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PubMed1998

The Eleventh Datta Lecture. The structural basis for substrate recognition and control by protein kinases.

Protein kinases catalyse phospho transfer reactions from ATP to serine, threonine or tyrosine residues in target substrates and provide key mechanisms for control of cellular signalling processes. The crystal structures of 12 protein kinases are now known. These include structures of kinases in the active state in ternary complexes with ATP (or analogues) and inhibitor or peptide substrates (e.g. cyclic AMP dependent protein kinase, phosphorylase kinase and insulin receptor tyrosine kinase); kinases in both active and inactive states (e.g. CDK2/cyclin A, insulin receptor tyrosine kinase and MAPK); kinases in the active state (e.g. casein kinase 1, Lck); and kinases in inactive states (e.g. twitchin kinase, calcium calmodulin kinase 1, FGF receptor kinase, c-Src and Hck). This paper summarises the detailed information obtained with active phosphorylase kinase ternary complex and reviews the results with reference to other kinase structures for insights into mechanisms for substrate recognition and control.

Adenosine Triphosphate↗
PubMed1998

BAPS prize lecture: New insight into mechanisms of parenteral nutrition-associated cholestasis: role of plant sterols. British Association of Paediatric Surgeons.

BACKGROUND PURPOSE: Infants on long-term parenteral nutrition frequently will have progressive cholestatic liver disease, the cause of which remains largely unknown. The aim of this study is to establish a possible role for plant sterols (phytosterols) in the pathogenesis of parenteral nutrition-associated cholestasis (PNAC). METHODS: Two experimental studies were used: (1) A study on neonatal piglets involved the daily injection of plant sterols; measurement of their concentrations in serum, liver, and bile during a 14-day period; and determination of serum bile acid concentrations, bile acid secretion, and bile flow at the end of the 14-day period. (2) Isolated rat hepatocyte couplets were used to study the effects of sterols on canalicular secretion. RESULTS: The daily injection of phytosterols (in amounts similar to those given to infants who receive parenteral nutrition) led to their progressive accumulation in the piglets' serum, liver, and bile. Serum bile acid levels were significantly higher in the sterol-treated piglets. Maximal bile acid excretion was significantly lower in the sterol group. Phytosterols caused a significant inhibition of secretory function in isolated rat hepatocyte couplets. CONCLUSION: Important contaminants of commercial lipid emulsions (phytosterols) have been identified as a possible cause of PNAC.

Animals↗
PubMedDate not supplied

Manson Lecture. Meningococcal meningitis in Africa.

This review covers the history of meningococcal meningitis in Africa since epidemics of the infection were first described around 100 years ago. It is possible that an epidemic strain of the meningococcus was introduced into West Africa from the Sudan by pilgrims returning from the Haj around the turn of the century. Since 1905 major epidemics of meningococcal meningitis have occurred in countries of the Sahel and sub-Sahel every few years, culminating in a massive epidemic in which nearly 200,000 cases were reported in 1996. Attempts to control epidemic meningococcal meningitis in Africa by vaccination with meningococcal polysaccharide vaccines have met with only modest success because epidemics can progress with great rapidity and vaccination is often started too late. This situation should be improved as a result of a recent initiative, the International Coordinating Group (ICG), which is contributing to better surveillance in countries at risk and ensuring that vaccine is available when needed. However, in the medium term, the best prospect for the control of meningococcal meningitis in Africa lies in the recent development of polysaccharide-protein conjugate vaccines which, unlike polysaccharide vaccines, are immunogenic in the very young, induce immunological memory and are likely to give long-lasting protection.

Africa↗
PubMedDate not supplied

Project Phoenix and beyond. Pesek Lecture.

Although there are no federally funded projects at this time, SETI (the search for extraterrestrial intelligence) is a vigorous exploratory science. There are currently eight observational programs on telescopes around the world, of which the Phoenix Project is the most comprehensive. Most of these projects are rooted in the conclusions of the pioneering studies of the early 1970's that are summarized in the Cyclops Report. Technology has experienced an exponential growth over the past two and a half decades. It is reasonable to reassess the Cyclops conclusions as SETI enters the next century. Listening for radio signals is still the preferred method of searching, however new technologies are making searches at other wavelengths possible and are modifying the ways in which the radio searches can and should be conducted. It may be economically feasible to undertake the construction of very large telescopes that can simultaneously provide multiple beams on the sky for use by SETI and the radioastronomy community.

Astronomy↗