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The Malayan, or Asian, tapir ( Tapirus indicus) has a diminishing wild population and is becoming more common in captivity as zoos attempt to manage sustainable ex situ populations. Tapirs can be relatively easy to maintain and breed, but captive animals appear to suffer from reduced activity budgets, obesity, and poor public image. A questionnaire-based survey was designed and sent specifically to 10 collections around the world that exhibit Malayan tapirs, with the aim of assessing husbandry regimes to determine prevalence of standardized practices as well as highlighting any key differences, and to showcase good practice, thus providing information beneficial to those maintaining this species in their zoo. Twenty-five animals were included in the survey from collections across four continents. The research's major conclusions show differing dietary make-up, with a lack of forage provision, contrasting with a diverse array of enrichment protocols used. Significant differences were noted between zoos for total amount of food offered ( P = 0.000) as well as ratios of forage to concentrate pellet offered ( P = 0.004). Comparing food offered to male and female tapirs with published requirements for an 'average' of either gender shows not all zoos providing the amount suggested in husbandry guidelines. Intelligently designed and original enrichment was provided to all animals but differences between zoos were noted in the application and 'usefulness' of enrichment for individual tapir. Overall, animals are benefiting from enrichment but welfare could be further improved via consistent feeding of ad libitum forage and regular use of browse as a constituent part of daily rations. Zoo Biol. 32:347-356, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU1 1274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers. [ABSTRACT FROM AUTHOR]

Zoo animal welfare is subject to increasing scrutiny by many audiences. Although zoo husbandry and management techniques have progressed, common welfare issues are still apparent. To encourage further improvements, converting theoretical welfare definition into practical application is key. This paper evaluates a familiar definition to form a baseline for practical welfare assessment that benefits animals and zoo operations. If we consider coping and comfort as measurable indicators, plus choice and control to cement autonomy for the animal, achieving positive welfare is more likely. Providing positive cognitive challenge results in improvements to behavioral diversity. When husbandry is ecologically relevant, this welfare-friendly approach evolves into husbandry-based evidence, further justifying approaches to animal care. The human element of husbandry (e.g., development and training of personnel) impacts on welfare, necessitating a compassionate approach to daily operations. Compassion - for animal and human wellbeing - ultimately embeds welfare as a core zoo goal. The unique environment of the zoo, with its mix of wild species, human workforce and visitors, coupled with the amount we still must learn about species' husbandry needs emphasizes continual development of welfare approaches.

Several reports have recently emerged regarding the identification of heteroarylsulfonamides as Na V 1.7 inhibitors that demonstrate high levels of selectivity over other Na V isoforms. The optimization of a series of internal Na V 1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities. The key to achieving this within a series prone to transporter-mediated clearance was the identification of a small range of optimal cLogD values and the discovery of subtle PXR SAR that was not lipophilicity dependent. This enabled the identification of compound 20, which was advanced into a target engagement pharmacodynamic model where it exhibited robust reversal of histamine-induced scratching bouts in mice.