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T Donaldson

Publications and source records attributed to T Donaldson.

7 recordsLinked to original sources
PubMed1999

Tissue-specific regulation of vein/EGF receptor signaling in Drosophila.

Signaling by the Drosophila EGF receptor (DER) is modulated by four known EGF-like proteins: the agonists Vein (Vn), Spitz (Spi), and Gurken (Grk) and the antagonist Argos (Aos). DER is broadly expressed and thus tissue-specific regulation of ligand expression and activity is an important mechanism for controlling signaling. Here we investigate the tissue-specific regulation of Vn signaling by examining vn transcriptional control and Vn target gene activation in the embryo and the wing. The results show a complex temporal and spatial regulation of vn transcription involving multiple signaling pathways and tissue-specific activation of Vn target genes. In the embryo, vn is a target of Spi/DER signaling mediated by the ETS transcription factor PointedP1 (PntP1). This establishes a positive feedback loop in addition to the negative feedback loop involving Aos. The simultaneous production of Vn provides a mechanism for dampening Aos inhibition and thus fine-tunes signaling. In the larval wing pouch, vn is not a target of Spi/DER signaling but is expressed along the anterior-posterior boundary in response to Hedgehog (Hh) signaling. Repression by Wingless (Wg) signaling further refines the vn expression pattern by causing a discontinuity at the dorsal-ventral boundary. The potential for vn to activate DER target genes correlates with its roles in development: vn has a minor role in embryogenesis and does not induce DER target genes such as aos and pntP1 in the embryo. Conversely, vn has a major role in wing development and Vn/DER signaling is a potent inducer of DER target genes in the wing disc. Spi also has the potential to induce DER target genes in the wing disc. However, the ligands appear to evoke specific responses that result in different patterns of target gene expression. Finally, we show that other factors modulate the potential of Vn so that induction of Vn/DER target genes in the wing pouch is cell specific.

Animals↗
PubMed1998

EGF domain swap converts a drosophila EGF receptor activator into an inhibitor.

In Drosophila the function of the epidermal growth factor (EGF) receptor is modulated zygotically by three EGF-like proteins: Spitz (Spi), which is a potent activator; Vein (Vn), which is a moderate activator; and Argos (Aos), which is an inhibitor. Chimeric molecules were constructed in which the EGF domain of Vn was swapped with the EGF domain from each factor. The modified Vn proteins behaved both in vitro and in vivo with properties characteristic of the factor from which the EGF domain was derived. These results demonstrate that the EGF domain is the key determinant that gives DER inhibitors and activators their distinct properties.

Amino Acid Sequence↗
PubMed1996

Vein is a novel component in the Drosophila epidermal growth factor receptor pathway with similarity to the neuregulins.

The activation signal from tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), is relayed via a highly conserved intracellular pathway involving Ras, Raf, and MAPK. In Drosophila, the EGFR and components of the intracellular pathway are broadly expressed, yet receptor activation evokes tissue-specific cell responses. Extracellular events that lead to receptor activation are one mechanism by which signaling is modulated. Here we show molecular and genetic evidence that Drosophila vein (vn) encodes a candidate EGFR ligand and that vn expression is spatially restricted. Consequently, vn may promote tissue-specific receptor activation. Unlike two other ligands, Gurken (Grk) and Spitz (Spi), which are transforming growth factor alpha-like proteins, Vn has both an immunoglobulin-like and an EGF-like domain. This combination of domains mirrors those in the vertebrate neuregulins that bind EGFR relatives.

Amino Acid Sequence↗
PubMed1996

Dynamic test to diagnose loose uncemented femoral total hip components.

A new computed tomographic rotation study was developed to determine the stability of uncemented femoral components after total hip arthroplasty. The computed tomographic rotation study measures femoral component version with the leg in maximum external and internal rotation. The component is considered rotationally unstable, and thus loose, if these angles differ by more than 2 degrees. The results of the computed tomographic rotation study were confirmed with intraoperative inspection in 50 patients: 13 patients (Group A) with definite radiographic loosening, 22 patients (Group B) with equivocal radiographic loosening, and 15 patients (Group C) with documented stability. The results of the computed tomographic rotation study agreed with intraoperative findings for all patients in Groups A and C, and 20 of 22 patients in Group B (1 false negative and 1 false positive). Statistical analysis of Group B showed that the computed tomographic rotation study had a sensitivity of 91.6% and a specificity of 90.0%. The positive predictive value was 91.6%. These results indicate that the computed tomographic rotation study can supplement equivocal radiographic findings in assessing loosening of an uncemented femoral component.

Biomechanical Phenomena↗
PubMed1995

Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.

Alzheimer's disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid beta-peptide (A beta), a 40-42-amino-acid fragment of the beta-amyloid precursor protein (APP). A primary pathogenic role for APP/A beta is suggested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD. A major obstacle to elucidating and treating AD has been the lack of an animal model. Animals transgenic for APP have previously failed to show extensive AD-type neuropathology, but we now report the production of transgenic mice that express high levels of human mutant APP (with valine at residue 717 substituted by phenylalanine) and which progressively develop many of the pathological hallmarks of AD, including numerous extracellular thioflavin S-positive A beta deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/A beta in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.

Alzheimer Disease↗
PubMed1994

A computer-interfaced falling ball viscometer.

We have developed a system that greatly facilitates viscosity measurement under low-shear conditions, based upon a falling ball viscometer interfaced to a personal computer. Three optical sensors indicate the rate of passage of a steel ball falling through a micro-capillary tube, and a potentiometer detects the angle of the tube. The resulting data are passed from a custom program with a graphical user interface to a spreadsheet. The spreadsheet then calculates and stores a value for the viscosity of the sample, using the data passed to it from the viscometer, and a look-up table of stored slope and intercept values calculated from precision viscosity standards. We used the viscometer to determine the kinetics of actin polymerization, and to measure the viscosity of F-actin-aldolase gels. This system provides significantly greater reproducibility and speed in data acquisition than does the traditional 'eyeball and stopwatch' method, and data reduction is virtually instantaneous.

Actins↗