Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure

Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.     

Long-wavelength sensitive visual pigments of the guppy (<Emphasis Type="Italic">Poecilia reticulata</Emphasis>): six opsins expressed in a single individual

Background

The diversity of visual systems in fish has long been of interest for evolutionary biologists and neurophysiologists, and has recently begun to attract the attention of molecular evolutionary geneticists. Several recent studies on the copy number and genomic organization of visual pigment proteins, the opsins, have revealed an increased opsin diversity in fish relative to most vertebrates, brought about through recent instances of opsin duplication and divergence. However, for the subfamily of opsin genes that mediate vision at the long-wavelength end of the spectrum, the LWS opsins, it appears that most fishes possess only one or two loci, a value comparable to most other vertebrates. Here, we characterize the LWS opsins from cDNA of an individual guppy, Poecilia reticulata, a fish that is known exhibit variation in its long-wavelength sensitive visual system, mate preferences and colour patterns.

Results

We identified six LWS opsins expressed within a single individual. Phylogenetic analysis revealed that these opsins descend from duplication events both pre-dating and following the divergence of the guppy lineage from that of the bluefin killifish, Lucania goodei, the closest species for which comparable data exists. Numerous amino acid substitutions exist among these different LWS opsins, many at sites known to be important for visual pigment function, including spectral sensitivity and G-protein activation. Likelihood analyses using codon-based models of evolution reveal significant changes in selective constraint along two of the guppy LWS opsin lineages.

Conclusion

The guppy displays an unusually high number of LWS opsins compared to other fish, and to vertebrates in general. Observing both substitutions at functionally important sites and the persistence of lineages across species boundaries suggests that these opsins might have functionally different roles, especially with regard to G-protein activation. The reasons why are currently unknown, but may relate to aspects of the guppy's behavioural ecology, in which both male colour patterns and the female mate preferences for these colour patterns experience strong, highly variable selection pressures.

     

Demographic stochasticity versus spatial variation in the competition between fast and slow dispersers

Dispersal is an important strategy that allows organisms to locate and exploit favorable habitats. The question arises: given competition in a spatially heterogeneous landscape, what is the optimal rate of dispersal? Continuous population models predict that a species with a lower dispersal rate always drives a competing species to extinction in the presence of spatial variation of resources. However, the introduction of intrinsic demographic stochasticity can reverse this conclusion. We present a simple model in which competition between the exploitation of resources and stochastic fluctuations leads to victory by either the faster or slower of two species depending on the environmental parameters. A simplified limiting case of the model, analyzed by closing the moment and correlation hierarchy, quantitatively predicts which species will win in the complete model under given parameters of spatial variation and average carrying capacity.