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: I begin with a rather unpromising dispute that Nozick once had with Ian Hacking in the pages of the London Review of Books, in which both vied with one another in their enthusiasm to repudiate the thesis that some human people or peoples are closer than others to animality. I shall attempt to show that one can build, on the basis of Nozick’s discussion of rationality, a defense of the view that the capacity for language places human rationality out of reach of a comparison with animals. The difference rests, paradoxi–cally, on the human capacity for irrationality. Irrationality depends on the capacity for language, which allows the detachment of explicit thoughts from their underlying dynamic implementation; these, in turn, condition the essential disputability of principles of rationality. That is what places every human potentially—if not actually—on the other side of an unbridge–able gulf that separates us from other animals.

Abstract: In recent years, it has become apparent that behavioural and brain lateralization at the population level is the rule rather than the exception among vertebrates. The study of these phenomena has so far been the province of neurology and neuropsychology. Here, we show how such research can be integrated with evolutionary biology to understand lateralization more fully. In particular, we address the fact that, within a species, left– and right–type individuals often occur in proportions different from one–half (e.g. hand use in humans). The traditional explanations offered for lateralization of brain function (that it may avoid unnecessary duplication of neural circuitry and reduce interference between functions) cannot account for this fact, because increased individual efficiency is unrelated to the alignment of lateralization at the population level. A further puzzle is that such an alignment may even be disadvantageous, as it makes individual behaviour more predictable to other organisms. Here, we show that alignment of the direction of behavioural asymmetries in a population can arise as an evolutionarily stable strategy when individual asymmetrical organisms must coordinate their behaviour with that of other asymmetrical organisms. Brain and behavioural lateralization, as we know it in humans and other vertebrates, may have evolved under basically ‘social’ selection pressures.

Abstract: Evolutionary theory predicts that mothers of different condition should adjust the birth sex ratio of their offspring in relation to future reproductive benefits. Published studies addressing variation in mammalian sex ratios have produced surprisingly contradictory results. Explaining the source of such variation has been a challenge for sex-ratio theory, not least because no mechanism for sex-ratio adjustment is known. I conducted a meta-analysis of previous mammalian sex-ratio studies to determine if there are any overall patterns in sex-ratio variation. The contradictory nature of previous results was confirmed. However, studies that investigated indices of condition around conception show almost unanimous support for the prediction that mothers in good condition bias their litters towards sons. Recent research on the role of glucose in reproductive functioning have shown that excess glucose favours the development of male blastocysts, providing a potential mechanism for sex-ratio variation in relation to maternal condition around conception. Furthermore, many of the conflicting results from studies on sex-ratio adjustment would be explained if glucose levels in utero during early cell division contributed to the determination of offspring sex ratios.

Abstract: Old breaks of the keel and furculum were identified by palpation in 500 end-of-lay hens from 10 flocks housed in free-range and barn systems, and the results were compared with the results obtained by a full dissection and inspection. The method was considered to be sufficiently precise to be used as a diagnostic tool although people using it would need to be trained. The results obtained by dissection indicated that 50 to 78 per cent of the birds in the flocks had breaks of the furculum and keel, but no other breaks of bones were detected.