Inhibition of human DNA topoisomerase II by hydroquinone and p-benzoquinone, reactive metabolites of benzene.

Chronic exposure of humans to benzene (BZ) causes acute myeloid leukemia (AML). Both BZ and therapy-related secondary AML are characterized by chromosomal translocations that may occur by inappropriate recombinational events. DNA topoisomerase II (topo II) is an essential sulfhydryl (SH)-dependent endonuclease required for replication, recombination, chromosome segregation, and chromosome structure. Topo II cleaves DNA at purine(R)/pyrimidine(Y) repeat sequences that have been shown to be highly recombinogenic in vivo. Certain antineoplastic drugs stabilize topo II-DNA cleavage complexes at RY repeat sequences, which leads to translocations of the type observed in leukemia. Hydroquinone (HQ) is metabolized to p-benzoquinone (BQ) in a peroxidase-mediated reaction in myeloid progenitor cells. BQ interacts wit SH groups of SH-dependent enzymes. Consequently, the aims of this research were to determine whether HQ and BQ are topo II inhibitors. The ability of the compounds to inhibit the activity of topo III was tested using an assay system that depends on the conversion, by homogeneous human topo II, of catenated kinetoplast DNA into open and/or nicked open circular DNA that can be separated from the catenated DNA by electrophoresis in a 1% agarose-ethidium bromide gel. We provide preliminary data that indicate that both HQ and BQ cause a time and concentration (microM)-dependent inhibition of topo II activity. These compounds, which potentially can form adducts with DNA, have no effect on the migration of the supercoiled and open circular forms in the electrophoretic gradient, and BQ-adducted KDNA can be decatenated by topo II. Using a pRYG plasmid DNA with a single RY repeat as a cleavage site, it was determined that BQ does not stimulate the production of linear DNA indicative of an inhibition of topo II religation of strand breaks by stabilization of the covalent topo III-DNA cleavage complex. Rather, BQ most probably inhibits the SH-dependent topo II by binding to an essential SH group. The inhibition of topo II by BQ has implications for the formation of deleterious translocations that may be involved in BZ-induced initiation of leukemogenesis

The Genetic Signature of Sex-Biased Migration in Patrilocal Chimpanzees and Humans

A large body of theoretical work suggests that analyses of variation at the maternally inherited mitochondrial (mt)DNA and the paternally inherited non-recombining portion of the Y chromosome (NRY) are a potentially powerful way to reveal the differing migratory histories of men and women across human societies. However, the few empirical studies comparing mtDNA and NRY variation and known patterns of sex-biased migration have produced conflicting results. Here we review some methodological reasons for these inconsistencies, and take them into account to provide an unbiased characterization of mtDNA and NRY variation in chimpanzees, one of the few mammalian taxa where males routinely remain in and females typically disperse from their natal groups. We show that patterns of mtDNA and NRY variation are more strongly contrasting in patrilocal chimpanzees compared with patrilocal human societies. The chimpanzee data we present here thus provide a valuable comparative benchmark of the patterns of mtDNA and NRY variation to be expected in a society with extremely female-biased dispersal

Fragilities Caused by Dosage Imbalance in Regulation of the Budding Yeast Cell Cycle

Cells can maintain their functions despite fluctuations in intracellular parameters, such as protein activities and gene expression levels. This commonly observed biological property of cells is called robustness. On the other hand, these parameters have different limitations, each reflecting the property of the subsystem containing the parameter. The budding yeast cell cycle is quite fragile upon overexpression of CDC14, but is robust upon overexpression of ESP1. The gene products of both CDC14 and ESP1 are regulated by 1∶1 binding with their inhibitors (Net1 and Pds1), and a mathematical model predicts the extreme fragility of the cell cycle upon overexpression of CDC14 and ESP1 caused by dosage imbalance between these genes. However, it has not been experimentally shown that dosage imbalance causes fragility of the cell cycle. In this study, we measured the quantitative genetic interactions of these genes by performing combinatorial “genetic tug-of-war” experiments. We first showed experimental evidence that dosage imbalance between CDC14 and NET1 causes fragility. We also showed that fragility arising from dosage imbalance between ESP1 and PDS1 is masked by CDH1 and CLB2. The masking function of CLB2 was stabilization of Pds1 by its phosphorylation. We finally modified Chen's model according to our findings. We thus propose that dosage imbalance causes fragility in biological systems

The effects of spatially heterogeneous prey distributions on detection patterns in foraging seabirds

Many attempts to relate animal foraging patterns to landscape heterogeneity are focused on the analysis of foragers movements. Resource detection patterns in space and time are not commonly studied, yet they are tightly coupled to landscape properties and add relevant information on foraging behavior. By exploring simple foraging models in unpredictable environments we show that the distribution of intervals between detected prey (detection statistics)is mostly determined by the spatial structure of the prey field and essentially distinct from predator displacement statistics. Detections are expected to be Poissonian in uniform random environments for markedly different foraging movements (e.g. L\'evy and ballistic). This prediction is supported by data on the time intervals between diving events on short-range foraging seabirds such as the thick-billed murre ({\it Uria lomvia}). However, Poissonian detection statistics is not observed in long-range seabirds such as the wandering albatross ({\it Diomedea exulans}) due to the fractal nature of the prey field, covering a wide range of spatial scales. For this scenario, models of fractal prey fields induce non-Poissonian patterns of detection in good agreement with two albatross data sets. We find that the specific shape of the distribution of time intervals between prey detection is mainly driven by meso and submeso-scale landscape structures and depends little on the forager strategy or behavioral responses.Comment: Submitted first to PLoS-ONE on 26/9/2011. Final version published on 14/04/201

Influence of acetylsalicylic acid on hematotoxicity of benzene

Objectives: The aim of the study was to evaluate the influence of acetylsalicylic acid (ASA) on benzene hematotoxicity in rats. Materials and Methods: The study was carried out on rats exposed for 2, 4 and 8 weeks to benzene vapour at a conentration of 1.5 or 4.5 mmol/m3 of air (5 days per week, 6 hours per day) alone or together with ASA at the doses of 5, 150 or 300 mg/kg body weight (per os). Results: Benzene at a concentration of 4.5 mmol/m3 caused a slight lymphopenia, granulocytosis and reticulocytosis in blood. In bone marrow traits of megaloblastic renewal, presence of undifferentiated cells and giant forms of granulocytes as well as an increase in myeloperoxidase and decrease in chloroacetate esterase activity and lipids content were noted. ASA (150 and 300 mg/kg b.w.) influenced some of hematological parameters, altered by benzene intoxication. ASA limited the solvent-induced alteration in blood reticulocyte count and in the case of bone marrow in the erythroblasts count. Traits of megaloblastic renewal in bone marrow were less pronounced. Besides, higher activity of myeloperoxidase and the decrease in the level of lipids in granulocytes were noted. Conclusion: Our results suggest that ASA limited the benzene-induced hematotoxicity

Increased energy expenditure by a seabird in response to higher food abundance

Variability in forage fish abundance strongly affects seabird behavior and reproductive success, although details of this relationship are unclear. During 1997 and 1998, we measured (1) daily energy expenditure (DEE) of 80 parent black-legged kittiwakes Rissa tridactyla at 2 colonies in Prince William Sound, Alaska (North Icy Bay and Shoup Bay), (2) abundance of surface-schooling forage fishes within the foraging range of each colony, and (3) diet composition, energy delivery rates to nestlings, and reproductive success of kittiwakes at these same colonies. Female DEE was highest at North Icy Bay in 1998, while male DEE did not differ by colony year. Abundances of Pacific herring Clupea pallasi and sand lance Ammodytes hexapterus were highest near North Icy Bay in 1998 and nearly equal in density, although Age 1+ herring comprised the majority of the diet there. Energy delivery rates to nestlings, nestling growth rates, and productivity were also highest at North Icy Bay in 1998. We suggest that female kittiwakes responded to the increased abundance of Age 1+ herring near North Icy Bay in 1998 by increasing their DEE, which in turn positively affected reproductive success. Given that adult kittiwakes have been shown to suffer decreased survival as a response to increased energy expenditure during brood rearing, the positive correlation we observed between increased abundance of a high quality food source, parental effort, and productivity is consistent with maximizing lifetime reproductive success. The lack of a response in male DEE suggests that brood-rearing roles in kittiwakes differ between genders