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Biomedical subjects

R S Bradley

Publications and source records attributed to R S Bradley.

14 recordsLinked to original sources
PubMed2006

Solar modulation of Little Ice Age climate in the tropical Andes.

The underlying causes of late-Holocene climate variability in the tropics are incompletely understood. Here we report a 1,500-year reconstruction of climate history and glaciation in the Venezuelan Andes using lake sediments. Four glacial advances occurred between anno Domini (A.D.) 1250 and 1810, coincident with solar-activity minima. Temperature declines of -3.2 +/- 1.4 degrees C and precipitation increases of approximately 20% are required to produce the observed glacial responses. These results highlight the sensitivity of high-altitude tropical regions to relatively small changes in radiative forcing, implying even greater probable responses to future anthropogenic forcing.

Climate↗
PubMed1999

Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors.

The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.

Crystallography, X-Ray↗
PubMed1998

NF-protocadherin, a novel member of the cadherin superfamily, is required for Xenopus ectodermal differentiation.

BACKGROUND: The assembly of complex tissues during embryonic development is thought to depend on differential cell adhesion, mediated in part by the cadherin family of cell-adhesion molecules. The protocadherins are a new subfamily of cadherins; their extracellular domains comprise cadherin-like repeats but their intracellular domains differ significantly from those of classical cadherins. Little is known about the ability of protocadherins to mediate the adhesion of embryonic cells, or whether they play a role in the formation of embryonic tissues. RESULTS: We report the isolation and characterization of a novel protocadherin, termed NF-protocadherin (NFPC), that is expressed in Xenopus embryos. NFPC showed a striking pattern of expression in early embryos, displaying predominant expression within the deep, sensorial layer of the embryonic ectoderm and in a restricted group of cells in the neural folds, but was largely absent from the neural plate and surrounding placodal regions. Ectopic expression in embryos demonstrated that NFPC could mediate cell adhesion within the embryonic ectoderm. In addition, expression of a dominant-negative form of NFPC disrupted the integrity of embryonic ectoderm, causing cells in the deep layer to dissociate, though leaving the outer layer relatively intact. CONCLUSIONS: Our results indicate that NFPC is required as a cell-adhesion molecule during embryonic development, and its function is distinct from that of classical cadherins in governing the formation of a two-layer ectoderm. These results suggest that NFPC, and protocadherins in general, are involved in novel cell-cell adhesion mechanisms that play important roles in tissue histogenesis.

Animals↗
PubMed1995

A soluble form of Wnt-1 protein with mitogenic activity on mammary epithelial cells.

The proto-oncogene Wnt-1 plays an essential role in fetal brain development and causes hyperplasia and tumorigenesis when activated ectopically in the mouse mammary gland. When expressed in certain mammary epithelial cell lines, the gene causes morphological transformation and excess cell proliferation at confluence. Like other members of the mammalian Wnt family, Wnt-1 encodes secretory glycoproteins which have been detected in association with the extracellular matrix or cell surface but which have not previously been found in a soluble or biologically active form. We show here that conditioned medium harvested from a mammary cell line expressing Wnt-1 contains soluble Wnt-1 protein and induces mitogenesis and transformation of mammary target cells. By immunodepletion of medium containing epitope-tagged Wnt-1, we show that at least 60% of this activity is specifically dependent on Wnt-1 protein. These results provide the first demonstration that a mammalian Wnt protein can act as a diffusible extracellular signaling factor.

Amino Acid Sequence↗
PubMed1993

Expression of Wnt-1 in PC12 cells results in modulation of plakoglobin and E-cadherin and increased cellular adhesion.

The Wnt-1 gene plays an essential role in fetal brain development and encodes a secreted protein whose signaling mechanism is presently unknown. In this report we have investigated intracellular mechanisms by which the Wnt-1 gene induces morphological changes in PC12 pheochromocytoma cells. PC12 cells expressing Wnt-1 show increased steady-state levels of the adhesive junction protein plakoglobin, and an altered distribution of this protein within the cell. This effect appears similar to a modulation of the plakoglobin homolog, Armadillo, that occurs in Drosophila embryos in response to the Wnt-1 homolog, wingless (Riggleman, B., P. Schedl, and E. Wieschaus. 1990. Cell. 63:549-560). In addition, PC12/Wnt-1 cells show elevated expression of E-cadherin and increased calcium-dependent cell-cell adhesion. These results imply evolutionary conservation of cellular responses to Wnt-1/wingless and indicate that in certain cell types Wnt-1 may act to modulate cell adhesion mechanisms.

Animals↗
PubMed1992

The mouse Wnt-1 gene can act via a paracrine mechanism in transformation of mammary epithelial cells.

The mouse Wnt-1 gene plays an essential role in fetal brain development and can contribute to tumorigenesis when activated aberrantly in the mammary gland. The gene encodes secretory glycoproteins associated with the extracellular or pericellular matrix, and it has been proposed that Wnt-1, as well as its Drosophila homolog wingless, may function in intercellular signalling. We show here that fibroblasts expressing Wnt-1 protein, although not transformed themselves, are able to elicit morphological transformation of neighboring C57MG mammary epithelial cells in coculture experiments. Heparin inhibits this effect, possibly by displacing Wnt-1 protein from its normal site of action. Our results indicate that the Wnt-1 gene can act via a paracrine mechanism in cell culture and strongly support the notion that in vivo the gene may function in cell-to-cell communication.

Animals↗
PubMed1990

The proto-oncogene int-1 encodes a secreted protein associated with the extracellular matrix.

The proto-oncogene int-1 plays an important role in mammary tumorigenesis when activated by proviral insertions of the mouse mammary tumor virus. In normal mouse tissues the gene is expressed in the embryonic neural tube, suggesting a developmental function, while in Drosophila the homolog of int-1 is the segment polarity gene wingless. In order to study the protein products of int-1 we have derived fibroblast cell lines infected with multiple copies of a retroviral vector expressing int-1 cDNA. By Western blot analysis and immunoprecipitation we have identified a 44 kd form of int-1 protein which is secreted from these cells. The 44 kd species is distinct from the major intracellular forms of int-1 protein as judged by its slower mobility in SDS-polyacrylamide gels and by its longer half-life in pulse-chase experiments. Under normal growth conditions, little or none of the 44 kd protein is detectable in the cell culture medium but instead the majority is found associated with the extracellular matrix (ECM). The protein appears to bind heparin in vitro, suggesting that it might bind glycosaminoglycans in the ECM. These data support the view that int-1 protein may play a role in cell-cell communication over short distances.

Animals↗