For many years it has been known that thymine auxotrophic microorganisms undergo cell death in response to thymine starvation [thymineless death (TLD)]. This effect is unusual in that deprivation of many other nutritional requirements has a biostatic, but not lethal, effect. Studies of numerous microbes have indicated that thymine starvation has both direct and indirect effects. The direct effects involve both single- and double-strand DNA breaks. The former may be repaired effectively, but the latter lead to cell death. DNA damaged by thymine starvation is a substrate for DNA repair processes, in particular recombinational repair. Mutations in recBCD recombinational repair genes increase sensitivity to thymineless death, whereas mutations in RecF repair protein genes enhance the recovery process. This suggests that the RecF repair pathway may be critical to cell death, perhaps because it increases the occurrence of double-strand DNA breaks with unique DNA configurations at lesion sites. Indirect effects in bacteria include elimination of plasmids, loss of transforming ability, filamentation, changes in the pool sizes of various nucleotides and nucleosides and in their excretion, and phage induction. Yeast cells show effects similar to those of bacteria upon thymine starvation, although there are some unique features. The mode of action of certain anticancer drugs and antibiotics is based on the interruption of thymidylate metabolism and provides a major impetus for further studies on TLD. There are similarities between TLD of bacteria and death of eukaryotic cells. Also, bacteria have "survival" genes other than thy (thymidylate synthetase), and this raises the question of whether there is a relationship between the two. A model is presented for a molecular basis of TLD.
Internationalising the curriculum (IOC) in order to produce graduates with global citizenship skills is a common strategic goal in modern higher education. The extent to which this is achieved and the level of understanding amongst staff and students of what IOC involves and the benefits it imparts are varied. In this study, activities and attitudes across 15 subject disciplines delivered in a modern UK university were surveyed through an analysis of official course documentation, and semi-structured interviews with a range of academic staff. The outcomes are discussed in relation to the level of understanding and ownership that staff have of IOC. Through the modification of a process control model Barnett (European Journal of Education, 29(2), [165][166][167][168][169][170][171][172][173][174][175][176][177][178][179] 1994), suggestions are made as to how to move this top-down strategic imperative forward through empowerment of the academic staff involved in course delivery.
Amniotic membrane samples were taken following preterm delivery from 15 women with preterm prelabour rupture of the membranes (PPROM) and 14 with unrelated reasons, and from 25 delivering at term. Fibrillar collagens were extracted and analysed by intermpted gel electrophoresis. Collagens were decreased in PPROM relative to controls, but showed similar sub-type distribution, with one exception. In this case an increased ratio of Type I to Type I11 collagen was observed, with normal collagen content. In conclusion, PPROM is accompanied by generalised reduction in amnion collagen content, involving all fibrillar sub-types monitored. This may reflect general changes in protease activity or in collagen expression in affected membranes.Preterm prelabour rupture of the membranes in pregnancy (PPROM) is a major cause of preterm delivery (accounting for 6% of deliveries), and hence of neonatal mortality'. The aetiology of prelabour membrane rupture is unclear, although it is estimated that up to 50% of cases are due to infection. Cervical infection with chlamydia, and bacteria exhibiting collagenase activity (Group B streptococci, S. aureus, Bacteroides sp, Enterobacter) have been implicated', and a significant number of PPROM patients have been shown to contain pathogenic organisms within the amniotic fluid2. Elsewhere' it has been suggested that there may be highly localised increases in enzyme release at rupture sites by either bacteria or in the inflammatory response to infection. More recently, studies of amniotic fluid levels of matrix metalloproteinases and their inhibitors have indicated clear elevation of the former (particularly matrix metalloproteinase 9 [MMP-91) accompanied by reduction of tissue inhibitor of matrix metalloproteinase 1 (TIMP-1)3-5 in membranes and fluid of patients affected by PPROM, a situation which would only normally be expected at term. These findings are of importance in the interpretation of data collected on collagen levels and tensile strength of prematurely rupturing membranes.In an elegant study published in 1993, Malak et aLb demonstrated that the major components of the extracellular matrix of fetal membranes are large banded fibres of Types I and I11 collagen cross-linked by networks of filaments containing Types V and VI collagen. These filaments also link the banded fibres to the basement membrane (containing Type IV collagen), and it is suggested that such extensive collagen networks are responsible for the mechanical integrity of the amniochorionic membranes. Disruption of this network by altered metabolism of any of the collagen components may contribute to PPROM.Previously published data on the involvement of collagen in PPROM have been contradictory, and generally confined to investigations of the major fibrillar types. In independent studies different individual collagen types have been implicated: Kanayama et aL7 have reported a reduction in the levels of Type I11 collagen, whereas Al-Zaid et aL8 reported an absence of Type V collagen from affected membranes. Different...
Fanconi anaemia (FA) comprises a group of autosomal recessive disorders resulting from mutations in one of eight genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF and FANCG). Although caused by relatively simple mutations, the disease shows a complex phenotype, with a variety of features including developmental abnormalities and ultimately severe anaemia and/or leukemia leading to death in the mid teens. Since 1992 all but two of the genes have been identified, and molecular analysis of their products has revealed a complex mode of action. Many of the proteins form a nuclear multisubunit complex that appears to be involved in the repair of double-strand DNA breaks. Additionally, at least one of the proteins, FANCC, influences apoptotic pathways in response to oxidative damage. Further analysis of the FANC proteins will provide vital information on normal cell responses to damage and allow therapeutic strategies to be developed that will hopefully supplant bone marrow transplantation.
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