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Biomedical subjects

M E Taylor

Publications and source records attributed to M E Taylor.

At least 19 recordsLinked to original sources
PubMed2001

An extended conformation of the macrophage mannose receptor.

The macrophage mannose receptor mediates phagocytosis of pathogenic microorganisms and endocytosis of potentially harmful soluble glycoproteins by recognition of their defining carbohydrate structures. The mannose receptor is the prototype for a family of receptors each having an extracellular region consisting of 8-10 domains related to C-type carbohydrate recognition domains (CRDs), a fibronectin type II repeat and an N-terminal cysteine-rich domain. Hydrodynamic analysis and proteolysis experiments performed on fragments of the extracellular region of the receptor have been used to investigate its conformation. Size and shape parameters derived from sedimentation and diffusion coefficients indicate that the receptor is a monomeric, elongated and asymmetric molecule. Proteolysis experiments indicate the presence of close contacts between several pairs of domains and exposed linker regions separating CRDs 3 and 6 from their neighboring domains. Hydrodynamic coefficients predicted for modeled receptor conformations are consistent with an extended conformation with close contacts between three pairs of CRDs. The N-terminal cysteine-rich domain and the fibronectin type II repeat appear to increase the rigidity of the molecule. The rigid, extended conformation of the receptor places domains with different functions at distinct positions with respect to the membrane.

Animals↗
PubMed2001

Complex encounters at the macrophage-mycobacterium interface: studies on the role of the mannose receptor and CD14 in experimental infection models with Mycobacterium avium.

The initial interactions between mycobacterial cell wall components and receptor structures on the surface of macrophages may be critical in determining the outcome of infection. They may trigger the ingestion and digestion of microorganisms, but they may also promote the intracellular persistence and growth of mycobacteria. Using Mycobacterium avium as a model system, three approaches of different complexities were used to analyse some structural features and some functional consequences of M. avium interacting with the macrophage mannose receptor or CD14, a pattern recognition receptor. Binding specificities of a recombinant, truncated extracellular portion of the mannose receptor were assayed in a novel ELISA-formatted system using viable M. avium cells as ligands. Infection with M. avium strains differing in their virulence were performed in murine bone marrow-derived macrophages and in mice with a targeted deletion of the CD14 gene. These parallel and converging approaches not only help define the molecular basis for understanding early events in the pathogenesis of mycobacterial infections, but are also necessary to ultimately determine the relevance of in vitro findings in the context of actual manifestations of disease in vivo.

Animals↗
PubMed2001

Bioassay and biochemical analyses of insecticide resistance in southern African Anopheles funestus (Diptera: Culicidae).

Anopheles funestus Giles has been implicated as a major malaria vector in sub-Saharan Africa where pyrethroid insecticides are widely used in agriculture and public health. Samples of this species from northern Kwazulu/Natal in South Africa and the Beluluane region of southern Mozambique showed evidence of resistance to pyrethroid insecticides. Insecticide exposure, synergist and biochemical assays conducted on A. funestus suggested that elevated levels of mixed function oxidases were responsible for the detoxification of pyrethroids in resistant mosquitoes in these areas. The data suggested that this mechanism was also conferring cross-resistance to the carbamate insecticide propoxur.

Animals↗
PubMed2000

Structure of a C-type carbohydrate recognition domain from the macrophage mannose receptor.

The mannose receptor of macrophages and liver endothelium mediates clearance of pathogenic organisms and potentially harmful glycoconjugates. The extracellular portion of the receptor includes eight C-type carbohydrate recognition domains (CRDs), of which one, CRD-4, shows detectable binding to monosaccharide ligands. We have determined the crystal structure of CRD-4. Although the basic C-type lectin fold is preserved, a loop extends away from the core of the domain to form a domain-swapped dimer in the crystal. Of the two Ca(2+) sites, only the principal site known to mediate carbohydrate binding in other C-type lectins is occupied. This site is altered in a way that makes sugar binding impossible in the mode observed in other C-type lectins. The structure is likely to represent an endosomal form of the domain formed when Ca(2+) is lost from the auxiliary calcium site. The structure suggests a mechanism for endosomal ligand release in which the auxiliary calcium site serves as a pH sensor. Acid pH-induced removal of this Ca(2+) results in conformational rearrangements of the receptor, rendering it unable to bind carbohydrate ligands.

Amino Acid Sequence↗
PubMed1999

Multiple interactions between pituitary hormones and the mannose receptor.

The macrophage mannose receptor, which has a well-documented role in the innate immune system, has an additional function in the clearance of pituitary hormones. Clearance is mediated by the recognition of sulphated terminal N-acetylgalactosamine residues (SO(4)-4GalNAc) on the hormones. Previous studies with an SO(4)-4GalNAc-containing neoglycoprotein suggest that the SO(4)-4GalNAc-binding site is localized to the N-terminal cysteine-rich domain of the receptor, distinct from the mannose/N-acetylglucosamine/fucose-specific C-type carbohydrate-recognition domains (CRDs). The present study characterizes the binding of natural pituitary hormone ligands to a soluble portion of the mannose receptor consisting of the whole extracellular domain and to a truncated form containing the eight CRDs but lacking the N-terminal cysteine-rich domain and the fibronectin type II repeat. Both forms of the receptor show high-affinity saturable binding of lutropin and thyrotropin. Binding to the full-length receptor is dependent on pH and ionic strength and is inhibited effectively by SO(4)-4GalNAc but only partly by mannose. In contrast, binding to the truncated form of the receptor, which is also dependent on pH and ionic strength, is inhibited by mannose but not by SO(4)-4GalNAc. The results are consistent with the presence of an SO(4)-4GalNAc-specific binding site in the cysteine-rich domain of the mannose receptor but indicate that interactions between other sugars on the hormones and the CRDs are also important in hormone binding.

Acetylgalactosamine↗
PubMed1999

Detection of glycopeptide-resistant enterococci in routine diagnostic faeces specimens.

Faeces received in a diagnostic laboratory were screened for glycopeptide-resistant enterococci (GRE) on modified Lewisham medium, with and without enrichment in Enterococcosel broth. Colonization by GRE was detected in 102/838 patients (12.2%). In 74 (73%) of colonized patients GRE were detected by both methods and in 28 (27%) they were detected only after enrichment. The carriage rate in hospitalized patients was 32% (93/289) compared with 2.3% (11/425) in the community (GP patients and food-handlers). Carriage of GRE increased with age. Clostridium difficile isolation was associated with GRE colonization, odds ratio 6.76 (P<0.001). Fifty-nine percent (60/102) of the GRE had the VanA phenotype and 41% (42/102) had the VanB phenotype. In the community VanA predominated (91%), whereas 64% (57/89) of the isolates from hospitalised patients were of the VanB phenotype.

Adolescent↗
PubMed1999

Mature results from a phase II trial of accelerated induction chemoradiotherapy and surgery for poor prognosis stage III non-small-cell lung cancer.

Mature results are reported from a phase II trial of accelerated induction chemoradiotherapy and surgical resection for stage III non-small-cell lung cancer whose prognosis is poor. Surgically staged patients with poor prognosis stage III non-small-cell lung cancer were eligible for this study. Four-day continuous intravenous infusions of cisplatin 20 mg/m2/day, 5-fluorouracil 1,000 mg/m2/day, and etoposide 75 mg/m2/day were given concurrently with accelerated fractionation radiation therapy, 1.5 Gy twice a day, to a total dose of 27 Gy. Surgical resection followed in 4 weeks. Identical postoperative chemotherapy and concurrent radiation to a total dose of 40 to 63 Gy was subsequently given. Between February 1991 and June 1994, 42 eligible and evaluable patients, 23 with stage IIIA disease and 19 with stage IIIB disease, were entered in this trial. Treatment was well tolerated. The pathologic response rate was 40%. This response was complete in 5%. With a median follow-up of 54 months, the Kaplan-Meier 4-year survival estimate is 19%: 26% for stage IIIA and 11% for stage IIIB patients. Patients with a pathologic response, resectable disease, or pathologic downstaging to stage 0, I, or II had a better survival. The 4-year estimates of locoregional and distant disease control are 70% and 19%, respectively. It is concluded that although the ultimate role of concurrent chemoradiotherapy and surgery in stage III non-small-cell lung cancer must await the results of phase III clinical trials, survival and locoregional control in this study appear improved in comparison with historical experience. There is a subset of patients, able to undergo resection with pathologic downstaging, who have a projected survival equivalent to that of patients with more limited disease. Clinical or pathologic tools to identify these patients before treatment would be highly useful.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Orientation of sugars bound to the principal C-type carbohydrate-recognition domain of the macrophage mannose receptor.

The extracellular region of the macrophage mannose receptor, a protein involved in the innate immune response, contains eight C-type carbohydrate-recognition domains (CRDs). The fourth of these domains, CRD-4, is central to ligand binding by the receptor, and binds mannose, fucose and N-acetylglucosamine by direct ligation to Ca2+. Site-directed mutagenesis combined with NMR and molecular modelling have been used to determine the orientation of monosaccharides bound to CRD-4. Two resonances in the 1H NMR spectrum of CRD-4 that are perturbed on sugar binding are identified as a methyl proton from a leucine side chain in the core of the domain and the H-2 proton of a histidine close to the predicted sugar-binding site. The effects of mutagenesis of this histidine residue, a nearby isoleucine residue and a tyrosine residue previously shown to stack against sugars bound to CRD-4 show the absolute orientation of sugars in the binding site. N-Acetylglucosamine binds to CRD-4 of the mannose receptor in the orientation seen in crystal structures of the CRD of rat liver mannose-binding protein. Mannose binds to CRD-4 in the orientation seen in the CRD of rat serum mannose-binding protein and is rotated by 180 degrees relative to GlcNAc bound to CRD-4. Interaction of the O-methyl group and C-1 of alpha-methyl Fuc with the tyrosine residue accounts for the strong preference of CRD-4 for this anomer of fucose. Both anomers of fucose bind to CRD-4 in the orientation seen in rat liver mannose-binding protein.

Acetylglucosamine↗
PubMed1998

Hospital-acquired infection in elderly patients.

Increasing numbers of elderly people are being treated in hospitals and are at particular risk of acquiring infections. The incidence, risk factors and types of hospital-acquired infection (HAI) in the elderly are reviewed. Special reference is made to urinary tract infections, respiratory tract infections, gastrointestinal infections including Clostridium difficile, bacteraemia, skin and soft tissue infections and infections with antibiotic-resistant organisms.

Aged↗
PubMed1998

Evolving views of protein glycosylation.

The composition, biosynthesis and known roles of oligosaccharides that are attached to glycoproteins suggest that multiple forces have driven the evolution of proteins that create and recognize these structures. The evolution of glycoprotein biosynthesis and recognition mechanisms can be best understood as a sequential development of functions associated with oligosaccharides.

Animals↗
PubMed1998

The C-type lectin superfamily in the immune system.

Protein-carbohydrate interactions serve multiple functions in the immune system. Many animal lectins (sugar-binding proteins) mediate both pathogen recognition and cell-cell interactions using structurally related Ca(2+)-dependent carbohydrate-recognition domains (C-type CRDs). Pathogen recognition by soluble collections such as serum mannose-binding protein and pulmonary surfactant proteins, and also the macrophage cell-surface mannose receptor, is effected by binding of terminal monosaccharide residues characteristic of bacterial and fungal cell surfaces. The broad selectivity of the monosaccharide-binding site and the geometrical arrangement of multiple CRDs in the intact lectins explains the ability of the proteins to mediate discrimination between self and non-self. In contrast, the much narrower binding specificity of selectin cell adhesion molecules results from an extended binding site within a single CRD. Other proteins, particularly receptors on the surface of natural killer cells, contain C-type lectin-like domains (CTLDs) that are evolutionarily divergent from the C-type lectins and which would be predicted to function through different mechanisms.

Amino Acid Sequence↗