Scaffold oriented synthesis. Part 4: design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing heterocycle forming and multicomponent reactions

We report the synthesis and biological evaluation of 5-substituted indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing heterocycle forming and multicomponent reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for Gsk3β, Rock2, and Egfr.     

Similarities between Line Fishing and Baited Stereo-Video Estimations of Length-Frequency: Novel Application of Kernel Density Estimates

Age structure data is essential for single species stock assessments but length-frequency data can provide complementary information. In south-western Australia, the majority of these data for exploited species are derived from line caught fish. However, baited remote underwater stereo-video systems (stereo-BRUVS) surveys have also been found to provide accurate length measurements. Given that line fishing tends to be biased towards larger fish, we predicted that, stereo-BRUVS would yield length-frequency data with a smaller mean length and skewed towards smaller fish than that collected by fisheries-independent line fishing. To assess the biases and selectivity of stereo-BRUVS and line fishing we compared the length-frequencies obtained for three commonly fished species, using a novel application of the Kernel Density Estimate (KDE) method and the established Kolmogorov–Smirnov (KS) test. The shape of the length-frequency distribution obtained for the labrid Choerodon rubescens by stereo-BRUVS and line fishing did not differ significantly, but, as predicted, the mean length estimated from stereo-BRUVS was 17% smaller. Contrary to our predictions, the mean length and shape of the length-frequency distribution for the epinephelid Epinephelides armatus did not differ significantly between line fishing and stereo-BRUVS. For the sparid Pagrus auratus, the length frequency distribution derived from the stereo-BRUVS method was bi-modal, while that from line fishing was uni-modal. However, the location of the first modal length class for P. auratus observed by each sampling method was similar. No differences were found between the results of the KS and KDE tests, however, KDE provided a data-driven method for approximating length-frequency data to a probability function and a useful way of describing and testing any differences between length-frequency samples. This study found the overall size selectivity of line fishing and stereo-BRUVS were unexpectedly similar.     

Increased PAI-1 in females compared with males is protective for abdominal aortic aneurysm formation in a rodent model

The serine proteases, along with their inhibitor plasmin activator inhibitor-1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1(-/-) mice 8-12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% (P < 0.001). PAI-1(-/-) males increased 204% and females 161%, significantly more than their WT counterparts (P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males (P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1(-/-) males and females compared with their WT counterparts. PAI-1(-/-) females had significantly higher serum plasmin levels compared with WT females (P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1(-/-) animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation.     

Hunting and Nesting Phenology Influence Gobbling of Wild Turkeys

Wild turkeys (Meleagris gallopavo) use a polygynous mating system whereby males engage in multiple courtship behaviors, including vocalizations (gobbling) to attract females and compete with other males for breeding opportunities. Males must balance the risk of courtship behaviors with the reproductive potential of each courtship behavior. Male turkeys are primarily hunted during the reproductive period, so the associated risk of courtship behaviors is increased. Many state agencies attempt to set hunting season frameworks that maximize hunter satisfaction by allowing hunting when gobbling activity is greatest and most females are theoretically incubating nests, but the relationship between gobbling activity and nesting phenology is unclear. We used autonomous recording units and global positioning system transmitters to monitor gobbling activity by male turkeys and reproductive behaviors of female turkeys in the Piedmont region of Georgia, USA. We used 13,177 gobbles, behavioral data from 82 females during the reproductive season, and daily estimates of harvest of males by hunters to examine relationships between daily gobbling activity, cumulative removal of males, and reproductive behaviors (laying, incubating) of females during 2017–2018. We observed a weak negative relationship between daily gobbling activity and gobbling activity the following day. As the reproductive season progressed, gobbling activity decreased. As the proportion of females engaged in laying or incubating behaviors increased, expected daily gobbling activity increased. Conversely, we observed that hunting and removal of males had a negative effect on daily gobbling activity, and this effect was disproportionately greater than the positive effect of female reproductive behaviors. Our findings suggest that hunting and removal of males are important determinants of gobbling activity, and that corresponding reductions in gobbling activity may have mediating effects on the mating system of wild turkeys. © 2019 The Wildlife Society.     

Isolation and characterization of 10 MHC Class I-associated microsatellite loci in tammar wallaby (Macropus eugenii)

The major histocompatibility complex (MHC) contain genes which play a key role in immune response and mate choice, and are therefore of functional importance to molecular ecologists. Here we describe the design of 10 MHC Class I-associated microsatellite loci from the tammar wallaby. All 10 loci are highly polymorphic, with the expected heterozygosity ranging from 0.547 to 0.919. Six loci successfully cross-amplify in other macropodid species. These microsatellites will serve as useful tools for studying the level of MHC diversity, the impact of selection on genetic variation and the unique structure of the tammar wallaby MHC.