Inactivation of DNA proofreading obviates the need for SOS induction in frameshift mutagenesis

Translesion synthesis at replication-blocking lesions requires the induction of proteins that are controlled by the SOS system in Escherichia coli. Of the proteins identified so far, UmuD′, UmuC, and RecA* were shown to facilitate replication across UV-light-induced lesions, yielding both error-free and mutagenic translesion-synthesis products. Similar to UV lesions, N-2-acetylaminofluorene (AAF), a chemical carcinogen that forms covalent adducts at the C8 position of guanine residues, is a strong replication-blocking lesion. Frameshift mutations are induced efficiently by AAF adducts when located within short repetitive sequences in a two-step mechanism; AAF adducts incorporate a cytosine across from the lesion and then form a primer-template misaligned intermediate that, upon elongation, yields frameshift mutations. Recently, we have shown that although elongation from the nonslipped intermediate depends on functional umuDC+ gene products, elongation from the slipped intermediate is umuDC+-independent but requires another, as yet biochemically uncharacterized, SOS function. We now show that in DNA Polymerase III-proofreading mutant strains (dnaQ49 and mutD5 strains), elongation from the slipped intermediate is highly efficient in the absence of SOS induction—in contrast to elongation from the nonslipped intermediate, which still requires UmuDC functions.

An epidemiological needs assessment of carotid endarterectomy in an English health region. Is the need being met?

Objective: To compare the level of provision of carotid endarterectomy (an intervention of proved efficacy for prevention of stroke in patients with symptomatic high grade carotid artery stenosis) with estimates of need.

Global environmental impacts of agricultural expansion: The need for sustainable and efficient practices

The recent intensification of agriculture, and the prospects of future intensification, will have major detrimental impacts on the nonagricultural terrestrial and aquatic ecosystems of the world. The doubling of agricultural food production during the past 35 years was associated with a 6.87-fold increase in nitrogen fertilization, a 3.48-fold increase in phosphorus fertilization, a 1.68-fold increase in the amount of irrigated cropland, and a 1.1-fold increase in land in cultivation. Based on a simple linear extension of past trends, the anticipated next doubling of global food production would be associated with approximately 3-fold increases in nitrogen and phosphorus fertilization rates, a doubling of the irrigated land area, and an 18% increase in cropland. These projected changes would have dramatic impacts on the diversity, composition, and functioning of the remaining natural ecosystems of the world, and on their ability to provide society with a variety of essential ecosystem services. The largest impacts would be on freshwater and marine ecosystems, which would be greatly eutrophied by high rates of nitrogen and phosphorus release from agricultural fields. Aquatic nutrient eutrophication can lead to loss of biodiversity, outbreaks of nuisance species, shifts in the structure of food chains, and impairment of fisheries. Because of aerial redistribution of various forms of nitrogen, agricultural intensification also would eutrophy many natural terrestrial ecosystems and contribute to atmospheric accumulation of greenhouse gases. These detrimental environmental impacts of agriculture can be minimized only if there is much more efficient use and recycling of nitrogen and phosphorus in agroecosystems.