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A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby's fundus dystrophy 总被引:4,自引:0,他引:4
Langton KP McKie N Curtis A Goodship JA Bond PM Barker MD Clarke M 《The Journal of biological chemistry》2000,275(35):27027-27031
Sorsby's fundus dystrophy (SFD) is a dominantly inherited degenerative disease of the retina that leads to loss of vision in middle age. It has been shown to be caused by mutations in the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3). Five different mutations have previously been identified, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP-3 molecule; however, the significance of these mutations to the disease phenotype was unknown. In this report, we describe the expression of several of these mutated genes, together with a previously unreported novel TIMP-3 mutation from a family with SFD that results in truncation of most of the C-terminal domain of the molecule. Despite these differences, all of these molecules are expressed and exhibit characteristics of the normal protein, including inhibition of metalloproteinases and binding to the extracellular matrix. However, unlike wild-type TIMP-3, they all form dimers. These observations, together with the recent finding that expression of TIMP-3 is increased, rather than decreased, in eyes from patients with SFD, provides compelling evidence that dimerized TIMP-3 plays an active role in the disease process by accumulating in the eye. Increased expression of TIMP-3 is also observed in other degenerative retinal diseases, including the more severe forms of age-related macular degeneration, the most common cause of blindness in the elderly in developed countries. We hypothesize that overexpression of TIMP-3 may prove to be a critical step in the progression of a variety of degenerative retinopathies. 相似文献
94.
Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes 总被引:1,自引:0,他引:1
Lewis RJ Nielsen KJ Craik DJ Loughnan ML Adams DA Sharpe IA Luchian T Adams DJ Bond T Thomas L Jones A Matheson JL Drinkwater R Andrews PR Alewood PF 《The Journal of biological chemistry》2000,275(45):35335-35344
omega-Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new omega-conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared with other omega-conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA-D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies, omega-conotoxins CVID and MVIIA had similar potencies to inhibit current through central (alpha(1B-d)) and peripheral (alpha(1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat beta(3) in Xenopus oocytes. However, the potency of CVID and MVIIA increased when alpha(1B-d) and alpha(1B-b) were expressed in the absence of rat beta(3), an effect most pronounced for CVID at alpha(1B-d) (up to 540-fold) and least pronounced for MVIIA at alpha(1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. (1)H NMR studies reveal that CVID possesses a combination of unique structural features, including two hydrogen bonds that stabilize loop 2 and place loop 2 proximal to loop 4, creating a globular surface that is rigid and well defined. 相似文献
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Jason E. Bond Brent D. Opell 《Evolution; international journal of organic evolution》1998,52(2):403-414
We combine statistical and phylogenetic approaches to test the hypothesis that adaptive radiation and key innovation have contributed to the diversity of the order Araneae. The number of unbalanced araneid clades (those whose species numbers differ by 90% or more) exceeds the number predicted by a null Markovian model. The current phylogeny of spider families contains 74 bifurcating nodes, of which 31 are unbalanced. As this is significantly more than the 14.8 expected unbalanced nodes, some of the diversity within the Araneae can be attributed to some deterministic cause (e.g., adaptive radiation). One of the more highly unbalanced (97%) bifurcations divides the orb-weaving spiders into the Deinopoidea and the larger Araneoidea. A simple statistical model shows that the inequality in diversity between the Deinopoidea and the Araneoidea is significant, and that it is associated with the replacement of primitive cribellar capture thread by viscous adhesive thread and a change from a horizontal to a vertical orb-web orientation. These changes improve an orb-web's ability to intercept and retain prey and expand the adaptive zone that orb-weaving spiders can occupy and are, therefore, considered to be “key innovations.” 相似文献
97.
Koltunow Anna M. Brennan Peter Bond James E. Barker Susan J. 《Molecular breeding : new strategies in plant improvement》1998,4(3):235-251
Seedlessness is a highly desirable characteristic in fresh fruit. Marketability of a fruit as seedless does not require complete absence of seeds as long as the seed structures are imperceptible during consumption. Chimaeric genes comprised of soybean -conglycinin seed storage protein gene promoters linked to the bacterial RNase gene, Barnase, were tested for their efficacy to cause seed death and decrease seed size in tobacco and Arabidopsis. These species were used because they undergo two distinct seed developmental pathways and produce albuminous and exalbuminous seeds, respectively. In both species, the death of embryo and endosperm tissues occurred, resulting in a dominant seed lethal phenotype with segregation distortion. Reduction in seed size was only observed in Arabidopsis seeds and the phenotype resembled that of stenospermocarpic seeds in grape. Some transformants of both species were male-sterile and this correlated with the expression of the gene in anthers indicating that expression of the gene is not strictly seed-specific. The promoters also direct expression of a linked GUS gene to Citrus embryos of various developmental stages, and Citrus forms exalbuminous seeds, therefore, the Barnase constructions may be useful in eliciting a reduction in seed size of around 75% of the seeds found in the fruit. This may be sufficient to warrant marketing as less seedy if trials in the cultivar of interest indicate that the smaller seeds are less detectable to the consumer. Abbreviations: GUS, -glucuronidase; PCR, polymerase chain reaction; DMSO, dimethyl sulfoxide; DTA, diphtheria toxin-A chain; CFDA, 5(6)-carboxy-fluorescein di-acetate; CG, -conglycinin; DAP, days after pollination; FAA, formaldehyde-acetic acid alcohol fixative. 相似文献
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Catherine B. Jardine Alexander L. Bond Peter J. A. Davidson Robert W. Butler Tomohiro Kuwae 《PloS one》2015,10(4)
Many shorebird species undertake long-distance migrations punctuated by brief stays at food-rich, estuarine stopover locations. Understanding use of these food resources helps guide conservation and responsible development decisions. We determined the extent and degree to which Western Sandpiper (Calidris mauri) utilized biofilm as a food resource across a large and variable stopover location during northward (spring) migration. We investigated the spatial heterogeneity in diet composition, to determine whether shorebirds were consistently feeding on biofilm or whether diet varied between naturally and anthropogenically delineated sites. We used stable isotope analysis to estimate that biofilm conservatively comprised 22% to 53% of Western Sandpiper droppings across all sampling sites and that prey composition differed significantly between areas within the stopover location. Widespread biofilm consumption demonstrates the importance of biofilm as a dietary component. Variable diet composition suggests that habitat heterogeneity may be an important component of high quality stopover locations in the context of “state-dependant trade-offs” of Western Sandpiper population sub-groups. Future management decisions must consider and address potential impacts on the biofilm community throughout a stopover location, as single site studies of diet composition may not be adequate to develop effective management strategies for entire stopover sites. 相似文献
100.
Giselle L. Saulnier Sholler Eugene W. Gerner Genevieve Bergendahl Robert B. MacArthur Alyssa VanderWerff Takamaru Ashikaga Jeffrey P. Bond William Ferguson William Roberts Randal K. Wada Don Eslin Jacqueline M. Kraveka Joel Kaplan Deanna Mitchell Nehal S. Parikh Kathleen Neville Leonard Sender Timothy Higgins Masao Kawakita Kyoko Hiramatsu Shun-suke Moriya André S. Bachmann 《PloS one》2015,10(5)
BackgroundNeuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.ConclusionsDFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.