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David Lowe

Publications and source records attributed to David Lowe.

12 recordsLinked to original sources
PubMed2006

The FoxM1 transcription factor is required to maintain pancreatic beta-cell mass.

The FoxM1 transcription factor is highly expressed in proliferating cells and activates several cell cycle genes, although its requirement appears to be limited to certain tissue types. Embryonic hepatoblast-specific inactivation of Foxm1 results in a dramatic reduction in liver outgrowth and subsequent late gestation lethality, whereas inactivation of Foxm1 in adult liver impairs regeneration after partial hepatectomy. These results prompted us to examine whether FoxM1 functions similarly in embryonic outgrowth of the pancreas and beta-cell proliferation in the adult. We found that FoxM1 is highly expressed in embryonic and neonatal endocrine cells, when many of these cells are proliferating. Using a Cre-lox strategy, we generated mice in which Foxm1 was inactivated throughout the developing pancreatic endoderm by embryonic d 15.5 (Foxm1(Deltapanc)). Mice lacking Foxm1 in their entire pancreas were born with normal pancreatic and beta-cell mass; however, they displayed a gradual decline in beta-cell mass with age. Failure of postnatal beta-cell mass expansion resulted in impaired islet function by 6 wk of age and overt diabetes by 9 wk. The decline in beta-cell mass in Foxm1(Deltapanc) animals is due to a dramatic decrease in postnatal beta-cell replication and a corresponding increase in nuclear localization of the cyclin-dependent kinase inhibitor, p27(Kip1), a known target of FoxM1 inhibition. We conclude that Foxm1 is essential to maintain normal beta-cell mass and regulate postnatal beta-cell turnover. These results suggest that mechanisms regulating embryonic beta-cell proliferation differ from those used postnatally to maintain the differentiated cell population.

Animals↗
PubMed2005

The ECOMAN project: A novel approach to defining sustainable ecosystem function.

The ECOMAN was initiated in 2001 by the University of Plymouth, UK, Plymouth Marine Laboratory and the Department of the Environment, Fisheries and Rural Affairs (DEFRA) to address the need for more pragmatic assessment techniques linking environmental degradation with its causes. The primary aim of the project was to develop an evidence-based approach in which suites of easy-to-use, cost-effective and environmentally valid biological responses (biomarkers) could be used together to assess the health of coastal systems through the general condition of individuals. A range of sub-lethal endpoints, chosen to reflect successive levels of biological organisation (molecular, cellular, physiological), was evaluated in common coastal organisms showing different feeding types (filter feeding, grazing, predation) and habitat requirements (estuary, rocky shore). Initially, the suite of biomarkers was used in laboratory studies to determine the relative sensitivities of key species within different functional groups to common contaminants. These results were then validated in field studies performed in a range of ecosystems exhibiting different degrees/signatures of contamination. Here, an example is provided of a field study in the Humber Estuary, UK, which illustrates how multivariate statistical analysis can be used to identify patterns of response to discriminate between contaminated and clean sites. The use of a holistic, integrated approach of this kind is advocated as a practical means of assessing the impact of chemical contamination on organismal health and of ranking the status of marine ecosystems.

Animals↗
PubMed2005

A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope.

HIV-1 entry into cells is mediated by the envelope glycoprotein receptor-binding (gp120) and membrane fusion-promoting (gp41) subunits. The gp41 heptad repeat 1 (HR1) domain is the molecular target of the fusion-inhibitor drug enfuvirtide (T20). The HR1 sequence is highly conserved and therefore considered an attractive target for vaccine development, but it is unknown whether antibodies can access HR1. Herein, we use gp41-based peptides to select a human antibody, 5H/I1-BMV-D5 (D5), that binds to HR1 and inhibits the assembly of fusion intermediates in vitro. D5 inhibits the replication of diverse HIV-1 clinical isolates and therefore represents a previously unknown example of a crossneutralizing IgG selected by binding to designed antigens. NMR studies and functional analyses map the D5-binding site to a previously identified hydrophobic pocket situated in the HR1 groove. This hydrophobic pocket was proposed as a drug target and subsequently identified as a common binding site for peptide and peptidomimetic fusion inhibitors. The finding that the D5 fusion-inhibitory antibody shares the same binding site suggests that the hydrophobic pocket is a "hot spot" for fusion inhibition and an ideal target on which to focus a vaccine-elicited antibody response. Our data provide a structural framework for the design of new immunogens and therapeutic antibodies with crossneutralizing potential.

Antibodies, Monoclonal↗
PubMed2005

MILVA: an interactive tool for the exploration of multidimensional microarray data.

MOTIVATION: Clustering techniques such as k-means and hierarchical clustering are commonly used to analyze DNA microarray derived gene expression data. However, the interactions between processes underlying the cell activity suggest that the complexity of the microarray data structure may not be fully represented with discrete clustering methods. RESULTS: A newly developed software tool called MILVA (microarray latent visualization and analysis) is presented here to investigate microarray data without separating gene expression profiles into discrete classes. The underpinning of the MILVA software is the two-dimensional topographic representation of multidimensional microarray data. On this basis, the interactive MILVA functions allow a continuous exploration of microarray data driven by the direct supervision of the biologist in detecting activity patterns of co-regulated genes. AVAILABILITY: The MILVA software is freely available. The software and the related documentation can be downloaded from http://www.ncrg.aston.ac.uk/Projects/milva. User 'surrey' as username and '3245' as password to login. The software is currently available for Windows platform only.

Cluster Analysis↗
PubMed2004

A multibiomarker approach to environmental assessment.

Incorporation of ecologically relevant biomarkers into routine environmental management programs has been advocated as a pragmatic means of linking environmental degradation with its causes. Here, suites of biomarkers, devised to measure molecular damage, developmental abnormality and physiological impairment, were combined with chemical analysis to determine exposure to and the effects of pollution at sites within Southampton Water (UK). Test species included a filter feeder, a grazer, and an omnivore to determine the sensitivity of organisms occupying different trophic levels. Linear regression confirmed a significant association between incidence of intersex in Littorina littorea and tributyltin (TBT) concentrations (R2 = 0.954) and between PAH metabolites in Carcinus maenas urine and PAHs in sediments (R2 = 0.754). Principal component analysis revealed a gradient of detrimental impact to biota from the head to the mouth of the estuary, coincident with high sediment concentrations of heavy metals, PAHs, and biocides. Multidimensional scaling identified C. maenas as the organism most sensitive to contamination. Carboxylesterase activity, metallothionein and total haemolymph protein were the most discriminating biomarkers among sites. This holistic approach to environmental assessment is encouraged as it helps to identify the integrated impact of chemical contamination on organisms and to provide a realistic measure of environmental quality.

Animals↗
PubMed2004

The diagnostic value of barium swallow in globus syndrome.

Serious lesions presenting as globus syndrome appear to be extremely rare, but many clinicians routinely request barium swallow to exclude these. No data yet exist on the diagnostic yield of contrast radiography. We reviewed 2854 barium swallows from one department over 7 years. The false-positive rate (37%) depended on presenting symptoms and differed between radiology departments, suggesting substantial subjectivity. No serious radiological abnormalities occurred in the estimated 2011 patients with globus syndrome. The 95% confidence interval for the likelihood of finding a significant abnormality on routine barium swallow in a patient with globus symptoms is 0-0.00145. The 2854 barium swallows cost an estimated pounds sterling 685,000 and 0.22-0.48 deaths. As the risk of missing a serious lesion in a patient with globus is very unlikely to exceed one in 700, we support the opinion that barium swallow should be reserved for those with risk factors or atypical features.

Adult↗
PubMed2004

Combinatorial protein biochemistry for therapeutics and proteomics.

This paper reviews progress towards the customised generation of proteins for applications as therapeutics, diagnostics and in proteomics. It particularly focuses on combinatorial approaches where proteins with pre-defined biochemical and biophysical characteristics are selected from large variant libraries.

Animals↗
PubMed2003

Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses.

The program death 1 (PD-1) receptor and its ligands, PD-1 ligand (PD-L)1 and PD-L2, define a novel regulatory pathway with potential inhibitory effects on T, B, and monocyte responses. In the present study, we show that human CD4(+) T cells express PD-1, PD-L1, and PD-L2 upon activation, and Abs to the receptor can be agonists or antagonists of the pathway. Under optimal conditions of stimulation, ICOS but not CD28 costimulation can be prevented by PD-1 engagement. IL-2 levels induced by costimulation are critical in determining the outcome of the PD-1 engagement. Thus, low to marginal IL-2 levels produced upon ICOS costimulation account for the greater sensitivity of this pathway to PD-1-mediated inhibition. Interestingly, exogenous IL-2, IL-7, and IL-15 but not IL-4 and IL-21 can rescue PD-1 inhibition, suggesting that among these cytokines only those that activate STAT5 can rescue PD-1 inhibition. As STAT5 has been implicated in the maintenance of IL-2Ralpha expression, these results suggest that IL-7 and IL-15 restore proliferation under conditions of PD-1 engagement by enhancing high-affinity IL-2R expression and hence, IL-2 responsiveness.

Antibodies↗
PubMed2003

Extracting multisource brain activity from a single electromagnetic channel.

This paper develops a methodology for the extraction of multisource brain activity using only single channel recordings of electromagnetic (EM) brain signals. Measured electroencephalogram (EEG) and magnetoencephalogram (MEG) signals are used to demonstrate the utility of the method on extracting multisource activity from a single channel recording. At the heart of the method is dynamical embedding (DE) where first an appropriate embedding matrix is constructed out of a series of delay vectors from the measured signal. The embedding matrix contains the information we require, but in a mixed form which therefore needs to be deconstructed. In particular, we demonstrate how one form of independent component analysis (ICA) performed on the embedding matrix can deconstruct the single channel recording into its underlying informative components. The components are treated as a convenient expansion basis and subjective methods are then used to identify components of interest relevant to the application. The framework has been applied to single channels of both EEG and MEG recordings and is shown to isolate multiple sources of activity which includes: (i) artifactual components such as ocular, electrocardiographic and electrode artefact, (ii) seizure components in epileptic EEG recordings, and (iii) theta band, tumour related, activity in MEG recordings. The results are intuitive and meaningful in a neurophysiological setting.

Brain↗
PubMed2002

Dangerous Doughty--a quantitative study of disproportion between the size of endotracheal tubes and splits in tonsillectomy gag blades.

The Doughty split tongue blade is used routinely with the Boyle Davis mouth gag during tonsillectomy. If the width of the slot in the blade is excessive, then the endotracheal tube may herniate through the slot in the blade and become fixed and inseparable from the blade. We report two cases of paediatric tonsillectomy where this potentially serious complication occurred. The slot widths of disposable and reusable Doughty blades were measured and specifications were obtained from several manufacturers. All disposable paediatric Doughty blades and some of the reusable blades were found to have excessively and potentially dangerously wide slots. Compression testing of endotracheal tubes by the manufacturer demonstrated marked increases in deformability on warming to body temperature. Ensuring that the slot width of the Doughty blade is not excessive for the endotracheal tube used is essential and we give recommendations.

Child↗
PubMedDate not supplied

Ecosystem management bioindicators: the ECOMAN project--a multi-biomarker approach to ecosystem management.

The ECOMAN project was initiated from an awareness of the complexity of the functioning of coastal marine systems and the clear need for more pragmatic environmental assessment techniques linking environmental degradation with its causes. The aim of the project is to develop a suite of easy to use, cost effective and environmentally valid biological responses (biomarkers) to assess the general health of coastal systems, including estuaries. To achieve this aim, various sublethal endpoints are being measured and evaluated from a range of common coastal organisms showing different feeding types (filter feeding, grazing and predation) and habitat requirements (estuary and rocky shore) and at different levels of biological response (cellular, physiological and behavioural). This holistic integrated approach is essential to identify the full impact of chemical contamination on organisms, and enables the sensitivity of organisms to be ranked and key sentinel species for specific habitats to be identified.

Animals↗