochondrially localized, bacterial-like, type I nitroreductase (NTR), and that down-regulation of this explains how resistance may emerge. Loss of a single copy of this gene in Trypanosoma cruzi, either through in vitro drug selection or by targeted gene deletion, is sufficient to cause significant cross-resistance to a wide range of nitroheterocyclic drugs. In Trypanosoma brucei, loss of a single NTR allele confers similar cross-resistance without affecting growth rate or the ability to establish an infection. This potential for drug resistance by a simple mechanism has important implications, because nifurtimox is currently undergoing phase III clinical trials against African trypanosomiasis. activation | nitroheterocyclic drugs | Trypanosoma brucei | Trypanosoma cruzi

Centromeres are the chromosomal loci that facilitate segregation, and, in most eukaryotes, they encompass extensive regions of genomic DNA. Topoisomerase-II has been identified as a crucial regulator of segregation in a wide range of organisms and exhibits premitotic accumulation at centromeres. Consistent with this property, treatment of cells with the topoisomerase-II inhibitor etoposide promotes chromosomal cleavage at sites within centromeric DNA. In the case of the human malaria parasite Plasmodium falciparum, despite a completed genome sequence, there are no experimental data on the nature of centromeres. To address this issue, we have used etoposide-mediated topoisomerase-II cleavage as a biochemical marker to map centromeric DNA on all 14 parasite chromosomes. We find that topoisomerase-II activity is concentrated at single chromosomal loci and that cleavage sites extend over [approximately equal to]10 kb. A shared feature of these topoisomerase-II cleavage sites is the presence of an extremely AT-rich ([approximately equal to]97%) domain with a strictly defined size limit of 2.3-2.5 kb. Repetitive arrays identified within the domains do not display interchromosomal conservation in terms of length, copy number, or sequence. These unusual properties suggest that P. falciparum chromosomes contain a class of 'regional' centromere distinct from those described in other eukaryotes, including the human host. chromosome | malaria | segregation

The capacity to synthesize vitamin C (ascorbate) is widespread in eukaryotes but is absent from humans. The last step in the biosynthetic pathway involves the conversion of an aldonolactone substrate to ascorbate, a reaction catalyzed by members of an FAD-dependent family of oxidoreductases. Here we demonstrate that both the African trypanosome, Trypanosoma brucei, and the American trypanosome, Trypanosoma cruzi, have the capacity to synthesize vitamin C and show that this reaction occurs in a unique single-membrane organelle, the glycosome. The corresponding T. brucei flavoprotein (TbALO) obeys Michaelis-Menten kinetics and can utilize both L-galactono-[gamma]-lactone and D-arabinono-[gamma]-lactone as substrate, properties characteristic of plant and fungal enzymes. We could detect no activity toward the mammalian enzyme substrate L-gulono-[gamma]-lactone. TbALO null mutants (bloodstream form) were found to display a transient growth defect, a trait that was enhanced when they were cultured in medium in which the essential serum component had been pretreated with ascorbate oxidase to deplete vitamin C. It is implicit, therefore, that bloodstream-form trypanosomes also possess a capacity for ascorbate transport. ascorbic acid | FAD | oxidase | Trypanosoma brucei

In most aerobic organisms hemoperoxidases play a major role in [H.sub.2][O.sub.2]-detoxification, but trypanosomatids have been reported to lack this activity. Here we describe the properties of an ascorbate-dependent hemoperoxidase (TcAPX) from the American trypanosome Trypanosoma cruzi. The activity of this plant-like enzyme can be linked to the reduction of the parasite-specific thiol trypanothione by ascorbate in a process that involves nonenzymatic interaction. The role of heme in peroxidase activity was demonstrated by spectral and inhibition studies. Ascorbate could saturate TcAPX activity indicating that the enzyme obeys Michaelis--Menten kinetics. Parasites that overexpressed TcAPX activity were found to have increased resistance to exogenous [H.sub.2][0.sub.2]. To determine subcellular location an epitope-tagged form of TcAPX was expressed in T. cruzi, which was observed to colocalize with endoplasmic reticulum resident chaperone protein BiP. These findings identify an arm of the oxidative defense system of this medically important parasite. The absence of this redox pathway in the human host may be therapeutically exploitable.

Luminescence lifetime analysis in the presence and absence of DNA resolves at least two distinct binding modes that exhibit markedly different accessibility to oxygen and dissimilar behavior under physiological salt conditions. Under low loading conditions the linked bimetallic complexes appear to bind very much as the monometallic complex in that they exhibit two types of site on the DNA, each with very different environments.

The chemical nature of the species produced by the reaction of photooxidizing ruthenium(II) complexes with double-helical DNA is investigated. Photolysis of Ru(tap)sub2(bpy)super2+ in the presence of native (calf thymus) DNA formed products that were enzymatically excised. The photochemical reaction of RU(tap)sub3super2_ with guanosine 5'-monophosphate formed a covalent linkage between a tap ligand and the 2-NHsub2 guanine group.

Resonance Raman (RR) spectroscopy was used to analyze the interaction between dipyridophenazine complexes of Ru(II) and DNA. The RR spectra derived from the short-lived MLCT excited states of both complexes were compared with those of the longer-lived states of the DNA complexes. The excited state studies were then applied to the delta and lambda enantiomers where the marker band for both appeared at the same frequency with varying relative intensities.

A series of Ru(II) complexes while interacting with DNA produce a photoelectron transfer from a guanine or adenine base for most oxidizing compounds. It establishes a correlation between the occurrence of the photoelectron transfer process and the appearance of plasmid DNA cleavage and photoadduct formation. Covalently bound adducts are formed between the metal complexes and calf thymus DNA, for complexes with ability to oxidize guanine.

We conducted two experiments to evaluate the flooding dose method for measuring intestinal and liver protein synthesis in sheep. Experiment 1 showed that large doses of phenylalanine did not cause marked metabolic disturbances. Experiment 2 examined the effectiveness of flooding with phenylalanine and the time dependency of the protein synthesis calculation. Rams were injected with 1.2 MBq L-(ring 2,6-3H)phenylalanine/kg body wt and slaughtered 20, 40 or 60 min later. Plasma specific radioactivity reached a plateau within 2.5 min and did not change significantly (P > 0.05) throughout the experiment. Tissue intracellular free pool specific radioactivity also remained constant from 20 to 60 min postinfusion. Flooding conditions were achieved in the intracellular free pool of intestinal tissues (specific radioactivity 70-96% of plasma specific radioactivity), although liver flooding was less successful (57-67%). Protein synthesis rates measured after 20 min were significantly (P < 0.05) higher in the liver, jejunum and ileum than those measured at 60 min. Protein synthesis rates also tended to decline with time in the duodenum and colon (P > 0.05). There were no significant differences (P > 0.05) between protein synthesis rates calculated using the intracellular specific radioactivity vs. plasma specific radioactivity in the duodenum, ileum or colon. Therefore, this method represents an improvement over continuous infusion methods for measurements of protein synthesis in visceral tissues. J. Nutr. 122: 2398-2407, 1992.

The dependence of DNA wrapping in single-walled nanotube (SWNT) dispersions is studied. The negative activation entropies have shown that the rate-limiting step is characterized by a change in the system from a less-ordered to a more-ordered state, which is consistent with the formation of an ordered DNA coating.

A classical, nonadiabatic Marcus model for electron transfer is used to estimate the electronic coupling and reorganization energies involved for thionine-[poly(dG-dC)](sub 2) complexes. A range of intercalating dye of similar chemical structure and redox potential is studied to investigate the femtosecond electron-transfer quenching reactions in mono- and polynucleotides and in DNA.

Research describing the chemical reactions involved in the process of electron transfer between guanosine and thionine bases is presented. Particular attention is given to the high speed of the transfers of DNA electrons.

Author(s): John M. Kelly [1] CHAGAS DISEASE is a debilitating condition that has a considerable impact on public health in Latin America. Disease pathology seems to be predominantly a consequence [...]

Some of the results of a study conducted by W. Chen, et al, on the interaction between (Ru(phen)2dppz)2+ and DNA invite comment. The lowest excited state of ruthenium(II) dppz complexes generated confusion resulting from data for rhenium-(I) dppz complexes. Chen's suggestion on the identity of the species responsible for TR2 spectra was also unlikely. In addition, the researchers should have considered the detection of the pseudo-steady-state population during a 10 ns laser pulse.

I. INTRODUCTION II. WHAT IS A SURFING RESOURCE? A. Peel Angle B. Breaking Intensity C. Holistic View III. WHY SHOULD WE PROTECT SURFING RESOURCES? A. Value to Surfers B. Cultural [...]

The Driftless Area of the Upper Midwestern United States offers a case study for the transition from hunter-gatherer (Late Woodland Effigy Mound) to agricultural (Oneota) societies between ca. A.D. 950 and 1150, a period that coincided with northward expansion of Middle Mississippian cultures from the American Bottom. Previous studies have not adequately explained the regional disappearance of Effigy Mound cultures, the appearance of Oneota cultures, or the cultural changes that occurred during this period. Our analysis considers ecological (deer and firewood) and cultural (population packing, community organization, hunting technology, and warfare) factors to develop a testable model applicable to broader regions. We propose that increasing Late Woodland populations reached the region's 'packing threshold,' disrupting a flexible seasonal round based on residential mobility and triggering shortages of two essential resources, white-toiled deer and firewood, which in turn led Late Woodland groups to abandon vast portions of the Driftless Area. The intrusion of Middle Mississippian peoples from the south created additional disruption and conflict. Remnant Woodland and Mississippian peoples amalgamated briefly in the region's first villages, which were palisaded. After A.D. 1150, Oneota cultures emerged, reoccupying specific localities in clustered settlements. El Area Driftless (una zona no cubierta por los glaciates) de la parte central del Norte de los Estados Unidos ofrece un ejemplo de la transicion de una sociedad cazadora-recolectora (Woodland Effigy Mound Tardfo) a una sociedad agricola (Oneota) entre 1050 y 1150 d.C., un perfodo que coincidio con la expansion hacia el Notre de culturas Mississippian Medio del Sur Americano. Estudios anteriores no han explicado adecuadamente la desaparici6n regional de las culturas Effigy Mound, la aparicion de las culturas Oneota, o los cambios culturales que ocurrieron durante este periodo. Nuestro analisis considera factores ecologicos (venado y lena) y culturales (densidad de poblacion, organizacion de comunidad, tecnologia de caza, y guerra) para desarrollar un modelo que se puede probar y que se puede aplicar a regiones mas extensas. Proponemos que las poblaciones Woodland Tardio aumentaron hasta que llenaron la region, rompiendo el patron flexible de movilidad estacional y causando escaseases de dos recursos esenciales, venado de cola blanca y lena. Esta situacion obligo a los grupos Woodland Tardio a abandonar vastas extensiones del Area Driftless. La intrusion de grupos Mississippian del Sur creo trastornos y conflictos adicionales. Grupos remanentes Woodland y Mississippian se fusionaron brevemente en las primeras aldeas de la region, que fueron empalizadas. Despues del ano 1150 d.C. emergieron las culturas Oneota, reocupando localidades especificas en asentamientos agrupados., A major change in human subsistence and settlement systems occurred in the Driftless Area of the Upper Mississippi River valley between ca. A.D. 950 and 1150. The Late Woodland Effigy [...]