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Biomedical subjects

W R Taylor

Publications and source records attributed to W R Taylor.

At least 91 records · Page 5Linked to original sources
PubMed1997

Randomized trial comparing the tolerability of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in cancer patients receiving myelosuppressive chemotherapy.

A prospective, randomized, double-blind, multicenter study in cancer patients receiving myelosuppressive chemotherapy was undertaken to evaluate and compare the tolerability of sargramostim (yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor, RhuGM-CSF) and filgrastim (bacteria-derived recombinant human granulocyte colony-stimulating factor, RhuG-CSF) in the prophylaxis or treatment of chemotherapy-induced neutropenia. In all, 137 evaluable patients received sargramostim (300 micrograms; 193 mg/m2) or filgrastim (481 mg; 7 mg/kg) once daily by self-administered s.c. injection, usually beginning within 48 h after completion of chemotherapy. With the exception of a slightly higher incidence of grade 1 fever (< 38.1 degrees C) with sargramostim, there were no statistically significant differences in the incidence or severity of local or systemic adverse events possibly related to the growth factors. Although the study was not designed to evaluate efficacy directly, there also were no statistically significant differences between treatment groups in total days of growth factor therapy, days of hospitalization, or days of i.v. antibiotic therapy during the treatment period. Both sargramostim and filgrastim were comparably well tolerated when given by s.c. injection in this group of patients, and no clinically significant differences between the growth factors were demonstrated.

Chi-Square Distribution↗
PubMed1997

Three-dimensional domain duplication, swapping and stealing.

Examination of multidomain and/or multimeric protein structures can reveal evolutionary paths to a more complex 3D organization. Over the past few years, proteins have been shown to evolve while preserving mutual domain organization and interfaces. The recent advances in understanding domain reorganization and mobility highlight the versatility and efficiency of protein structural evolution.

Binding Sites↗
PubMed1997

Distance geometry based comparative modelling.

A distance geometry based protein modelling algorithm is presented which relies on the projection of simple model chain coordinates into Euclidean spaces with gradually decreasing dimensionality. Fast embedding was achieved by performing separate distance matrix projections on subsets of the model points. Structural equivalences between the unknown target and related proteins with known structures were deduced either from a mixed sequence/structure multiple alignment or from the output of various fold recognition (threading) approaches. These equivalences were mapped onto the model as structure-specific conserved C alpha atom distances and secondary structure assignments. Additional nonspecific distance restraints derived from general stereochemical properties of folded protein chains were used to guide the modelling process. The method quickly constructed a large number of low-resolution models which could then serve as starting conformations for full-atom refinement. Structure predictions for some targets in the 'Asilomar Challenge' (CASP2) are presented to illustrate potential applications of the approach.

Algorithms↗
PubMed1997

Multiple sequence threading: conditional gap placement.

Preliminary work to improve on the gap placement in a novel multiple sequence threading method is presented here. Using the globin family, we construct measures for the assessment of gaps in a multiple sequence threading alignment based on the structural comparison of two of the proteins in the family. We take into account information from multiple sequence alignments on both the structure and sequence side of the problem. This work shows the parameterization of the problem allowing the foundation to optimize and test a gap placement weight or penalty. Four states were considered: deleted structure, inserted sequence, gap ends in structure, and broken ends in sequence. Each of these states was analyzed for exposure, occupancy and secondary structure. These measures enable us to gain insight into the placement of gaps in a multiple sequence threading alignment. We analyzed the most extreme violations of these properties and found in these cases that most secondary structures are broken by gaps. However, sequence inserts in structure were never found in deeply buried positions. Most end separations were 3-4 A in excess of the minimum 6 A, although some were larger. We show that the maximum amount of observed secondary structure found in inserts was about half of the predicted structure (typically 5 and 10%, respectively). A similar trend occurred with observed and predicted exposure in inserts. Our eventual aim is to devise a weight incorporating these measures of gap placement to further refine our algorithm for the threading of sequence on structure.

Amino Acid Sequence↗
PubMed1997

Effectiveness of correlation analysis in identifying protein residues undergoing correlated evolution.

Various methods for detecting correlation between sites were evaluated by ascertaining their ability to discriminate positively correlated sites from background correlation at randomly evolved sites. A model for generating pairwise correlations of different degrees is also described. An assortment of physicochemical vectors and similarity and difference matrices were used to discriminate correlated change. There was little difference in effectiveness between the different matrices, but there were significant differences between the matrices and the physicochemical vectors. It is shown that all methods investigated exhibit significant inability to screen out background correlation, particularly in the presence of phylogenetic relatedness between the sequences. Methods using the matrices are unable to distinguish positively correlated from negatively correlated, or compensatory, replacements.

Amino Acid Sequence↗
PubMed1997

Cyclic strain induces an oxidative stress in endothelial cells.

Hypertension imposes an oxidant stress on the aorta and also causes mechanical deformation of the aortic wall. To assess whether deformation causes an oxidative stress, isolated porcine aortic endothelial cells (PAEC) were subjected to cyclic strain, and the cumulative amount of thiobarbituric acid reactive substances (TBARS, an index of lipid peroxidation) and H2O2 (a reactive oxygen species) was measured in the eluent at 2, 6, and 24 h. TBARS were increased by 40.5 +/- 9.2% after 24 h in cells exposed to cyclic strain vs. static controls (P < 0.05). No difference was seen at 2 and 6 h. H2O2 release was increased after 6 and 24 h of cyclic strain by 22.0 +/- 8.0 and 57.6 +/- 11.1 nmol H2O2/mg, respectively (P < 0.005), but was not increased after 2 h of strain. In vascular smooth muscle cells, TBARS were not observed and H2O2 release was not increased by cyclic strain. To investigate a potential source of H2O2 induced by strain, the activity of NADH/NADPH oxidase, a superoxide-generating enzyme, was measured by chemiluminescence. After 2 h, cells exposed to cyclic strain had greater activity than static controls (531.0 +/- 68.4 vs. 448.3 +/- 54.2 pmol O2- x mg(-1) x s(-1), respectively, when incubated with NADH, P < 0.005; 85.8 +/- 8.9 vs. 71.6 +/- 3.8 pmol O2- x mg(-1) x s(-1) when incubated with NADPH, P < 0.05). No effect on NADH/NADPH oxidase activity was seen after 6 or 24 h. The following conclusions were made: 1) cyclic strain induces an oxidant stress in PAEC monolayers as measured by TBARS formation and H2O2 release, 2) NADH/NADPH oxidase is a potential source of H2O2 release in cyclically strained cells, and 3) mechanical deformation of endothelial cells may play a critical role in the generation of oxidative stress within the vessel wall.

Animals↗
PubMed1997

Monocyte chemoattractant protein-1 expression in aortic tissues of hypertensive rats.

Monocyte chemoattractant protein-1 (MCP-1), a potent monocyte chemoattractant synthesized by vascular cells and monocytes, has been proposed to be an important mediator of inflammatory responses in the arterial vasculature. It was recently demonstrated that hypertension is associated with an inflammatory response in the arterial wall. To determine the effect of hypertension on arterial MCP-1 expression, we induced hypertension in Sprague-Dawley rats by infusing angiotensin II (0.75 mg x kg[-1] x d[-1] SC) for 7 days. Using Northern blot analysis, we detected a 3.6-fold increase in MCP-1 mRNA in the aortas of hypertensive rats. When we normalized blood pressure in angiotensin II-treated rats through oral administration of the nonspecific vasodilator hydralazine (15 mg x kg[-1] x d[-1]), aortic MCP-1 mRNA expression was significantly reduced. Similar results were obtained with a norepinephrine model of hypertension. Taken together, these data suggest that mechanical factors may be responsible in part for the upregulation of expression. Consistent with this interpretation, we found that cultured rat aortic vascular smooth muscle cells exposed to mechanical strain (20% peak deformation at 1 Hz) exhibited a marked increase in MCP-1 expression, suggesting the hemodynamic strain imparted onto arterial cells in hypertension is an important stimulus underlying this phenomenon. These results provide important insights into the in vivo regulation of MCP-1 and have potential implications for understanding the influence of hypertension on atherosclerosis.

Angiotensin II↗
PubMed1997

p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats.

Recent studies suggest that superoxide production by the NADPH/NADH oxidase may be involved in smooth muscle cell growth and the pathogenesis of hypertension. We previously showed that angiotensin II (Ang II) activates a p22phoxbased NADPH/NADH oxidase in cultured rat vascular smooth muscle cells and in animals made hypertensive by infusion of Ang II. To investigate the mechanism responsible for this increased oxidase activity, we examined p22phox mRNA expression in rats made hypertensive by implanting an osmotic minipump that delivered Ang II (0.7 mg/kg per day). Blood pressure began to increase 3 days after the start of Ang II infusion and remained elevated for up to 14 days. Expression of p22phox mRNA in aorta was also increased after 3 days and reached a maximum increase of 338 +/- 41% by 5 days after pump implantation compared with the value after sham operation. This increase in mRNA expression was accompanied by an increase in the content of the corresponding cytochrome (twofold) and NADPH oxidase activity (179 +/- 11% of that in sham-operated rats 5 days after pump implantation). Treatment with the antihypertensive agents losartan (25 mg/kg per day) or hydralazine (15 mg/kg per day) inhibited this upregulation of mRNA levels and activity. Furthermore, infusion of recombinant heparin-binding superoxide dismutase decreased both blood pressure and p22phox mRNA expression. In situ hybridization of aortic tissue showed that p22phox mRNA was expressed in medial smooth muscle as well as in the adventitia. These findings suggest that Ang II-induced hypertension activates the NADPH/NADH oxidase system by upregulating mRNA levels of one or several components of this oxidase system, including the p22phox, and that the NADPH/NADH oxidase system is associated with the pathology of hypertension in vivo.

Angiotensin II↗
PubMed1997

Vascular thrombin receptor regulation in hypertensive rats.

Thrombin has been implicated as an important mediator of vascular lesion formation in atherosclerosis and restenosis. To investigate a potential role for thrombin signaling in the vascular response to hypertension, we have studied thrombin receptor (TR) expression and regulation in hypertensive rats. Aortic TR mRNA was upregulated by angiotensin II (Ang II)-induced hypertension (10.7 +/- 2.5 times control, P < .02), which correlated with a 4-fold increase in thrombin-induced constriction in isolated endothelium-denuded aortic rings. The AT1 receptor antagonist losartan normalized blood pressure and TR mRNA. Conversely, lowering blood pressure to the same degree with hydralazine did not abolish the upregulation of TR mRNA expression. When low-renin low-Ang II hypertension was induced in Dahl salt-sensitive rats, there was no detectable increase in the expression of aortic thrombin receptor mRNA. Finally, treatment with a chimeric heparin-binding form of the recombinant human Cu/Zn superoxide dismutase caused complete inhibition of TR mRNA upregulation, suggesting that an increased rate of superoxide anion production is an important signaling mechanism. Thus, increased TR expression via a redox-sensitive mechanism in the aortic smooth muscle of rats treated with Ang II represents a novel in vivo mechanism through which the hypertensive effects of Ang II are mediated.

Angiotensin II↗
PubMed1996

A non-local gap-penalty for profile alignment.

The length of an alignment of biological sequences is typically longer than the mean length of its component sequences. (This arises from the insertion of gaps in the alignment.) When such an alignment is used as a profile for the alignment of further sequences (or profiles), it will have a bias toward additional sequences that match the length of the profile, rather than the mean length of sequences in the profile, as the alignment of these will entail fewer (or smaller) insertions (so avoiding gap-penalties). An algorithm is described to correct this bias that entails monitoring the correspondence, for every pair of positions, of the mean separations in both profiles as they are aligned. The correction was incorporated into a standard dynamic programming algorithm through a modification of the gap-penalty, but, unlike other approaches, this modification is not local and takes into consideration the overall alignment of the sequences. This implies that the algorithm cannot guarantee to find the optimal alignment, but tests suggest that close approximations are obtained. The method was tested on protein families by measuring the area in the parameter space of the phase containing the correct multiple alignment. No improvement (increase in phase area) was found with a family that required few gaps to be aligned correctly. However, for highly gapped alignments, a 50% increase in area was obtained with one family and the correct alignment was found for another that could not be aligned with the unbiased method.

Algorithms↗
PubMed1996

Natural history of severe atheromatous disease of the thoracic aorta: a transesophageal echocardiographic study.

OBJECTIVES: This study sought to prospectively observe the morphologic and clinical natural history of severe atherosclerotic disease of the thoracic aorta as defined by transesophageal echocardiography. BACKGROUND: Atherosclerosis of the thoracic aorta has been shown to be highly associated with risk for embolic events in transesophageal studies, but the natural history of the disease under clinical conditions has not been reported. METHODS: During a 20-month period, 191 of 264 patients undergoing transesophageal echocardiography had adequate visualization of the aorta to allow atherosclerotic severity to be graded as follows: grade I = normal (44 patients); grade II = intimal thickening (52 patients); grade III = atheroma < 5 mm (62 patients); grade IV = atheroma > or = 5 mm (19 patients); grade V = mobile lesion (14 patients). All available patients with grades IV (8 patients) and V (10 patients) disease as well as a subgroup of 12 patients with grade III disease had follow-up transesophageal echocardiographic studies (mean [+/- SD] 11.7 +/- 0.9 months, range 6 to 22). RESULTS: Of 30 patients undergoing follow-up transesophageal echocardiographic studies, 20 (66%) had no change in atherosclerotic severity grade. Of the remaining 10 patients, atherosclerotic severity progressed one grade in 7 and decreased in 3 with resolved mobile lesions. Of 18 patients with grade IV or V disease of the aorta who underwent a follow-up study, 11 (61%) demonstrated formation of new mobile lesions. Of 10 patients with grade V disease on initial study who underwent follow-up study, 7 (70%) demonstrated resolution of a specific previously documented mobile lesion. However, seven patients (70%) with grade V disease also demonstrated development of a new mobile lesion. Of 33 patients with grade IV or V disease, 8 (24%) died during the study period, and 1 (3%) had a clinical embolic event. CONCLUSIONS: The presence of severe atherosclerotic disease of the thoracic aorta as defined by transesophageal echocardiography is associated with a high mortality rate. Although the morphologic natural history of the disease process itself is marked by stability over a 1-year period, individual lesion morphology is dynamic, with formation and resolution of mobile components occurring frequently over the same period. The dynamic nature of individual lesion morphology potentially enhances the possibility of developing a successful therapeutic strategy.

Aged↗
PubMed1996

Homology modelling by distance geometry.

BACKGROUND: Unknown protein structures can be predicted from known structures (the scaffolds) with sequences sufficiently homologous to that of the target, based on the observation that similar sequences usually adopt the same fold. When structural equivalences between residues in the scaffold and target proteins are expressed in terms of conserved interatomic distances, the resulting 'distance geometry' representation provides an elegant mechanism for simultaneous restraint satisfaction and bias-free conformation space exploration. RESULTS: We present a homology modelling algorithm based on distance geometry that relies on the gradual projection of simple model chain coordinates into Euclidean spaces with decreasing dimensionality. The similarity between the unknown target structure and the scaffold proteins with known structures was described by mapping secondary structure assignments and specific distance restraints between C alpha atoms onto the model through a multiple alignment. This information was complemented by additional restraints derived from stereochemical considerations and other general aspects of protein structure such as hydrophobic core formation or the absence of tangled mainchains. CONCLUSIONS: The method was capable of quickly locating the correct fold even from an alignment with modest average conservation indicating that it could serve as a fast tool for obtaining correct low-resolution starting conformations for detailed refinement.

Amino Acid Sequence↗
PubMed1996

Acute effects of the potent lacrimator o-chlorobenzylidene malononitrile (CS) tear gas.

1. The use of tear gas to control civil unrest is accepted practice by government authorities worldwide. It is rarely used in Hong Kong but during a recent riot at a Vietnamese detention centre large quantities were used and this was cause for some concern. 2. All patients presenting to the British Red Cross Clinic after the incident were seen by one of the authors. To establish if exposure to tear gas had serious effects on the health of the detainees, the case records of the 184 patients with symptoms consistent with CS exposure were reviewed 2 months later. 3. The most common complaints were burns (52%), cough (38%), headache (29%), shortness of breath (21%), chest pain (19%), sore throat (15%) and fever (13%). However, the only common findings on examination by a physician were burns (52%) and an inflamed throat (27%). All burns could be categorised as "minor' according to the American Burns Association classification and all were consistent with CS gas exposure. 4. Some patients complained of other symptoms that had not been previously reported in the literature, such as haemoptysis (8%) and haematemesis (4%), but these were only confirmed in one patient. 5. The majority of patients had recovered within 2 weeks of exposure although one asthmatic patient complained of shortness of breath lasting for 33 days and a sore throat lasting for 38 days after the incident. She had abnormally low peak expiratory flow readings, but had a clinical history of asthma. 6. No serious sequelae were encountered, but the incidence of burns in these patients was higher than would be expected from a review of the literature. However, very little data on the effects of tear gas in a riot situation has been published. There have been reports of high concentrations of CS gas causing reactive airways dysfunction but this was not seen in our group of patients.

Adolescent↗
PubMed1995

Fibroblasts transformed by combinations of ras, myc and mutant p53 exhibit increased phosphorylation of histone H1 that is independent of metastatic potential.

H1 histones play an important role in regulating higher order structure of chromatin and are potential regulators of gene expression. H1s are phosphorylated, a modification which alters their interaction with DNA. We measured the abundance of three phosphorylated H1 subtypes in mouse fibroblasts transformed by combinations of ras, myc and mutant p53 which differ in metastatic potential. We found that there is an increase in phosphorylation of H1 subtypes in fibroblasts transformed with ras, myc and mutant p53. This increase was found to correlate with cellular transformation but not with induction of the metastatic phenotype.

Animals↗
PubMed1995

An investigation of conservation-biased gap-penalties for multiple protein sequence alignment.

Sequence conservation in a multiple sequence alignment (or profile) is often used to influence the alignment of further sequences onto the profile. Most methods, however, have considered only the opening of a gap at a single point and not what is contained in the inserted segment of one sequence (or profile) or what terminates the 'broken' ends of the other. An alignment algorithm is described that incorporates these aspects and the relative importance of the contribution from the insert and the 'broken' ends has been assessed. The approach was tested on families of very remotely related sequences using a novel protocol that was developed to quantify both the stability and generality of the solution.

Algorithms↗