Three distinct molecular surfaces in ephrin-A5 are essential for a functional interaction with EphA3

Eph receptor tyrosine kinases (Ephs) function as molecular relays that interact with cell surface-bound ephrin ligands to direct the position of migrating cells. Structural studies revealed that, through two distinct contact surfaces on opposite sites of each protein, Eph and ephrin binding domains assemble into symmetric, circular heterotetramers. However, Eph signal initiation requires the assembly of higher order oligomers, suggesting additional points of contact. By screening a random library of EphA3 binding-compromised ephrin-A5 mutants, we have now determined ephrin-A5 residues that are essential for the assembly of high affinity EphA3 signaling complexes. In addition to the two interfaces predicted from the crystal structure of the homologous EphB2 center dot ephrin-B2 complex, we identified a cluster of 10 residues on the ephrin-A5 E alpha-helix, the E-F loop, the underlying H beta-strand, as well as the nearby B - C loop, which define a distinct third surface required for oligomerization and activation of EphA3 signaling. Together with a corresponding third surface region identified recently outside of the minimal ephrin binding domain of EphA3, our findings provide experimental evidence for the essential contribution of three distinct protein-interaction interfaces to assemble functional EphA3 signaling complexes.

Desperately seeking donors: The 'saviour siblings' decision in quintaville v human fertilisation embryology authority (UK)

The recent House of Lords decision in Quintavalle v Human Fertilisation and Embryology Authority has raised difficult and complex issues regarding the extent to which embryo selection and reproductive technology can be used as a means of rectifying genetic disorders and treating critically ill children. This comment outlines the facts of Quintavalle and explores how the House of Lords approached the legal, ethical and policy issues that arose out of the Human Fertilisation and Embryology Authority's (UK) decision to allow reproductive and embryo technology to be used to produce a 'saviour sibling' whose tissue could be used to save the life of a critically ill child. Particular attention will be given to the implications of the decision in Quintavalle for Australian family and medical law and policy. As part of this focus, the comment explores the current Australian legislative and policy framework regarding the use of genetic and reproductive technology as a mechanism through which to assist critically ill siblings. It is argued that the present Australian framework would appear to impose significant limits on the medical uses of genetic technology and, in this context, would seem to reflect many of the principles that were articulated by the House of Lords in Quintavalle.

Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis

The mechanisms for progressive fibrosis and exacerbation by steatosis in patients with chronic hepatitis C (HCV) are still unknown. We hypothesized that proliferative blockade in HCV-infected and steatotic hepatocytes results in the default activation of hepatic progenitor cells (HPC), capable of differentiating into both biliary and hepatocyte lineages, and that the resultant ductular reaction promotes portal fibrosis. To study this concept, 115 liver biopsy specimens from subjects with HCV were scored for steatosis, inflammation, and fibrosis. Biliary epithelium and HPC were decorated by cytokeratin 7 immunoperoxidase, and the replicative state of hepatocytes was assessed by p21 and Ki-67 immunohistochemistry. A ductular reaction at the portal interface was common. There was a highly significant correlation between the area of ductular reaction and fibrosis stage (r = 0.453, P < .0001), which remained independently associated after multivariate analysis. HPC numbers also correlated with fibrosis (r = 0.544, P < .0001) and the ductular area (r = 0.624, P < .0001). Moreover, steatosis correlated with greater HPC proliferation (r = 0.372, P = .0004) and ductular reaction (r = 0.374, P < .0001) but was not an obligate feature. Impaired hepatocyte replication by p21 expression was independently associated with HPC expansion (P = .002) and increased with the body mass index (P < .001) and lobular inflammation (P = .005). In conclusion, the strong correlation between portal fibrosis and a periportal ductular reaction with HPC expansion, the exacerbation by steatosis, and the associations with impaired hepatocyte replication suggest that an altered regeneration pathway drives the ductular reaction. We believe this triggers fibrosis at the portal tract interface. This may be a stereotyped response of importance in other chronic liver diseases.

The oil shock of 2005

During the course of 2005, the price of crude oil reached unprecedented high levels, at least in nominal terms. Australian motorists have become used to paying more than a dollar a litre for petrol. Given the past volatility in oil prices, often described in terms of a series of oil ‘shocks’ (the large price increases in 1973, 1979 and 1999), several questions arise. First, will current high prices persist, or will prices decline substantially as occurred after previous oil shocks? Second, is the current shortage of oil a temporary phenomenon, caused by inadequate investment in oil exploration, drilling and refining capacity, or is it a signal that the supply of oil available to the world has peaked? Third, will high oil prices lead to broader economic disruption, as is commonly supposed to have happened after previous shocks? Fourth, how painful will an adjustment to lower use of oil be? Finally, how does all this relate to our efforts to deal with the problem of climate change? This article is an effort to answer some of these questions in the light of the knowledge available to us.