Properties of nonblocking single-substrate optical space switching networks constructed from directional couplers.

Some of the properties of single-substrate nonblocking optical space switching networks that are constructed from directional couplers, waveguide bends, and waveguide crossovers are considered. Expressions are given for the ratio of network output signal to cross talk, insertion loss, and total switch count for ten different structures. Based on these expressions, estimates of the maximum switch sizes attainable are made.

Novel replication inhibitory function of the developmental regulator/transcription repressor protein WT1 encoded by the Wilms' tumor gene.

The tumor suppressor/developmental regulator protein WT1 encoded by the Wilms' tumor gene is a zinc finger-containing transcription factor which binds to the G+C-rich motif 5'-GCGGGGGCG-3' and represses transcription. Alternatively spliced variants of WT1 (termed+KTS) having an insertion in the zinc finger region are defective for binding to and hence for repression of transcription from promoters containing this motif. Due to the known interactions of two other tumor suppressor proteins with the simian virus 40 (SV40) oncoprotein large tumor antigen (TAg) [which in one case (p53) results in inhibition of the replication initiation activity of TAg], and because of the presence of G+C-rich sequences in the SV40 origin region, we tested the effect of WT1 on TAg- and SV40 origin-dependent DNA replication.

Bioactivation and bioinactivation of drugs and drug metabolites: Relevance to adverse drug reactions.

Adverse drug reactions that cannot be predicted from the pharmacological properties of the drug and which are not easily reproduced in laboratory animals are a major complication of drug therapy. It is necessary to investigate the mechanisms of such reactions in order to (1) define structural features within a given drug molecule which are responsible for causing toxicity and (2) to identify those individuals who are particularly sensitive to a given drug reaction. In theory, drug toxicity may arise by direct toxicity, genotoxicity or immune-mediated toxicity caused by either parent drug or chemical.

The effect of enzyme inhibition on the metabolism and activation of tacrine by human liver microsomes.

1. Tacrine (1,2,3,4-tetrahydro-9-aminoacridine-hydrochloride: THA) underwent metabolism in vitro by a panel (n = 12) of human liver microsomes genotyped for CYP2D6, in the presence of NADPH, to both protein-reactive and stable metabolites. 2.

DNA recognition by splicing variants of the Wilms' tumor suppressor, WT1.

The Wilms' tumor suppressor, WT1, is a zinc finger transcriptional regulator which exists as multiple forms owing to alternative mRNA splicing. The most abundant splicing variants contain a nine-nucleotide insertion encoding lysine, threonine, and serine (KTS) in the H-C link region between the third and fourth WT1 zinc fingers which disrupts binding to a previously defined WT1-EGR1 binding site. We have identified WT1[+KTS] binding sites in the insulin-like growth factor II gene and show that WT1[+KTS] represses transcription from the insulin-like growth factor II P3 promoter.

RNA editing in the Wilms' tumor susceptibility gene, WT1.

Rat kidney WT1 cDNAs contain either a thymidine or a cytosine residue at position 839. Genomic WT1 DNA contains only T839. To explain these results, we propose the WT1 transcript undergoes RNA editing in which U839 is converted to C, resulting in the replacement of leucine 280 in WT1 by proline.

The Wilms' tumor suppressor gene WT1 is negatively autoregulated.

The Wilms' tumor suppressor gene WT1 encodes a zinc-finger DNA-binding protein that functions as a transcriptional repressor. WT1 is expressed in a dramatic spatial and temporal pattern during kidney development and is thought to be critical during mesenchymal-epithelial conversion. The WT1 protein bound multiple sites in the WT1 promoter and functioned as a powerful transcriptional repressor of its gene in vivo (> 50-fold).

An investigation of the formation of cytotoxic, genotoxic, protein-reactive and stable metabolites from naphthalene by human liver microsomes.

Chemically reactive epoxide metabolites have been implicated in various forms of drug and chemical toxicity. Naphthalene, which is metabolized to a 1,2-epoxide, has been used as a model compound in this study in order to investigate the effects of perturbation of detoxication mechanisms on the in vitro toxicity of epoxides in the presence of human liver microsomes. Naphthalene (100 microM) was metabolized to cytotoxic, protein-reactive and stable, but not genotoxic, metabolites by human liver microsomes.

An investigation into the formation of stable, protein-reactive and cytotoxic metabolites from tacrine in vitro. Studies with human and rat liver microsomes.

Tacrine (1,2,3,4-tetrahydro-9-aminoacridine hydrochloride; THA) is known to undergo extensive oxidative metabolism to a variety of mono- and dihydroxylated metabolites in animals and humans. The potential for tacrine to undergo metabolism to stable, protein-reactive and cytotoxic metabolites has been investigated in incubations with human and rat liver microsomes. Using lymphocytes as sensitive markers to quantify cytotoxicity, THA (50 microM) underwent NADPH-dependent bioactivation to a cytotoxic metabolite(s).

A structure-function analysis of transcriptional repression mediated by the WT1, Wilms' tumor suppressor protein.

The chromosome 11p13 Wilms' tumor locus (wt1) encodes a zinc finger-containing transcription factor (WT1). WT1 binds to the consensus sequence (5'-GCGGGGGCG-3') and represses transcription when bound to this site in vivo. The mechanism of repression is not yet defined.

Molecular analysis of the PHO81 gene of Saccharomyces cerevisiae.

The PHO81 gene product is a positive regulatory factor required for the synthesis of the phosphate repressible acid phosphatase (encoded by the PHO5 gene) in Saccharomyces cerevisiae. Genetic analysis has suggested that PHO81 may be the signal acceptor molecule; however, the biochemical function of the PHO81 gene product is not known. We have cloned the PHO81 gene and sequenced the promoter.

Comprehensive inpatient treatment for intractable migraine: a prospective long-term outcome study.

This paper describes outcome data for 100 patients with severe, intractable, persistent migraine (chronic daily headache), who were admitted to a comprehensive inpatient Head-Pain Treatment Unit for a mean of 8.5 days. Headache, pain-related behavior, depression, sleep disturbance, functional performance, work status, and medication use were assessed at admission, post-discharge (mean = 2.

Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms tumor suppressor WT1.

Wilms tumor, an embryonic kidney malignancy, accounts for approximately 6% of all pediatric neoplasms. A gene implicated in the genesis of this tumor, the Wilms tumor suppressor gene (WT1), encodes a zinc-finger DNA-binding protein (WT1) that functions as a transcriptional repressor. In certain Wilms tumors, the platelet-derived growth factor A chain (PDGF-A) is overexpressed; it has therefore been suggested that it may play an autocrine role in development of these neoplasms.

The Wilms' tumor gene product, WT1, represses transcription of the platelet-derived growth factor A-chain gene.

The Wilms' tumor locus on chromosome 11p13 contains a tumor suppressor gene, wt1, which encodes a DNA binding protein (WT1) with four zinc fingers and a glutamine-proline-rich N terminus and which functions as a repressor of transcription. The platelet-derived growth factor (PDGF) A-chain gene encodes a potent growth factor, which is expressed in high levels in a number of tumor cell lines. We initiated a search for WT1 target genes and now report that WT1 strikingly represses transcription of the PDGF A-chain gene in transient transfection assays and that the WT1 protein interacts directly with a highly G+C-rich region of the PDGF A-chain promoter in gel mobility shift assays.

Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1.

The Wilms tumor suppressor gene wt1 encodes a zinc finger DNA binding protein, WT1, that functions as a transcriptional repressor. The fetal mitogen insulin-like growth factor II (IGF-II) is overexpressed in Wilms tumors and may have autocrine effects in tumor progression. The major fetal IGF-II promoter was defined in transient transfection assays as a region spanning from nucleotides -295 to +135, relative to the transcription start site.

Characterization of the zinc finger protein encoded by the WT1 Wilms' tumor locus.

We analysed the biochemical properties of the transcription factor encoded by the putative tumor-suppressor gene present at the WT1 Wilms' tumor locus. A gene containing the full-length amino acid coding sequence of human wt1 was reconstructed from synthetic oligonucleotides and cloned into expression vectors for in vitro and in vivo protein synthesis. Polyclonal rabbit antibodies specific for the WT1 protein were raised to an Escherichia coli-produced 91 amino acid N-terminal segment and to a 136 amino acid C-terminal segment, which contains the zinc finger domain.

Transcriptional repression mediated by the WT1 Wilms tumor gene product.

The wt1 gene, a putative tumor suppressor gene located at the Wilms tumor (WT) locus on chromosome 11p13, encodes a zinc finger-containing protein that binds to the same DNA sequence as EGR-1, a mitogen-inducible immediate-early gene product that activates transcription. The transcriptional regulatory potential of WT1 has not been demonstrated. In transient transfection assays, the WT1 protein functioned as a repressor of transcription when bound to the EGR-1 site.

Metabolism of norgestimate by human gastrointestinal mucosa and liver microsomes in vitro.

The metabolism of the progestogen oral contraceptive norgestimate has been studied in vitro using human intestinal mucosa and human liver microsomes. Metabolites have been separated using radiometric high-performance liquid chromatography (HPLC) and identified by co-chromatography with authentic standards and by mass spectrometry. Histologically normal colon was obtained from 6 patients undergoing various resections and the mucosa mounted between 2 perspex (Ussing) chambers.

Gastrointestinal metabolism of contraceptive steroids.

A number of oral contraceptive steroids undergo first-pass metabolism in the gastrointestinal mucosa. Ethinyl estradiol (mean systemic bioavailability 40% to 50%) is extensively metabolized, principally to a sulfate conjugate. In vivo studies that use portal vein catheterization and the administration of radiolabeled ethinyl estradiol have shown that the fraction of steroid metabolized in the gut wall is 0.

Molecular and expression analysis of the negative regulators involved in the transcriptional regulation of acid phosphatase production in Saccharomyces cerevisiae.

The PHO80 and PHO85 gene products encode proteins necessary for the repression of transcription from the major acid phosphatase gene (PHO5) of Saccharomyces cerevisiae. The deduced amino acid sequences of these genes have revealed that PHO85 is likely to encode a protein kinase, whereas no potential function has been revealed for PHO80. We undertook several approaches to aid in the elucidation of the PHO80 function, including deletion analysis, chemical mutagenesis, and expression analysis.

Clinical outcome following coronary balloon angioplasty in 100 consecutive patients with multivessel coronary artery disease.

Prompted by current uncertainties regarding the precise role of percutaneous transluminal coronary balloon angioplasty (PTCA) in patients with multivessel disease, we reviewed the records of 100 such patients undergoing their first PTCA at our centre between 1 March 1987 and 23 March 1989. Thirty had three-vessel coronary disease (stenoses greater than or equal to 70% in all three major coronary artery territories), 51 had a previous myocardial infarction and 25 had undergone previous coronary bypass surgery. The mean number of lesions of greater than or equal to 70% per patient was 2.

Metabolism of the contraceptive steroid desogestrel by human liver in vitro.

The metabolism of the progestogen oral contraceptive desogestrel (Dg) has been studied in vitro using human liver microsomes. Metabolites have been separated using radiometric high performance liquid chromatography and identified by co-chromatography with authentic standards and by mass spectrometry. All the livers examined (n = 6) were able to form 3-keto desogestrel as the main identifiable metabolite and also the presumed intermediates 3 alpha-hydroxydesogestrel (3 alpha-OHDg) and 3 beta-hydroxydesogestrel (3 beta-OHDg).