Protein deiminases: new players in the developmentally regulated loss of neural regenerative ability

Spinal cord regenerative ability is lost with development, but the mechanisms underlying this loss are still poorly understood. In chick embryos, effective regeneration does not occur after E13, when spinal cord injury induces extensive apoptotic response and tissue damage. As initial experiments showed that treatment with a calcium chelator after spinal cord injury reduced apoptosis and cavitation, we hypothesized that developmentally regulated mediators of calcium-dependent processes in secondary injury response may contribute to loss of regenerative ability. To this purpose we screened for such changes in chick spinal cords at stages of development permissive (E11) and non-permissive (E15) for regeneration. Among the developmentally regulated calcium-dependent proteins identified was PAD3, a member of the peptidylarginine deiminase (PAD) enzyme family that converts protein arginine residues to citrulline, a process known as deimination or citrullination. This post-translational modification has not been previously associated with response to injury. Following injury, PAD3 up-regulation was greater in spinal cords injured at E15 than at E11. Consistent with these differences in gene expression, deimination was more extensive at the non-regenerating stage, E15, both in the gray and white matter. As deimination paralleled the extent of apoptosis, we investigated the effect of blocking PAD activity on cell death and deiminated-histone 3, one of the PAD targets we identified by mass-spectrometry analysis of spinal cord deiminated proteins. Treatment with the PAD inhibitor, Cl-amidine, reduced the abundance of deiminated-histone 3, consistent with inhibition of PAD activity, and significantly reduced apoptosis and tissue loss following injury at E15. Altogether, our findings identify PADs and deimination as developmentally regulated modulators of secondary injury response, and suggest that PADs might be valuable therapeutic targets for spinal cord injury.

Evolution of lactase persistence: an example of human niche construction

Niche construction is the process by which organisms construct important components of their local environment in ways that introduce novel selection pressures. Lactase persistence is one of the clearest examples of niche construction in humans. Lactase is the enzyme responsible for the digestion of the milk sugar lactose and its production decreases after the weaning phase in most mammals, including most humans. Some humans, however, continue to produce lactase throughout adulthood, a trait known as lactase persistence. In European populations, a single mutation (−13910*T) explains the distribution of the phenotype, whereas several mutations are associated with it in Africa and the Middle East. Current estimates for the age of lactase persistence-associated alleles bracket those for the origins of animal domestication and the culturally transmitted practice of dairying. We report new data on the distribution of −13910*T and summarize genetic studies on the diversity of lactase persistence worldwide. We review relevant archaeological data and describe three simulation studies that have shed light on the evolution of this trait in Europe. These studies illustrate how genetic and archaeological information can be integrated to bring new insights to the origins and spread of lactase persistence. Finally, we discuss possible improvements to these models.

The BBC's role in the changing production ecology of pre-school television in Britain

This paper examines the changing production ecology of British pre-school television in light of developments since the mid-1990s and the specific role played by the BBC. Underpinning the research is the perception that pre-school television is characterised by a complex set of industry relationships and dependencies that demands content which needs to satisfy a wide range of international circumstances and commercial prerogatives. For the BBC this has created tension between its public service goals and commercial priorities. Pre-school programming began in Britain in 1950, but it was not until the mid-1990s that Britain emerged as a leading producer of pre-school programming worldwide with government/industry reports regularly identifying the children’s production sector as an important contributor to exports. The rise of pre-school niche channels (CBeebies, Nick Junior, Playhouse Disney), audience fragmentation and the internationalisation and commercialisation of markets have radically altered the funding base of children’s television and the relationships that the BBC enjoys with key players. The international success of much of its pre-school programming is based on the relationships it enjoys with independent producers who generate significant revenues from programme-related consumer products. This paper focuses on the complex and changing relationships between the BBC, independent producers, and financiers, that constitute the production ecology of pre-school television and shape its output. Within the broader setting of cultural production and global trends the paper investigates the following questions: 1) In the light of changes to the sector since the mid-1990s, what makes pre-school television significant both generally and as an ideal public service project? 2) What is the nature of the current funding crisis in British children’s television and what implications does this crisis have for the BBC’s involvement in pre-school television? 3) How is the Corporation reacting to and managing the wider commercial, cultural, regulatory and technological forces that are likely to affect its strategies for the commissioning, production and acquisition of pre-school content?