The dynamics of chromosome evolution in birds and mammals

Comparative mapping, which compares the location of homologous genes in different species, is a powerful tool for studying genome evolution. Comparative maps suggest that rates of chromosomal change in mammals can vary from one to ten rearrangements per million years. On the basis of these rates we would expect 84 to 600 conserved segments in a chicken comparison with human or mouse. Here we build comparative maps between these species and estimate that numbers of conserved segments are in the lower part of this range. We conclude that the organization of the human genome is closer to that of the chicken than the mouse and by adding comparative mapping results from a range of vertebrates, we identify three possible phases of chromosome evolution. The relative stability of genomes such as those of the chicken and human will enable the reconstruction of maps of ancestral vertebrates.     

A Systemic Action Learning Cycle as the Key Element of an Ongoing Spiral of Analyses

The Systems movement in the United Kingdom, in addressing the task of enquiry, has created a surfeit of methodologies. Each, like some closely guarded religious sect, demands adherence to its own presentational rules and procedures, its own epistemological and ontological position. Much of the secondary literature of the U.K. Systems movement focuses on examining the strengths and weaknesses of these separate approaches, devises complex decision rules for when to use which methodology, and attempts to map particular methodologies onto "appropriate" scenarios. This paper attempts to present a generalized form of the cyclic activity of investigation and action which is encompassed by many of the methodologies. It is shown that this does not require the presentation of a "lowest common denominator" activity set, which is of no value, but rather draws on the underlying power of the approaches to present a robust and defensible cycle of activities which are continuously reenacted over time. The implications of this spiral model of Action Learning are examined, both in relation to the development of existing methodologies and in relation to the issues related to managing a complex analysis project. The paper concludes by showing how individual analysis cycles merge into a never-ending learning spiral in a complex, dynamic, real-world environment.     

Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin

AB(5) toxins comprise an A subunit that corrupts essential eukaryotic cell functions, and pentameric B subunits that direct target-cell uptake after binding surface glycans. Subtilase cytotoxin (SubAB) is an AB(5) toxin secreted by Shiga toxigenic Escherichia coli (STEC), which causes serious gastrointestinal disease in humans. SubAB causes haemolytic uraemic syndrome-like pathology in mice through SubA-mediated cleavage of BiP/GRP78, an essential endoplasmic reticulum chaperone. Here we show that SubB has a strong preference for glycans terminating in the sialic acid N-glycolylneuraminic acid (Neu5Gc), a monosaccharide not synthesized in humans. Structures of SubB-Neu5Gc complexes revealed the basis for this specificity, and mutagenesis of key SubB residues abrogated in vitro glycan recognition, cell binding and cytotoxicity. SubAB specificity for Neu5Gc was confirmed using mouse tissues with a human-like deficiency of Neu5Gc and human cell lines fed with Neu5Gc. Despite lack of Neu5Gc biosynthesis in humans, assimilation of dietary Neu5Gc creates high-affinity receptors on human gut epithelia and kidney vasculature. This, and the lack of Neu5Gc-containing body fluid competitors in humans, confers susceptibility to the gastrointestinal and systemic toxicities of SubAB. Ironically, foods rich in Neu5Gc are the most common source of STEC contamination. Thus a bacterial toxin's receptor is generated by metabolic incorporation of an exogenous factor derived from food.