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• Journal article
  Palmer LJ, Burton PR, Faux JA, James AL, Musk AW, Cookson WOet al., 2000,

  Independent inheritance of serum immunoglobulin E concentrations and airway responsiveness.

  , Am J Respir Crit Care Med, Vol: 161, Pages: 1836-1843, ISSN: 1073-449X

  Elevated serum Immunoglobulin E (IgE) levels and increased airway responsiveness (AR) are correlated traits that are characteristic of asthma. It is not known to what extent these traits arise from distinct or shared genetic determinants. We investigated the genetic and environmental components of variance of serum total and specific IgE levels and AR in an Australian population-based sample of 232 Caucasian nuclear families. The inter-relationships of the genetic determinants of these traits were also investigated. Log(e) total serum IgE levels had a narrow-sense heritability (h(2)(N)) of 47.3% (SE = 10.0%). Specific serum IgE levels against house dust mite and timothy grass, measured as a RAST Index, ad a h(2)(N) of 33.8% (SE = 7.3%). AR, quantified by the log(e) dose-response slope to methacholine (DRS), had a h(2)(N) of 30.0% (SE = 12.3%). Extended modeling demonstrated an approximate 70% overlap in the genetic determinants of total and specific serum IgE levels. The genetic determinants of serum IgE levels and AR exhibited less than 30% sharing. These data are consistent with the existence of multiple genetic determinants of the pathophysiologic traits associated with asthma, and suggest that AR is genetically distinct from atopy. These results have implications for gene discovery programs.

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• Journal article
  Adcock IM, Ito K, 2000,

  Molecular mechanisms of corticosteroid actions.

  , Monaldi Arch Chest Dis, Vol: 55, Pages: 256-266, ISSN: 1122-0643

  Corticosteroids are the most effective therapy for the treatment of inflammatory diseases such as asthma. Functionally, they act partly by inducing anti-inflammatory genes such as secretary leukocyte proteinase inhibitor, Lipocortin-1 and interleukin-1 receptor antagonist, but mainly by repression of inflammatory genes, such as cytokines, adhesion molecules, inflammatory enzymes and receptors. They act by binding to a cytosolic glucocorticoid receptor (GR), which upon binding is activated and rapidly translocates to the nucleus. Within the nucleus, the GR either induces gene transcription by binding to specific deoxyribonucleic acid elements in the promoter/enhancer regions of responsive genes or reduces gene transcription by transrepression. The GR reduces gene transcription by interaction with pro-inflammatory transcription factors such as activation protein-1 and nuclear factor-kappa B. These effects of the GR on gene expression involve changes in the chromatin structure localized to the promoter sites of responsive genes. Many of the detrimental side-effects of corticosteroids are believed to be due to gene induction, leading to the search for novel corticosteroids which can repress inflammatory genes without inducing gene transcription.

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• Journal article
  Ober C, Moffatt MF, 2000,

  Contributing factors to the pathobiology. The genetics of asthma.

  , Clin Chest Med, Vol: 21, Pages: 245-261, ISSN: 0272-5231

  Markers in 19 chromosomal regions have shown some evidence of linkage to asthma, atopy, or related phenotypes in multiple independent genome-wide searches. Linkages to five of these regions (5q, 6p, 11q, 12q, and 13q) have also been reported in non-genome-wide screens. In addition, at least two independent studies have reported linkages to markers on 16p. Numerous candidate genes in these regions have shown varying levels of association to asthma or atopic phenotypes, potentially implicating them as disease susceptibility loci. These include the IL4, CD14, and B2ADR genes on 5q, the HLA-DRB1 and TNF genes on 6p, the FCERB1 and CC16 genes on 11q, and the IL4RA gene on 16p. It still remains to be determined whether polymorphisms in these genes account for the reported linkages in these regions. Studies are underway in laboratories around the world to identify the disease-causing variations in these genes that account for the linkages just discussed. Identifying specific genetic polymorphisms that influence asthma and atopic phenotypes will shed light on the molecular pathways involved in these complex disorders and provide a better understanding of the pathophysiology of asthma and atopy.

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• Journal article
  Davies J, Neth O, Alton E, Klein N, Turner Met al., 2000,

  Differential binding of mannose-binding lectin to respiratory pathogens in cystic fibrosis

  , LANCET, Vol: 355, Pages: 1885-1886, ISSN: 0140-6736
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  • Citations: 43
• Journal article
  Espeso EA, Roncal T, Díez E, Rainbow L, Bignell E, Alvaro J, Suárez T, Denison SH, Tilburn J, Arst HN, Peñalva MAet al., 2000,

  On how a transcription factor can avoid its proteolytic activation in the absence of signal transduction

  , EMBO JOURNAL, Vol: 19, Pages: 2391-2391, ISSN: 0261-4189
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  • Citations: 1
• Journal article
  Espeso EA, Arst HN, 2000,

  On the mechanism by which alkaline pH prevents expression of an acid-expressed gene

  , MOLECULAR AND CELLULAR BIOLOGY, Vol: 20, Pages: 3355-3363, ISSN: 0270-7306
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  • Citations: 83
• Journal article
  Chabat F, Hansell DM, Yang GZ, 2000,

  Gradient correction and classification of CT lung images for the automated quantification of mosaic attenuation pattern?

  , Journal of Computer Assisted Tomography, Vol: 24, Pages: 437-447
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• Journal article
  Moffatt MF, Traherne JA, Abecasis GR, Cookson WOet al., 2000,

  Single nucleotide polymorphism and linkage disequilibrium within the TCR alpha/delta locus.

  , Hum Mol Genet, Vol: 9, Pages: 1011-1019, ISSN: 0964-6906

  Much attention is being given to the identification of common disease genes through whole-genome linkage disequilibrium (LD) screens with single nucleotide polymorphisms (SNPs). Simulation studies have suggested that useful LD is unlikely to extend beyond 3 kb, and that > 500,000 SNPs may be needed for comprehensive coverage of the genome. The TCR alpha/delta locus on chromosome 14q contains many V, J and D segments that combine with constant domains to produce either an alpha or a delta chain of the T cell receptor. Multiple SNPs have been recognized within the V segments, and it has been suggested that variation within the locus may modify the course of autoimmune and allergic diseases. We have examined LD within an 850 kb section of the TCR alpha/delta locus on chromosome 14q by typing 24 V gene segment SNPs and two microsatellites. One hundred and fifty-nine nuclear and extended families were genotyped in order to derive haplotypes, and the pair-wise LD between SNPs was investigated in 600 haplotypes from unrelated individuals (the parents). The mean extent of useful LD was much greater than suggested by simulations: significant LD was relatively common at 250 kb and was detectable beyond 500 kb. The mean extent of LD was twice as far between alleles of low frequency than between common alleles. The distribution of LD was highly irregular and concentrated in three distinct islands. The results differ from those obtained by simulation, and if they are typical of other genomic regions, suggest that the minimum number of markers necessary for comprehensive LD mapping may be reduced by at least an order of magnitude.

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• Conference paper
  Mohanty AK, Bismarck A, Aranberri I, Czapla S, Springer J, Misra M, Hinrichsen Get al., 2000,

  Characterization of natural fibers using ζ-potential measurements:: Surface properties and the water uptake behavior of modified jute, sisal, and coir fibers.

  , Publisher: AMER CHEMICAL SOC, Pages: U527-U527, ISSN: 0065-7727
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• Conference paper
  Willi O, Barringer L, Bell A, Borghesi M, Davies J, Gaillard R, Iwase A, MacKinnon A, Malka G, Meyer C, Nuruzzaman S, Taylor R, Vickers C, Hoarty D, Gobby P, Johnson R, Watt RG, Blanchot N, Canaud B, Croso H, Meyer B, Miquel JL, Reverdin C, Pukhov A, Meyer-ter-Vehn Jet al., 2000,

  Inertial confinement fusion and fast ignitor studies

  , 17th IAEA Fusion Energy Conference, Publisher: INT ATOMIC ENERGY AGENCY, Pages: 537-545, ISSN: 0029-5515
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  • Citations: 9

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