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Biomedical subjects

W R Taylor

Publications and source records attributed to W R Taylor.

At least 37 records · Page 2Linked to original sources
PubMed2001

Controlling malaria: challenges and solutions.

Antimalarial drug resistance is a major public health challenge and the principal reason for the erosion of efficacious treatments. Cost and the limited number of antimalarial drugs in current use impose considerable constraints on malaria control, especially in sub-Saharan Africa. The paper describes a multilateral, multidisciplinary research project on artemisinin-based combination therapy, which offers a new and potentially highly effective way to prevent or retard the development of drug resistance.

Advisory Committees↗
PubMed2001

Amino acid substitution matrices from an artificial neural network model.

An amino acid substitution matrix specifies probabilities of substitutions for each pair of the 20 amino acids. Log-odds scores transformed from the values in substitution matrices are widely used to construct protein sequence alignments. Any given substitution matrix is suited to matching sequences diverged by a specific evolutionary distance. However, for a given set of sequences, it is not always clear what matrix should be used. We used an artificial neural network model to predict probabilities of amino acid substitutions with alignment samples of different evolutionary distances. From this internal description, substitution matrices suitable for detecting relationships at any chosen evolutionary distance can be instantly generated. By using the additional information of evolutionary distances, the average cross entropy error of our neural network model is lower than that of a series of BLOSUM and PET matrices over all testing sets. Our model is more accurate on the prediction of amino acid substitution probabilities.

Amino Acid Substitution↗
PubMed2001

Finite element biphasic indentation of cartilage: a comparison of experimental indenter and physiological contact geometries.

In experimental cartilage indentation studies, the indenter is typically a plane-ended or hemispherically ended cylinder and can be either porous or non-porous. Joints such as the hip and knee, however, have much higher radii of curvature than those used in experimental indentation testing. In order to interpret the results from such testing in a physiological context it is therefore useful to explore the effect of contact geometry on the pore pressure and strain distribution generated in the cartilage layer. Articular cartilage can be described as a saturated porous medium, and can be considered a biphasic material consisting of a porous, permeable solid matrix, and an interstitial fluid phase. This behaviour has been predicted in this study using the ABAQUS soils consolidation procedure. Four contact geometries were modelled: two typical experimental configurations (5 mm radii cylindrical indenter and hemispherical indenters) and two effective radii representative of the hip and knee (20 and 100 mm). A 10 per cent deformation, or a load of 0.9 kN, was applied over a ramp time of 2 s, which was then maintained for a further 100 s. The porous indenter generated less pore pressure compared with the equivalent non-porous indenter and produced higher values of compressive strain in the solid matrix. The predictions made using the cylindrical indenters, porous and non-porous, were dominated by the concentrations at the edge of the indenter and overestimated the peak compressive strain in the tissue by a factor of 21 and a factor of 14 respectively when compared with the hip model. The hemispherical indenter predicted peak strains in similar positions to those predicted using physiological radii, however, the magnitude was overestimated by a factor of 2.3 when compared with the knee and by 5.7 when compared with the hip. The pore pressure throughout the cartilage layer reduced significantly as the radius of the indenter was increased.

Cartilage, Articular↗
PubMed2000

Searching the protein structure databank with weak sequence patterns and structural constraints.

A method is described in which proteins that match PROSITE patterns are filtered by the root-mean-square deviation of the local 3D structures of the probe and target over the pattern components. This was found to increase the discrimination between true and false members of the protein family but was dependent on how unique the structural features in the pattern were compared to equivalent fragments extracted from the structure databank (for example; if the pattern fell in an alpha-helix, then discrimination was poor.) We then generalised the sequence patterns (by widening the range of amino acid residues allowed at each position) and monitored how well the structural information helped retain specificity. While the discrimination of the pure sequence pattern had generally disappeared at information content values less than ten bits, the discrimination of the combined sequence structure probe remained high at this point before following a similar decay. The displacement between these curves indicates that the structural component is, on average, equivalent to about ten bits. The sequence patterns were also filtered using the structure comparison program SAP, giving a global, rather than local "view" of the proteins. This allowed the information content of the sequence patterns to become even less specific but raised problems of whether some proteins encountered with the same fold but no PROSITE pattern should constitute family members.

Amino Acid Motifs↗
PubMed2000

p130/E2F4 binds to and represses the cdc2 promoter in response to p53.

p53 represses the transcription of cdc2 and cyclin B1, causing loss of Cdc2 activity and G(2) arrest. Here we show that the region -22 to -2 of the cdc2 promoter called the R box is required for repression by p53 but not for basal promoter activity. The R box confers p53-dependent repression on heterologous promoters and binds to p130/E2F4 in response to overexpression of p53. R box-dependent repression requires p21/waf1, and overexpression of p21/waf1 also represses the cdc2 promoter. These observations suggest that p53 represses the cdc2 promoter by inducing p21/waf1, which inhibits cyclin-dependent kinase activity, enhancing the binding of p130 and E2F4, which together bind to and repress the cdc2 promoter.

Base Sequence↗
PubMed2000

Dendritic computation of direction selectivity by retinal ganglion cells.

Direction-selective ganglion cells (DSGCs) in the retina respond strongly when stimulated by image motion in a preferred direction but are only weakly excited by image motion in the opposite null direction. Such coding represents an early manifestation of complex information processing in the visual system, but the cellular locus and the synaptic mechanisms have yet to be elucidated. We recorded the synaptic activity of DSGCs using strategies to observe the asymmetric inhibitory inputs that underlie the generation of direction selectivity. The critical nonlinear interactions between the excitatory and inhibitory inputs took place postsynaptically within the dendrites of the DSGCs.

Action Potentials↗
PubMed2000

A deeply knotted protein structure and how it might fold.

The search for knots in protein has uncovered little that would cause Alexander the Great to reach for his sword. Excluding knots formed by post-translational crosslinking, the few proteins considered to be knotted form simple trefoil knots with one end of the chain extending through a loop by only a few residues, ten in the 'best' example. A knot in an open chain (as distinct from a closed circle) is not rigorously defined and many weak protein knots disappear if the structure is viewed from a different angle. Here I describe a computer algorithm to detect knots in open chains that is not sensitive to viewpoint and that can define the region of the chain giving rise to the knot. It characterizes knots in proteins by the number of residues that must be removed from each end to abolish the knot. I applied this algorithm to the protein structure database and discovered a deep, figure-of-eight knot in the plant protein acetohydroxy acid isomeroreductase. I propose a protein folding pathway that may explain how such a knot is formed.

Alcohol Oxidoreductases↗
PubMed2000

Response characteristics and receptive field widths of on-bipolar cells in the mouse retina.

Voltage-clamp and current-clamp recordings were made from bipolar cells in dark-adapted mouse retinal slices. Light-evoked responses fell into three groups corresponding to the rod bipolar cells, on-cone bipolar cells and off-cone bipolar cells. The morphology of the recorded cells confirmed this classification. Intensity-response relations were well fitted by a Michaelis saturation function with Hill coefficients of 1.15 +/- 0.11 (n = 6) for rod bipolar cells and 2.33 +/- 0.06 (n = 4) for cone inputs onto on-cone bipolar cells. In the absence of antagonists for GABA or glycine receptors, light-evoked synaptic currents for all cells displayed linear current-voltage relations that reversed near 0 mV, indicating that very little inhibition was activated under dark-adapted recording conditions. Saturating light stimuli evoked conductances of 0.81 +/- 0.56 nS (n = 4) in rod bipolar cells and 1.1 +/- 0.8 nS (n = 4) in on-cone bipolar cells. Receptive field widths were estimated by flashing a vertical light bar at various locations along the slice. Rod and on-cone bipolar cells had receptive field widths of 67 +/- 16 micrometer (n = 6) and 43 +/- 7 microm (n = 5), respectively. The maximum spatial resolution of an array of such cone bipolar cells was estimated to be 0.3 cycles deg-1, compared with a maximum resolution of 0.5 cycles deg-1 obtained from behavioural studies in mice. Our results suggest that this limit to spatial resolution could be imposed early in the visual system by the size of the bipolar cell receptive fields.

Animals↗
PubMed2000

Multiple protein sequence alignment using double-dynamic programming.

A method of multiple sequence alignment is described based on the double dynamic programming (DDP) algorithm previously used for treating structural constraints encountered in structure comparison and threading. Following these applications, the inconsistencies that emerge when trying to combine pair-wise alignments into a multiple alignment are reconciled by summing all the, possibly inconsistent, paths (low-level alignments) into a matrix which is then used to provide a final (high-level) alignment. This process is applied to all sequence pairs and the pair-wise results combined in a simple multiple sequence alignment program. From this alignment, further constraints are selected to bias the low-level alignments in the DDP algorithm and the process iterated. The results, however, showed that this overall iteration was not needed and one-pass gave results at least as good as the 'standard' progressive method of multiple sequence alignment. Further applications of the method are discussed.

Algorithms↗
PubMed2000

Felodipine improves left ventricular emptying in patients with chronic heart failure: V-HeFT III echocardiographic substudy of multicenter reproducibility and detecting functional change.

BACKGROUND: The echocardiographic substudy of the Vasodilator-Heart Failure Trial III (V-HeFT III) aimed to determine if felodipine treatment in patients with heart failure who were taking an angiotensin-converting enzyme inhibitor had a favorable effect on left ventricular (LV) structure and function. Earlier V-HeFT trials showed that hydralazine-isosorbide dinitrate improved ejection fraction (EF) and survival, whereas enalapril achieved greater survival with smaller increases in EF. Would the combination of a potent vasodilator and enalapril produce greater improvements in function and survival? METHODS AND RESULTS: Doppler-echocardiographic data were collected from 260 males with heart failure who were randomized to felodipine or a placebo. Mean intrasubject differences between baseline, at 3 months, and at 12 months were compared. Intersite and intrareader reproducibilities were measured from duplicate recordings and readings. At 3 months, no changes in ultrasound variables from baseline occurred in either group. At 12 months, felodipine patients achieved greater increases in EF, shortening of LV end-systolic length, and increases in stroke volume index. Reproducibility coefficients of variation were 7.4% (EF), 6.0% (end-diastolic length), and 13.0% (stroke volume index). CONCLUSIONS: The echocardiographic substudy showed that felodipine, added to heart failure therapy, increased EF, shortened end-systolic length, and increased stroke volume index. The changes were small and confirmed that reproducibility from multiple laboratories can be coordinated into a useful research tool.

Calcium Channel Blockers↗
PubMed2000

Plasma norepinephrine and atrial natriuretic peptide in heart failure: influence of felodipine in the third Vasodilator Heart Failure Trial. V-HeFT III investigators.

BACKGROUND: Reflex activation of the sympathetic nervous system by short-acting dihydropyridine calcium channel antagonists has been reported to harm hypertensive patients. Different neurohormonal profiles and their response to treatment may influence the effectiveness of dihydropyridine vasodilator treatment of heart failure. METHODS: Four hundred fifty men with left ventricular (LV) systolic dysfunction were administered standard heart failure treatment and felodipine extended release (ER) or placebo in the Vasodilator Heart Failure Trial III (V-HeFT III). Plasma norepinephrine (PNE) levels, atrial natriuretic peptide (ANP) levels, exercise capacity, LV ejection fraction (EF), cardiac dimensions and function, and arrhythmia frequency were measured. Hospital-free survival for baseline neurohormonal classes was assessed. RESULTS: Distributions of ANP and PNE levels at baseline in patients with heart failure of ischemic and nonischemic causes were virtually identical. ANP levels at baseline were inversely related to LVEF (r = -0.39; P = .0001), exercise duration (r = -0.19; P = .0001), and peak oxygen consumption (r = -0.27; P = .008) and directly related to LV (r = 0.23; P = .0006) and right ventricular dilatation (r = 0.23; P = .0008). The increase in ANP levels between baseline and 3 months (P = .02) and 1 year (P = .03) was significantly less in the felodipine-ER group than in the placebo group, but PNE levels did not differ between treatment groups. Hospital-free survival was directly related to baseline ANP (P = .0002) and PNE levels (P = .004). All-cause mortality was related to baseline PNE levels (P = .02) but not baseline ANP levels. CONCLUSION: Levels of ANP and PNE hormones are related to LV dysfunction, exercise performance, and hospital-free survival in heart failure and PNE levels are related to all-cause mortality. Treatment with felodipine ER did not adversely affect survival in any neurohormone subclass.

Administration, Oral↗
PubMed2000

Searching for the ideal forms of proteins.

A modification of the Structure Alignment Program (SAP), combined with a novel automatic method for the definition of structural elements, correctly identified the core folds of a variety of small beta/alpha proteins when compared with a series of ideal architectures. This approach opens the possibility of not just determining whether one structure is like another, but given a range of ideal forms, determining what the protein is. Preliminary studies have shown it to work equally well on the all alpha-class and the all-beta class of protein, each of which have corresponding ideal forms. Given the speed of the algorithm, it will be possible to compare all of these against the Protein Structure Database and determine the extent to which the current ideal forms can account for the variety of protein structure. Analysis of the remainder should provide a base for the development of further forms.

Algorithms↗
PubMed2000

Structure comparison and structure patterns.

This article investigates aspects of pairwise and multiple structure comparison, and the problem of automatically discover common patterns in a set of structures. Descriptions and representation of structures and patterns are described, as well as scoring and algorithms for comparison and discovery. A framework and nomenclature is developed for classifying different methods, and many of these are reviewed and placed into this framework.

Algorithms↗
PubMed2000

Convergence of redox-sensitive and mitogen-activated protein kinase signaling pathways in tumor necrosis factor-alpha-mediated monocyte chemoattractant protein-1 induction in vascular smooth muscle cells.

Monocyte chemoattractant protein-1 (MCP-1) is an important component of the inflammatory response of the vessel wall and has been shown to be regulated by cytokines, such as tumor necrosis factor-alpha (TNF-alpha). However, the precise signaling pathways leading to MCP-1 induction have not been fully elucidated in vascular smooth muscle cells (VSMCs). Cytokine signal transduction involves protein kinases as well as reactive oxygen species (ROS). The relation between these 2 factors is not clear. In this study, we show that TNF-alpha induces a parallel phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) and increases MCP-1 mRNA expression in cultured VSMCs. Inhibition of ERK1/2 but not p38MAPK caused a partial attenuation of MCP-1 induction (43+/-10% inhibition). Incubation of VSMCs with multiple antioxidants (diphenylene iodonium, liposomal superoxide dismutase, catalase, N-acetylcysteine, dimethylthiourea, and pyrrolidine dithiocarbamate) had no effect on TNF-alpha-mediated MCP-1 upregulation. However, simultaneous blockade of the ERK1/2 and ROS pathways by using PD098059 combined with diphenylene iodonium or N-acetylcysteine potently enhanced the ability of MAPK kinase inhibitors to abrogate MCP-1 mRNA expression (100+/-2% inhibition). Thus, parallel ROS-dependent and ERK1/2-dependent pathways converge to regulate TNF-alpha-induced MCP-1 gene expression in VSMCs. These data unmask a complex but organized integration of ROS and protein kinases that mediates cytokine-induced vascular inflammatory gene expression.

Animals↗
PubMed2000

CC chemokine receptor 2 is required for macrophage infiltration and vascular hypertrophy in angiotensin II-induced hypertension.

Recent studies have identified the presence of macrophages in the arterial wall of hypertensive animals and suggested that as is the case in atherosclerosis, macrophage products may be important mediators of the adaptive response of the arterial wall. In support of this, we have previously shown that the expression of monocyte chemoattractant protein-1 is upregulated in the arteries of hypertensive animals. We hypothesized that macrophage recruitment is a critical step in the pathogenesis of hypertension. To obtain insights into this potential mechanism, we made use of mice deficient in the CC chemokine receptor 2 (CCR2), the receptor for monocyte chemoattractant protein-1. Hypertension was induced with the subcutaneous administration of angiotensin II (0.75 mg. kg(-1). d(-1)) for 7 days. Using in situ hybridization with a probe for c-fms to identify macrophages, we found that hypertension-induced macrophage infiltration of the arterial wall was virtually eliminated in CCR2-deficient mice. In addition, vascular hypertrophy was reduced by approximately 65% compared with wild-type animals. These data demonstrate that CCR2 is essential for the recruitment of macrophages into the arterial wall in the setting of hypertension. Furthermore, the decreased hypertrophic response suggests that vascular hypertrophy occurs in part as a consequence of macrophage infiltration. In angiotensin II-induced hypertension, CCR2-mediated responses are critical to the process of macrophage recruitment and vascular hypertrophy and may represent one mechanism by which at least some forms of hypertension may lead to the development of atherosclerosis.

Angiotensin II↗