The public should pay for the Medical Council's activities: a reader's viewpoint.
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Financial Support↗
Biomedical subjects
Alastair Grant
Publications and source records attributed to Alastair Grant.
Hydrobia ulvae feeding rates: A novel way to assess sediment toxicity.
Standard acute toxicity tests are widely used to assess contaminated sediments. However, such tests last 10 d or more and only provide information regarding lethality. Here, we present data concerning the use of a 28-d growth test and a 24-h test using feeding rate, as measured by egestion rate, of the marine snail Hydrobia ulvae. The test was used to assess the toxicity of estuarine sediments from a gradient of heavy metal contamination, and its sensitivity and ease of use were compared with those of 10-d tests using the amphipod crustacean Corophium volutator. Mortality of C. volutator and H. ulvae in 10-d lethal toxicity tests showed similar patterns of sensitivity. Lethality tests with both species showed no effects when carried out using sediments from a number of sites at which ecological impacts are known to occur. By contrast, growth over 28 d in H. ulvae was reduced at all sites where other studies have detected adverse ecological effects. Feeding rate after 24 h also was decreased at moderately contaminated sites where sediments were not acutely toxic, and it was a very good predictor of 28-d growth (r2 = 0.74). Both tests were straightforward to carry out, so H. ulvae has considerable potential as a test organism for chronic toxicity.
Animal Feed↗
Identification and distribution of protein families in 120 completed genomes using Gene3D.
Using a new protocol, PFscape, we undertake a systematic identification of protein families and domain architectures in 120 complete genomes. PFscape clusters sequences into protein families using a Markov clustering algorithm (Enright et al., Nucleic Acids Res 2002;30:1575-1584) followed by complete linkage clustering according to sequence identity. Within each protein family, domains are recognized using a library of hidden Markov models comprising CATH structural and Pfam functional domains. Domain architectures are then determined using DomainFinder (Pearl et al., Protein Sci 2002;11:233-244) and the protein family and domain architecture data are amalgamated in the Gene3D database (Buchan et al., Genome Res 2002;12:503-514). Using Gene3D, we have investigated protein sequence space, the extent of structural annotation, and the distribution of different domain architectures in completed genomes from all kingdoms of life. As with earlier studies by other researchers, the distribution of domain families shows power-law behavior such that the largest 2,000 domain families can be mapped to approximately 70% of nonsingleton genome sequences; the remaining sequences are assigned to much smaller families. While approximately 50% of domain annotations within a genome are assigned to 219 universal domain families, a much smaller proportion (< 10%) of protein sequences are assigned to universal protein families. This supports the mosaic theory of evolution whereby domain duplication followed by domain shuffling gives rise to novel domain architectures that can expand the protein functional repertoire of an organism. Functional data (e.g. COG/KEGG/GO) integrated within Gene3D result in a comprehensive resource that is currently being used in structure genomics initiatives and can be accessed via http://www.biochem.ucl.ac.uk/bsm/cath/Gene3D/.
Amino Acid Sequence↗
Survey of current protein family databases and their application in comparative, structural and functional genomics.
The last two decades have witnessed significant expansions in the databases storing information on the sequences and structures of proteins. This has led to the creation of many excellent protein family resources, which classify proteins according to their evolutionary relationship. These have allowed extensive insights into evolution and particularly how protein function mutates and evolves over time. Such analyses have greatly assisted the inheritance of functional annotations between experimentally characterised and uncharacterised genes. Moreover, the development of bioinformatics tools acts as a companion to the new technologies emerging in biology, such as transcriptomics and proteomics. The latter enable researchers to analyse gene expression profiles and interactions on a genome-wide scale, generating vast datasets of proteins, many of which include experimentally uncharacterised proteins. Protein family/function databases can be used to help interpret this data and allow us to benefit more fully from these technologies. This review aims to summarise the most popular sequence- and structure-based protein family databases. We also cover their application to comparative genomics and the functional annotation of the genomes.
Biological Evolution↗
Microeconomic principles explain an optimal genome size in bacteria.
Bacteria can clearly enhance their survival by expanding their genetic repertoire. However, the tight packing of the bacterial genome and the fact that the most evolved species do not necessarily have the biggest genomes suggest there are other evolutionary factors limiting their genome expansion. To clarify these restrictions on size, we studied those protein families contributing most significantly to bacterial-genome complexity. We found that all bacteria apply the same basic and ancestral 'molecular technology' to optimize their reproductive efficiency. The same microeconomics principles that define the optimum size in a factory can also explain the existence of a statistical optimum in bacterial genome size. This optimum is reached when the bacterial genome obtains the maximum metabolic complexity (revenue) for minimal regulatory genes (logistic cost).
Bacteria↗
RNA/DNA ratios as a sublethal endpoint for large-scale toxicity tests with the nematode Caenorhabditis elegans.
Caenorhabditis elegans increasingly is attractive as a toxicity test organism, particularly as a model system to study mechanisms of toxicity at a molecular level and the way that these lead to whole organism and population level effects. Inhibitions of growth, reproduction, movement, and feeding rate all have been proposed as sublethal toxicity endpoints. These endpoints are more sensitive than 24-h acute toxicity endpoints, but assays are much more time consuming, making them difficult to use in mass screening. The RNA/DNA ratio, after 48-h exposure to metals, has median effective concentration (EC50) values of 0.05, 0.6, 6.1, and 35 mg/L for Cu, Pb, Cd, and Zn, respectively. This makes it a slightly more sensitive toxicity endpoint than reduction of individual growth after 72-h exposure to the same concentrations. This facilitates the near-simultaneous assessment of sublethal toxicity in many nematode samples. The constant cell number of C. elegans means that different stages in the life history have very different RNA/DNA ratios even in the absence of toxins. So, RNA/DNA ratios can be used only on prereproductive, age-synchronized cultures. Assessing the sublethal toxicity of metals to C. elegans shows that it is sensitive particularly to Cu.
Animals↗
Ecotypic differentiation and phenotypic plasticity in reproductive traits of Armadillidium vulgare (Isopoda: Oniscidea).
Armadillidium vulgare differed in growth and survivorship on two field sites. Growth rates were higher at a site with consistently higher quality food than at the other site where less high-quality food was produced and which was less predictably accessible. Survivorship was higher at the second site where temperature fluctuations were consistently smaller. Individuals from the two populations were kept for 6 months under the same food and temperature conditions and patterns of resource allocation to reproductive traits analysed. Members of the population from the site with good growth conditions had significantly higher reproductive allocation, by 13.5%, and larger broods, by 9.1%, than those from the site with poor growth conditions. Contrary to theoretical predictions, they also had significantly larger offspring, by 7.5% dry mass. Larger offspring survived better than small ones. This differential survivorship, by 20% for a 3.4% difference in live mass, was much more pronounced under conditions of moisture stress and under fluctuating temperature regimes. Larger offspring would therefore be at a selective advantage on the site with more severe temperature fluctuations. Phenotypic plasticity in reproductive traits in response to experimental changes in food quality, temperature and crowding were monitored. Reproductive allocation was increased by 20.8% under conditions of higher food quality, by 14.7% at higher temperatures, and by 12.5% under less crowded conditions. Brood size, but not offspring dry mass, increased when food quality increased. When crowding increased by 25.0%, the size of broods remained the same but the dry mass of individual offspring decreased by 11.2%. Members of the population from the site with more variable access to high-quality food showed more plasticity in reproductive traits in response to changes in food supply than members of the population from the site with the more predictable food supply. Members of the population from the site with more stable temperatures showed less plasticity to temperature changes than members of the population from the site with greater temperature fluctuations. It is concluded that the observed microevolutionary processes and phenotypic plasticity have adaptative value as responses to spatial and temporal heterogeneity in environmental conditions.
Adaptation, Physiological↗
Visibility of the impact of environmental noise: a response to Kaitala and Ranta.
Based on simulation modelling, Kaitala and Ranta (2001 Proc. R. Soc. Lond. B 268, 1769-1774) have argued that detecting the statistical relationships between environmental variability and population fluctuations will be difficult. However, their study was limited in that only one pattern of density dependence and one detection method were used. Here, we show that their conclusion is in part a consequence of their choice of population model and in part a consequence of using relatively weak or inappropriate statistical methods. Other patterns of density dependence respond differently to environmental fluctuations, and the impact of the disturbance on these is clearly visible using their methods. For some patterns of population dynamics, environmental impacts are more readily detectable by correlating running-average environmental conditions with the population time-series or by correlating the first differences of the population time-series with environmental noise. When more appropriate statistical methods are used, environmental forcing is detectable in the majority of cases used by Kaitala and Ranta. The interplay between environmental stochasticity and density-dependent population growth means that there is no single best method to detect the influence of environmental forcing, even when population dynamics are approximately linear. But environmental forcing will often be detectable, contrary to Kaitala and Ranta's assertions.
Age Factors↗
Progress towards mapping the universe of protein folds.
Although the precise aims differ between the various international structural genomics initiatives currently aiming to illuminate the universe of protein folds, many selectively target protein families for which the fold is unknown. How well can the current set of known protein families and folds be used to estimate the total number of folds in nature, and will structural genomics initiatives yield representatives for all the major protein families within a reasonable time scale?
Chromosome Mapping↗
Long-term region-wide declines in Caribbean corals.
We report a massive region-wide decline of corals across the entire Caribbean basin, with the average hard coral cover on reefs being reduced by 80%, from about 50% to 10% cover, in three decades. Our meta-analysis shows that patterns of change in coral cover are variable across time periods but largely consistent across subregions, suggesting that local causes have operated with some degree of synchrony on a region-wide scale. Although the rate of coral loss has slowed in the past decade compared to the 1980s, significant declines are persisting. The ability of Caribbean coral reefs to cope with future local and global environmental change may be irretrievably compromised.
Animals↗
Can turbidity caused by Corophium volutator (Pallas) activity be used to assess sediment toxicity rapidly?
The standard toxicity test organism, Corophium volutator, exhibits a behavioural response to contaminated sediments that causes increased turbidity of overlying water. We quantify the effects of this response to an estuarine sediment spiked with copper and hydrocarbon contaminated sediments from an oil installation in the North Sea. Turbidity measured 24 h after the start of a toxicity test shows a strong relationship with contaminant concentrations and with mortality after 10 days. Turbidity measurements can therefore give a rapid indication of sediment toxicity, permitting a reduction in storage time of sediments to be used in dilution series and toxicity identification evaluation (TIE) tests, reducing the likelihood of contaminants degrading prior to testing.
Amphipoda↗
A structural perspective on genome evolution.
Protein translations of over 100 complete genomes are now available. About half of these sequences can be provided with structural annotation, thereby enabling some profound insights into protein and pathway evolution. Whereas the major domain structure families are common to all kingdoms of life, these are combined in different ways in multidomain proteins to give various domain architectures that are specific to kingdoms or individual genomes, and contribute to the diverse phenotypes observed. These data argue for more targets in structural genomics initiatives and particularly for the selection of different domain architectures to gain better insights into protein functions.
Evolution, Molecular↗
Terminal restriction fragment length polymorphism data analysis.
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Bacteria↗
Toxicity of sediments from around a North Sea oil platform: are metals or hydrocarbons responsible for ecological impacts?
Discharges of contaminated drill cuttings have caused appreciable ecological change of the benthos adjacent to many oil and gas platforms in the North Sea. Many platforms have large piles of cuttings lying beneath them and these probably present the greatest potential hazard to the environment during platform decommissioning and removal. There is, however, a lack of consensus on which aspects of drill cuttings are responsible for the adverse ecological effects. This hinders risk assessment of management options. Here we report data on the toxicity of sediments from around the North West Hutton platform to the amphipod Corophium volutator, the polychaete Arenicola marina and the Microtox" acute test system. Sediment was acutely toxic to Corophium out as far as 600 m from the platform. Sediment from 100 m from the platform remained acutely toxic to Corophium when 3% contaminated sediment was mixed with clean sediment. A 10% dilution of this sediment also inhibited Arenicola feeding almost completely. Sediment elutriates did not inhibit Microtox light output, but organics extracted by dichloromethane were very toxic. Fifteen minute EC50 values were as low as 0.25 mg ml(-1) and were strongly correlated with hydrocarbon concentrations. Metal concentrations in whole sediments were correlated with their toxicity to Corophium but the relationship was much weaker when data on dilutions were included. Except at sites immediately adjacent to the platform, metal concentrations were well below ERL values from the literature, so were too low to explain sediment toxicity. Toxicity of sediments to Corophium was closely correlated with their hydrocarbon content, even when tests on dilutions were included in the analysis. We conclude that hydrocarbons are the most significant cause of toxicity in these sediments contaminated with oil based drill cuttings and that polar organics, sulphide. ammonia and other water soluble substances are of much lower significance. Applying OSPAR guidelines to our data on the toxicity of cuttings pile material to Corophium data would give a maximum allowable concentration of 0.03% in clean sediments. The Microtox data indicate that sediments from deeper in the pile would require an even greater dilution than this.
Animals↗
The stress-associated acetylcholinesterase variant AChE-R is expressed in human CD34(+) hematopoietic progenitors and its C-terminal peptide ARP promotes their proliferation.
OBJECTIVE: Hematopoietic stress responses involve increases in leukocyte and platelet counts, implying the existence of stress responsive factors that modulate hematopoiesis. Acetylcholinesterase (AChE) is expressed in mammalian neurons and hematopoietic cells. In brain, it responds to stress by mRNA overexpression and alternative splicing, yielding the rare stress-associated "readthrough" AChE-R variant protein. This led us to explore the hematopoietic involvement of AChE-R and its cleavable C-terminal peptide ARP. MATERIALS AND METHODS: AChE mRNA variants were labeled in CD34(+) hematopoietic progenitor cells by in situ hybridization. ARP expression was detected by multicolor flow cytometry. Bromo-deoxyuracil incorporation and viable cell counts served to evaluate the proliferative effects of ARP and suppressive effects of the AChE antisense oligonucleotide AS1 on CD34(+) cells. RESULTS: The distal enhancer, proximal promoter, and first intron of the human AChE gene include consensus binding sites for hematopoietically active and stress-induced transcription factors. CD34(+) cells from human cord blood were found to express all three variant AChE mRNAs, having different intracellular distributions. ARP was found in 5 to 15% of adult peripheral blood, bone marrow, and fetal CD34(+) cells (both committed CD38(+) and uncommitted CD38(-)) and in acute myeloid leukemia blasts. Externally supplied ARP by itself facilitated the proliferation of CD34(+) cells in an antisense suppressible manner. When combined with early-acting cytokines, ARP enhanced survival and expansion of CD34(+) cells up to 28 days in culture. CONCLUSIONS: Our findings support ARP, the C-terminal peptide of AChE-R, as a new hematopoietic growth factor that may promote the myelopoietic expansion and thrombopoiesis characteristic of stress and may be used to enhance the efficiency of ex vivo expansion for bone marrow transplantation.
Acetylcholinesterase↗