Abstract: Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators.

Abstract: Both humans and group-living animals associate and behave affiliatively more with some individuals than others. Human friendship has long been acknowledged, and recently scientists studying animal behaviour have started using the term friendship for close social associates in animals. Yet, while biologists describe friends as social tools to enhance fitness, social scientists describe human friendship as unconditional. We investigate whether these different descriptions reflect true differences in human friendship and animal close social associations or are a by-product of different research approaches: namely social scientists focussing on proximate and biologists on ultimate explanations. We first stress the importance of similar measures to determine close social associations, thereafter examine their ultimate benefits and proximate motivations, and discuss the latest findings on the central-neural regulation of social bonds. We conclude that both human friendship and animal close social associations are ultimately beneficial. On the proximate level, motivations for friendship in humans and for close social associations in animals are not necessarily based on benefits and are often unconditional. Moreover, humans share with many animals a similar physiological basis of sociality. Therefore, biologists and social scientist describe the same phenomenon, and the use of the term friendship for animals seems justified.

Abstract: Social group size has been shown to correlate with neocortex size in primates. Here we use comparative analyses to show that social group size is independently correlated with the size of non-V1 neocortical areas, but not with other more proximate components of the visual system or with brain systems associated with emotional cueing (e.g. the amygdala). We argue that visual brain components serve as a social information 'input device' for socio-visual stimuli such as facial expressions, bodily gestures and visual status markers, while the non-visual neocortex serves as a 'processing device' whereby these social cues are encoded, interpreted and associated with stored information. However, the second appears to have greater overall importance because the size of the V1 visual area appears to reach an asymptotic size beyond which visual acuity and pattern recognition may not improve significantly. This is especially true of the great ape clade (including humans), that is known to use more sophisticated social cognitive strategies.