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Biomedical subjects

L A McDonald

Publications and source records attributed to L A McDonald.

13 recordsLinked to original sources
PubMed2001

Complete genome sequence of a virulent isolate of Streptococcus pneumoniae.

The 2,160,837-base pair genome sequence of an isolate of Streptococcus pneumoniae, a Gram-positive pathogen that causes pneumonia, bacteremia, meningitis, and otitis media, contains 2236 predicted coding regions; of these, 1440 (64%) were assigned a biological role. Approximately 5% of the genome is composed of insertion sequences that may contribute to genome rearrangements through uptake of foreign DNA. Extracellular enzyme systems for the metabolism of polysaccharides and hexosamines provide a substantial source of carbon and nitrogen for S. pneumoniae and also damage host tissues and facilitate colonization. A motif identified within the signal peptide of proteins is potentially involved in targeting these proteins to the cell surface of low-guanine/cytosine (GC) Gram-positive species. Several surface-exposed proteins that may serve as potential vaccine candidates were identified. Comparative genome hybridization with DNA arrays revealed strain differences in S. pneumoniae that could contribute to differences in virulence and antigenicity.

Antigens, Bacterial↗
PubMed1998

The potential of subtype-selective neuronal nicotinic acetylcholine receptor agonists as therapeutic agents.

Neuronal nicotinic acetylcholine receptors (NAChRs) are pentameric ligand-gated ion channel receptors which exist as different functional subunit combinations which apparently subserve different physiological functions as indicated by molecular biological and pharmacological techniques. It is possible to design and synthesize novel compounds that have greater selective affinities and efficacies than nicotine for different NAChRs, which should translate into different behavioral profiles and therapeutic potentials. Examples of NAChR agonists studied are nicotine, SIB-1508Y, SIB-1553A and epibatidine. These compounds have different degrees of selectivity for human recombinant NAChRs, different neurotransmitter release profiles in vitro and in vivo and differential behavioral profiles. Preclinical studies suggest that SIB-1508Y is a candidate for the treatment of the motor and cognitive deficits of Parkinson's disease, whereas SIB-1553A appears to have potential as a candidate for the treatment of Alzheimer's disease. Epibatidine has a strong analgesic profile, however the ratio between pharmacological activity and undesirable effects is so low that it is difficult to envisage the use of this compound therapeutically. Nicotine has a broad profile of pharmacological activity, for instance demonstrating activity in models for cognition and analgesia. As for epibatidine, the adverse effects of nicotine severely limits its therapeutic use in humans. The discovery of subtype-selective NAChR agonists such as SIB-1508Y and SIB-1553A provides a new class of neuropsychopharmacological agents with better therapeutic ratios than nonspecific agents such as nicotine.

Animals↗
PubMed1998

Biosynthesis of ganefromycin: results from blocked mutants and bioconversion experiments.

The biosynthetic pathway of ganefromycin alpha (8) was investigated using blocked mutants of Streptomyces lydicus spp. tanzanius, the ganefromycin alpha producer, in conjunction with bioconversion experiments with the products of these mutants. Compounds 1-7 and 9-15, which are structurally related to ganefromycin alpha, were produced by cultures of secretor mutants showing blockage or diminished production of 8. These compounds were isolated, characterized, and subjected to bioconversion experiments using converter and other secretor mutants. Some of the compounds were shown to be products resulting from blocks at various stages in the biosynthetics pathway beyond construction of the polyketide skeleton (e.g., furan ring closure, hydroxylation, glycosylation, etc.). Other compounds were not bioconverted by biosynthetically capable mutants and were deemed shunt products. A mutant's metabolites and bioconverting ability were used to surmise the location of the block. A picture of the later sequence of events leading to the synthesis of ganefromycin alpha emerged, including C23-hydroxylation, C13a-O-methylation, C21a-hydroxylation, and C21a-O-glycosylation. Some of the later steps in the biosynthetic pathway for ganefromycin alpha are proposed.

Anti-Bacterial Agents↗
PubMed1998

Cervical lymph node involvement in head and neck cancer detectable as expression of a spliced transcript of type II keratin K5.

Metastatic spread to cervical lymph nodes is a major determinant of outcome in head and neck cancer. One hundred and ninety-six lymph nodes dissected from fresh surgical specimens from 24 patients with primary head and neck squamous cell carcinoma (SCC) were bisected. Messenger RNA (mRNA) extracted from one half and from a segment of the primary tumour was amplified by reverse transcriptase (RT)-polymerase chain reaction (PCR) with primers flanking the fifth intron of human type II keratin K5. DNA bands resolved by agarose gel electrophoresis were confirmed as specific transcripts by sequencing. The other half of each node was fixed in formalin for histology and, in selected nodes, for immunohistology for cytokeratins. Of 153 nodes suitable for analysis, 14 nodes contained metastatic tumour detected by light microscopy and also tested positive for K5 mRNA by RT-PCR. Fifty-six nodes were histologically negative for tumour but positive for K5 mRNA, and 83 nodes were negative for both histology and K5 mRNA. Extracts of the primary tumour always reacted positively for K5 by RT-PCR, whereas lymph nodes from patients without malignancies, and blood lymphocytes from a healthy volunteer reacted negatively. RT-PCR designed to detect the presence of processed transcripts of type II keratin K5 in stratified squamous epithelial cells may be a sensitive technique to detect the presence of viable and potentially metastatic carcinoma cells in lymph nodes draining head and neck SCC.

Biomarkers, Tumor↗
PubMed1997

Antifungal activity of conjugated styryl ketones.

The susceptibility of Aspergillus fumigatus to a series of alpha, beta-unsaturated styryl ketones known to be thiol-alkylators was examined, and the results were compared with those obtained for Candida albicans. Among 13 compounds used in our study, one (designated NC1110) inhibited the growth of A. fumigatus completely at low concentrations (minimum inhibitory concentration = 32 microM). Structure-activity analysis of these compounds indicated that the electron attracting property as well as the overall hydrophobicity of the compounds are important parameters for their antifungal activity. These preliminary results suggest that further modification of these molecules to enhance their hydrophobicity and the electron attracting property may result in more active compounds with improved antifungal activity.

Antifungal Agents↗
PubMed1995

Optimization of Applied Biosystems 373 sequencer stretch modification.

We have optimized the conditions for using the Stretch modification for the Applied Biosystems 373 Automated DNA Sequencers for sequencing double-stranded DNA using 34-cm well-to-read and 48-cm well-to-read configurations. With the manufacturer's recommended settings, uneven spacing within the first 100 bases was observed, which led to miscalls, insertions and deletions in the analyzed data. A significant decrease in accuracy for reads greater than 400 bases was also observed. Various gel concentrations were tested to improve the base spacing for the first 100 bases while maintaining accuracy and usable length of data. A longer average usable length and better resolution of smaller fragments were achieved by increased acrylamide concentration coupled with increased wattage. Using the Applied Biosystems CATALYST 800 Molecular Biology LabStation, Taq dye primer cycle sequencing reactions were optimized for -21 M13 and M13RP1 primers to produce a more even distribution of dye-labeled fragments that increased the overall signal strengths and decreased background signal. These reaction products, run on the Stretch sequencers using the new gel conditions, provided longer reads with increased reliability and accuracy of the data.

Acrylamides↗
PubMed1994

Inhibition of topoisomerase II catalytic activity by pyridoacridine alkaloids from a Cystodytes sp. ascidian: a mechanism for the apparent intercalator-induced inhibition of topoisomerase II.

Several new pyridoacridine alkaloids, dehydrokuanoniamine B (1), shermilamine C (2), and cystodytin J (3), in addition to the known compounds cystodytin A (4), kuanoniamine D (5), shermilamine B (6), and eilatin (7), were isolated from a Fijian Cystodytes sp. ascidian. Their structures were determined by analyses of spectroscopic data. These compounds along with a previously reported pyridoacridine, diplamine (8), showed dose-dependent inhibition of proliferation in human colon tumor (HCT) cells in vitro. All compounds inhibited the topoisomerase (TOPO) II-mediated decatenation of kinetoplast DNA (kDNA) in a dose-dependent manner. The pyridoacridines' ability to inhibit TOPO II-mediated decatenation of kDNA correlated with their cytotoxic potencies and their ability to intercalate into calf thymus DNA. These results suggest that disruption of the function of TOPO II, subsequent to intercalation, is a probable mechanism by which pyridoacridines inhibit the proliferation of HCT cells. Incorporation studies show that pyridoacridines disrupt DNA and RNA synthesis with little effect on protein synthesis. It appears that DNA is the primary cellular target of the pyridoacridine alkaloids. These results are consistent with those for known DNA intercalators.

Acridines↗
PubMed1992

Patellamide E: a new cyclic peptide from the ascidian Lissoclinum patella.

A new cyclic peptide, patellamide E [1], was isolated from the ascidian Lissoclinum patella collected at Pulau Salu, Singapore. Its structure was determined by nmr spectroscopy, and its absolute configuration by acid hydrolysis and analysis of the derivatized constituent amino acids by hplc. Patellamide E was mildly cytotoxic against human colon tumor cells in vitro.

Animals↗
PubMed1991

Chronic K depletion stimulates rat renal brush-border membrane Na-citrate cotransporter.

Chronic K depletion (KD) causes hypocitraturia. In the present studies, the effect of KD, induced by a low-K diet for 14 days (serum [K] 4.1 +- 0.1, control vs. 2.2 +/- 0.1 meq/l, KD, P less than 0.01), on renal cortical brush-border membrane (BBM) Na-citrate cotransporter activity was examined. KD significantly decreased fractional citrate excretion (3.90 +/- 0.68 vs. 0.53 +/- 0.10%, P less than 0.01). This was paralleled by a significant increase in the initial linear rate of BBM Na-dependent citrate transport (81 +/- 4 vs. 141 +/- 6 pmol citrate.5 s-1.mg protein-1, P less than 0.01). Kinetic studies varying extravesicular citrate concentration demonstrated that KD increased the maximal activity (Vmax) (152 +/- 17 vs. 296 +/- 14 pmol citrate.5 s-1.mg protein-1, P less than 0.01) with no difference in citrate affinity (118 +/- 23, control vs. 135 +/- 22 microM citrate, KD). Similarly, when extravesicular Na concentration was varied, KD increased the Vmax (132 +/- 9 vs. 206 +/- 6 pmol citrate.5 s-1.mg protein-1, P less than 0.01) with no difference in Na affinity (29 +/- 3, control vs. 28 +/- 1 mM Na, KD). The effect of KD on Na-citrate cotransport was specific in that KD did not alter Na-glucose (84 +/- 12, control vs. 89 +/- 5 pmol glucose.5 s-1.mg protein-1, KD) or Na-proline (87 +/- 3, control vs. 84 +/- 5 pmol proline.5 s-1.mg protein-1, KD) cotransport. In conclusion, KD increases the Vmax of the proximal tubule apical membrane Na-citrate cotransporter.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1985

Cognitive spatial processing and the regulation of posture.

Subjects performed the Brooks (1967) spatial and nonspatial memory tasks either while sitting or while maintaining a difficult standing balance position. The balance task disrupted spatial but not nonspatial memory performance. Balance steadiness during spatial and nonspatial memory conditions did not differ. These results suggest that cognitive spatial processing may rely on neural mechanisms that are also required for the regulation of posture.

Adult↗