Search PubMed⌕ Search

Biomedical subjects

B Dickson

Publications and source records attributed to B Dickson.

At least 19 recordsLinked to original sources
PubMed1995

Biochemical and genetic analysis of the Drk SH2/SH3 adaptor protein of Drosophila.

The Drk SH3-SH2-SH3 adaptor protein has been genetically identified in a screen for rate-limiting components acting downstream of the Sevenless (Sev) receptor tyrosine kinase in the developing eye of Drosophila. It provides a link between the activated Sev receptor and Sos, a guanine nucleotide release factor that activates Ras1. We have used a combined biochemical and genetic approach to study the interactions between Sev, Drk and Sos. We show that Tyr2546 in the cytoplasmic tail of Sev is required for Drk binding, probably because it provides a recognition site for the Drk SH2 domain. Interestingly, a mutation at this site does not completely block Sev function in vivo. This may suggest that Sev can signal in a Drk-independent, parallel pathway or that Drk can also bind to an intermediate docking protein. Analysis of the Drk-Sos interaction has identified a high affinity binding site for Drk SH3 domains in the Sos tail. We show that the N-terminal Drk SH3 domain is primarily responsible for binding to the tail of Sos in vitro, and for signalling to Ras in vivo.

Amino Acid Sequence↗
PubMed1995

Nuclear factors in sevenless signalling.

Recent studies in both vertebrates and invertebrates support an 'hourglass' model for signal transduction from receptor tyrosine kinases: Ras channels signals from diverse receptor tyrosine kinases into a common cytoplasmic kinase cascade, the targets of which are an even more diverse collection of nuclear proteins. What are these nuclear factors, and how do they interact to direct specific cellular responses to a generic signal? The past year has brought considerable progress in our quest to answer these questions in one model genetic system, the Drosophila eye.

Animals↗
PubMed1994

Elucidation of the role of breathless, a Drosophila FGF receptor homolog, in tracheal cell migration.

DFGF-R1 (breathless), a Drosophila FGF receptor homolog, is required for the migration of tracheal cells and the posterior midline glial cells during embryonic development. To define the role of this receptor in cell migration, we have monitored the biological effects of a deregulated receptor containing the extracellular and transmembrane regions of the torso dominant allele and the cytoplasmic domain of DFGF-R1. Ubiquitous expression of the chimeric receptor at the time of tracheal cell migration did not disrupt migration in wild-type embryos. However, induction of the chimeric receptor corrected the tracheal defects of breathless (btl) mutant embryos, allowing the tracheal cells to migrate along their normal tracts. This result indicates that the normal activity of DFGF-R1 in promoting cell migration does not require spatially restricted cues. Late inductions of the chimeric construct, after the normal initiation of tracheal migration, allowed the definition of a broad time window during which the external signals guiding migration persist and the tracheal cells retain the capacity to respond to these cues. Rescue of tracheal migration in btl mutant embryos by the chimeric construct provides a sensitive biological assay for the activity of other Drosophila receptor tyrosine kinases (RTKs). Deregulated receptors containing the cytoplasmic domains of DFGF-R2, DER, torso, and sevenless were all able to partially rescue the migration defects. Consistent with the notion that these RTKs share a common signaling pathway, constructs containing the activated downstream elements Dras1 and Draf were also able to rescue tracheal migration, demonstrating that these two proteins are key players in the DFGF-R1 signaling pathway.

Animals↗
PubMed1994

Genetic dissection of signal transduction mediated by the sevenless receptor tyrosine kinase in Drosophila.

The specification of the R7 photoreceptor cell fate in the developing eye of Drosophila depends on the local activation of the sevenless (sev) receptor tyrosine kinase by boss, a protein expressed on the membrane of the neighboring R8 cell. Constitutive activation of the sev receptor results in a dosage dependent increase in the number of R7 cells per ommatidium. Genetic screens have been used to identify mutations that alter the efficiency of signal transduction. Subsequent molecular characterization of the corresponding genes has led to the identification of a number of proteins involved in transducing the signal from the receptor to the nucleus. In contrast to the receptor and its ligand, these components are shared between different signal transduction pathways not only in Drosophila but are also homologous to components involved in signal transduction in other organisms.

Animals↗
PubMed1993

Genetic dissection of signal transduction mediated by the sevenless receptor tyrosine kinase in Drosophila.

The specification of the R7 photoreceptor cell fate in the developing eye of Drosophila depends on the local activation of the sevenless (Sev) receptor tyrosine kinase by Boss, a protein expressed on the membrane of the neighbouring R8 cell. Constitutive activation of the Sev receptor results in a dosage-dependent increase in the number of R7 cells per ommatidium. Genetic screens have been used to identify mutations that alter the efficiency of signal transduction. Subsequent molecular characterization of the corresponding genes has led to the identification of a number of proteins involved in transducing the signal from the receptor to the nucleus. In contrast to the receptor and its ligand, these components are shared between different signal transduction pathways not only in Drosophila but are also homologous to components involved in signal transduction in other organisms.

Animals↗
PubMed1993

Genetic analysis of the sevenless signal transduction pathway of Drosophila.

The specification of the R7 photoreceptor cell fate in the developing eye of Drosophila depends on the local activation of the sevenless (sev) receptor tyrosine kinase (RTK) by boss, a protein expressed on the membrane of the neighboring R8 cell. Constitutive activation of the sev receptor results in a dosage dependent increase in the number of R7 cells per ommatidium. Genetic screens have been used to identify mutations that alter the efficiency of signal transduction. Subsequent molecular characterization of the corresponding genes has led to the identification of a number of proteins involved in transducing the signal from the receptor to the nucleus. In contrast to the receptor and its ligand, these components are shared between different signal transduction pathways not only in Drosophila but homologous components are also involved in signal transduction in other organisms.

Animals↗
PubMed1992

Raf functions downstream of Ras1 in the Sevenless signal transduction pathway.

Specification of the R7 cell fate in the developing Drosophila eye requires activation of the Sevenless (Sev) receptor tyrosine kinase, located on the surface of the R7 precursor cell, by its interaction with the Boss protein, expressed on the surface of the neighbouring R8 cell. Four genes that participate in the intracellular transmission of this signal have so far been identified and molecularly characterized: Ras1, Sos, Gap1 and sina (refs 4-8). The Drosophila homologue of the mammalian Raf-1 serine/threonine kinase, which has been implicated in signal transduction pathways activated by many receptor tyrosine kinases (reviewed in refs 9 and 10), is encoded by the raf locus (also known as l(1)polehole, Draf-1 or Draf). Here we show that the Drosophila Raf serine/threonine kinase also plays a crucial role in the R7 pathway: the response to Sev activity is dependent on raf function, and a constitutively activated Raf protein can induce R7 cell development in the absence of sev function. We also present genetic evidence suggesting that Raf acts downstream of Ras1 and upstream of Sina in this signal transduction cascade.

Animals↗
PubMed1992

Embryonal sarcoma of the liver in an adult treated with preoperative chemotherapy, radiation therapy, and hepatic lobectomy.

A rare case of embryonal sarcoma of the liver in a 28-year-old man is reported. The patient was treated preoperatively with a combination of chemotherapy and radiation therapy. Complete surgical resection, 4.5 months after diagnosis, consisted of a left hepatic lobectomy. No viable tumor was found in the operative specimen. The patient was disease-free 20 months postoperatively.

Adult↗
PubMed1992

Prepattern in the developing Drosophila eye revealed by an activated torso--sevenless chimeric receptor.

Induction of the R7 photoreceptor cell fate in the developing eye of Drosophila depends on the activation of the sevenless receptor tyrosine kinase in the R7 precursor cell. The sevenless protein is expressed transiently in 8 of the 20 precursors of an ommatidium. Activation of the sevenless kinase in these eight cells indicates that six of them are competent to become R7 cells. To test the competence of all 20 ommatidial precursors in a temporally unrestricted manner we have used a constitutively activated sevenless kinase created by fusing the extracellular domain of a mutant torso protein, another Drosophila receptor tyrosine kinase, to the sevenless kinase. Our results show that competence to develop as neuronal cells in response to sevenless activity is spatially and temporally limited to the cells expressing sevenless. Therefore, the expression of sevenless marks a preexisting pattern of developmental potential in the disc epithelium.

Animals↗
PubMed1991

Importance of the position of TYR R boxes for repression and activation of the tyrP and aroF genes in Escherichia coli.

Tyrosine-mediated repression of aroF and tyrP was studied by inserting DNA sequences between the two adjacent TYR R boxes which, in each case, overlap the respective RNA polymerase binding sites of these genes. In both cases, repression was greatest when homologous regions of these two TYR R boxes were on the same face of the DNA helix and the boxes were directly adjacent. An insertion of 3 bases was sufficient to abolish repression, which was reestablished as the boxes became separated by one full turn of the helix. These observations, coupled with the results of in vitro DNase I protection studies, supported the hypothesis that the binding of TyrR protein to the downstream boxes required cooperative interaction with TyrR protein already bound to the upstream boxes. In the case of tyrP, moving the upstream box also affected activation. Maximal activation was observed when the box was moved 3 or 12 to 14 residues upstream. Practically no activation was seen at intermediate positions, such as +7 and -4. It is hypothesized that these results indicate positions allowing maximal interaction between TyrR protein bound to the upstream box and RNA polymerase bound to the RNA polymerase binding site.

Base Sequence↗
PubMed1989

The role of a static bend in the DNA of the aroF regulatory region of Escherichia coli.

DNA fragments containing the regulatory regions of two genes repressed by the tyrR gene product exhibit retarded electrophoretic mobility in polyacrylamide gels indicating the presence of static bends in the DNA. In the aroF gene this bend has been localized to a region containing two TyrR protein-binding sites. A point mutation between these two sites reduced the degree of bending observed but did not reduce the level of repression, indicating the static bend may not be an important component of the repression mechanism.

Base Sequence↗
PubMed1988

Law and medicine: conflict or collaboration? The 1988 Harvey Cushing oration.

Doctors and lawyers share the common goal of pursuit of the welfare of the patient and client. Even where litigation brings physicians into conflict with the law, collaboration must be our guide. The standard of care is defined by reference to the expertise of the medical profession. The need for informed consent is based upon the moral and ethical values our professions share. In assessing fair compensation, legal rules are shaped by the need to make the lives of the injured and disabled bearable, again an ethical value we hold in common. The nature of our day-to-day tasks and the methods we employ may be different, but we must never lose sight of the fact that the interests of society can only be met if we work closely together.

Canada↗
PubMed1988

A blinded endoscopic comparative study of misoprostol versus sucralfate and placebo in the prevention of aspirin-induced gastric and duodenal ulceration.

In a series of previous studies, we showed that misoprostol protects the gastric and duodenal mucosae against ulceration seen with the administration of both aspirin and the nonsteroidal antiinflammatory drug tolmetin. The purpose of this study was to confirm, in addition, that misoprostol protects the mucosae against aspirin-induced damage and, for the first time, to compare its cytoprotective properties with those of sucralfate. Thirty healthy volunteers were randomized into three equal groups receiving either misoprostol 200 micrograms, sucralfate 1 g, or placebo, co-administered with 650 mg of aspirin, four times a day for 7 days. All subjects had endoscopically normal mucosae on entry and were reendoscoped 2 h after a single final dose on day 7. The mucosae were graded on a 0-4 scale as follows: 0 = normal, 1 = single hemorrhage or erosion, 2 = 2-10 hemorrhages or erosions, 3 = 11-25 hemorrhages or erosions, 4 = more than 25 hemorrhages or erosions or an invasive ulcer of any size. Utilizing a previously established criterion of a score of 2 or less as a clinically significant degree of protection to the gastric mucosae, we found that the success rate for misoprostol was 100% (10/10), compared to 20% (2/10) for sucralfate and 0% (0/10) for placebo. Misoprostol was statistically significantly superior to both sucralfate (p = 0.0001) and placebo (p = 0.00001), with 95% confidence intervals on the difference in success rates between misoprostol and sucralfate and between misoprostol and placebo of (44%; 100%) and (61%; 100%), respectively. In the duodenum, nine of 10 subjects taking misoprostol showed no damage (0 grade), whereas this was seen in only five sucralfate and three placebo patients. Misoprostol was significantly superior to placebo (p = 0.020) and marginally superior to sucralfate (p = 0.141) with confidence intervals of (29%; 91%) and (-5%; 67%), respectively. Adverse experiences were minor and did not differ in the three groups.

Alprostadil↗
PubMed1988

Comparison of equal-weight oral dosages of verapamil hydrochloride and diltiazem hydrochloride in patients with mild to moderate hypertension.

The clinical efficacy, safety, and tolerability of oral verapamil and diltiazem, at total daily dosages of equal weight, were evaluated in a placebo-controlled, double-blind crossover study. Thirty-six ambulatory patients with chronic, stable, mild to moderate hypertension (supine diastolic blood pressure of 94-116 mm Hg) received a dosage of either verapamil or diltiazem 80 mg t.i.d. as the hydrochloride salt for one week after an antihypertensive-drug washout period. Each then received 120 mg of the same drug t.i.d. for one week. After another two-week washout period, the patients were crossed over to the other drug. Each patient had a 12-lead electrocardiogram and measurement of supine and standing blood pressure weekly. In the 32 patients completing the study, low-dose verapamil reduced supine diastolic blood pressure (DBP) from a mean of 101.5 +/- 5.2 to 95.3 +/- 9.5 mm Hg; high dose verapamil reduced DBP to 90.9 +/- 7.4 mm Hg. Standing DBP was reduced to a similar degree. Diltiazem showed an almost identical effect: Supine DBP was reduced from a mean of 101.7 +/- 5.3 to 94.0 +/- 10.1 mm Hg with the low dose and to 91.0 +/- 8.6 mm Hg with the high dose, with similar effects on standing DBP. The high dose of both drugs significantly increased the QTc interval, and both doses of diltiazem significantly increased the PR interval compared with baseline. Both drugs exhibited consistent efficacy with minimal adverse effects. The electrophysiologic safety profile of verapamil was superior to that of diltiazem.

Aged↗
PubMed1986

Pharmacokinetics of albendazole in man.

The pharmacokinetics of albendazole were investigated in healthy volunteers and in patients receiving albendazole for treatment of hydatid disease. Unchanged albendazole was below detectable limits in plasma, urine, bile and cyst fluid. The major metabolite present in all fluids was the sulfoxide. Maximum concentrations of albendazole sulfoxide in plasma were very variable, probably due to variable absorption of albendazole.

Absorption↗
PubMed1986

The effect of single intravenous doses of cimetidine or ranitidine on gastric secretion.

Intravenous cimetidine, 300 mg or 400 mg, or ranitidine, 50 mg, was administered as a single dose to 36 volunteers in a randomized, crossover fashion. Aspirates of gastric juice were obtained after dosing, and the pH, titratable acidity, gastric fluid volume, and gastric acid output were determined from baseline through 71/2 hours for each subject. Each intervention significantly increased pH and suppressed hydrogen ion concentration, gastric fluid volume, and gastric acid output. Both the magnitudes of the changes when compared with baseline and the time of the mean maximum effects were similar in all three drug regimens. The effect of all three interventions on gastric fluid volume and gastric acid output diminished sharply after 6 hours. The data indicate that the gastric secretory response to all three interventions did not differ substantially.

Adolescent↗
PubMed1986

The effect of age on theophylline clearance in normal subjects.

Dose-interval AUC and clearance of theophylline at steady-state were determined in healthy male subjects in each of three age groups (18-35, 36-54 and 55-70 years old). Mean AUC in the oldest group was significantly higher than in the youngest and clearance in both the middle and oldest groups was significantly lower than in the youngest. Though clearance was significantly correlated with age, age alone accounted for only 31% of the variability in clearance.

Adult↗