Potentiation of cytotoxic drug activity in human tumour cell lines, by amine-substituted 2-arylbenzimidazole-4-carboxamide PARP-1 inhibitors

The synthesis and biological evaluation of a new series of amine-substituted 2-arylbenzimidazole-4-carboxamide inhibitors of the DNA-repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is reported. The introduction of an amine substituent at the 2-aryl position is not detrimental to activity, with most inhibitors exhibiting K(i) values for PARP-1 inhibition in the low nanomolar range. Two compounds in this series were found to potentiate the cytotoxicity of the DNA-methylating agent temozolomide by 4-5-fold in a human colorectal cancer cell line.     

Fluorescent sodium ion indicators based on the 1,7-diaza-15-crown-5 system

A series of novel sodium ion-sensitive fluorescent reagents suitable for biological applications is described. The chelator nitrogen atom substituents affect the selectivity and affinity of cation binding, while the nature of the fluorophore determines the type of fluorescent response to metal ion chelation.     

Indecent exposure: when telomeres become uncapped

The protective "cap" that assembles at chromosome ends recruits and controls an intricate network of biochemical activities, each one critical for telomere structure and the maintenance of genomic stability. Recent studies have uncovered the components of telomere caps and have started to define the pathways that lead from telomere dysfunction to chromosomal catastrophe.     

The beta-subunit of the signal recognition particle receptor is a novel GTP-binding protein without intrinsic GTPase activity

The beta-subunit of the signal recognition particle receptor (SRbeta), a member of the Ras family of small molecular weight GTPases, is involved in the targeting of nascent polypeptide chains to the protein translocation machinery in the endoplasmic reticulum membrane. We purified SRbeta from an expressing strain of Escherichia coli and investigated the properties of the isolated GTPase. We find that, unlike other Ras family GTPases, most SRbeta purifies bound to GTP, and SRbeta-bound GTP is not easily exchanged with solution GTP. SRbeta possesses no detectable GTPase activity. Although a stable interaction between SRbeta and ribosomes is observed, SRbeta is not stimulated to hydrolyze GTP when incubated with ribosomes or ribosome-nascent chains. A GTPase mutant harboring a mutation in a region predicted to be functionally important, based on observations made in related GTPases, binds GTP with faster kinetics and appears to be a less stable protein but otherwise displays similar properties to the wild-type SRbeta GTPase. Our results demonstrate that as an isolated GTPase, SRbeta functions differently from the Arf- and Ras-type GTPases that it is most closely related to by sequence.     

A hierarchy of lipid constructs for the sperm plasma membrane

We have presented a series of lipid constructs as models of the sperm plasma membrane. We also isolated the plasma membrane from rabbit sperm cells and characterized the lipid composition. The behavior of these various membrane systems was evaluated using a vesicle leakage assay, in which surfactant (nonoxynol-9, N-9; or benzalkonium chloride, BZK) exposure induced membrane permeabilization. These studies shed light on the relative importance and significance of particular components present in the lipid constructs. In particular, a highly unsaturated phospholipid component characterized by an ether-linkage to position 1 of the glycerol backbone (as opposed to the more conventional ester linkage) as well as the presence of sulfogalactosyl ceramide were found to have an effect on the surfactant-induced leakage response. The presence of cholesterol had the greatest influence on membrane behavior. The construct series also demonstrated the ability of the surfactants studied to discriminate between different membrane systems. We found that N-9 displayed little sensitivity to membrane composition while BZK showed specific behavior with the various membrane systems.     

Bergmann's rule in nonavian reptiles: turtles follow it,lizards and snakes reverse it

Abstract Bergmann's rule is currently defined as a within-species tendency for increasing body size with increasing latitude or decreasing environmental temperature. This well-known ecogeographic pattern has been considered a general trend for all animals, yet support for Bergmann's rule has only been demonstrated for mammals and birds. Here we evaluate Bergmann's rule in two groups of reptiles: chelonians (turtles) and squamates (lizards and snakes). We perform both nonphylogenetic and phylogenetic analyses and show that chelonians follow Bergmann's rule (19 of 23 species increase in size with latitude; 14 of 15 species decrease in size with temperature), whereas squamates follow the converse to Bergmann's rule (61 of 83 species decrease in size with latitude; 40 of 56 species increase in size with temperature). Size patterns of chelonians are significant using both nonphylogenetic and phylogenetic methods, whereas only the nonphylogenetic analyses are significant for squamates. These trends are consistent among major groups of chelonians and squamates for which data are available. This is the first study to document the converse to Bergmann's rule in any major animal group as well as the first to show Bergmann's rule in a major group of ectotherms. The traditional explanation for Bergmann's rule is that larger endothermic individuals conserve heat better in cooler areas. However, our finding that at least one ectothermic group also follows Bergmann's rule suggests that additional factors may be important. Several alternative processes, such as selection for rapid heat gain in cooler areas, may be responsible for the converse to Bergmann's rule in squamates.     

Genetic variation and structure of fisher (Martes pennanti) populations across North America

Fishers are mid-sized forest carnivores indigenous to North America that experienced sharp population declines from the early 1800s through to the mid-1900s. To evaluate levels of genetic variation within and subdivision among northern fisher populations 459 individuals were genotyped using 13 microsatellite loci. Genetic diversity was found to be slightly lower in re-introduced populations than in adjacent indigenous populations. Furthermore, fisher populations revealed much more genetic structuring than two closely related mustelids. Further investigation is needed to determine if fishers are more philopatric than martens and wolverines or if barriers to dispersal explain the levels of structure identified in this study.