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Biomedical subjects

R Parsons

Publications and source records attributed to R Parsons.

At least 91 records · Page 5Linked to original sources
PubMed1993

Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer.

Recent studies have shown that a locus responsible for hereditary nonpolyposis colorectal cancer (HNPCC) is on chromosome 2p and that tumors developing in these patients contain alterations in microsatellite sequences (RER+ phenotype). We have used chromosome microdissection to obtain highly polymorphic markers from chromosome 2p16. These and other markers were ordered in a panel of somatic cell hybrids and used to define a 0.8 Mb interval containing the HNPCC locus. Candidate genes were then mapped, and one was found to lie within the 0.8 Mb interval. We identified this candidate by virtue of its homology to mutS mismatch repair genes. cDNA clones were obtained and the sequence used to detect germline mutations, including those producing termination codons, in HNPCC kindreds. Somatic as well as germline mutations of the gene were identified in RER+ tumor cells. This mutS homolog is therefore likely to be responsible for HNPCC.

Amino Acid Sequence↗
PubMed1993

Hypermutability and mismatch repair deficiency in RER+ tumor cells.

A subset of sporadic colorectal tumors and most tumors developing in hereditary nonpolyposis colorectal cancer patients display frequent alterations in microsatellite sequences. Such tumors have been thought to manifest replication errors (RER+), but the basis for the alterations has remained conjectural. We demonstrate that the mutation rate of (CA)n repeats in RER+ tumor cells is at least 100-fold that in RER- tumor cells and show by in vitro assay that increased mutability of RER+ cells is associated with a profound defect in strand-specific mismatch repair. This deficiency was observed with microsatellite heteroduplexes as well as with heteroduplexes containing single base-base mismatches and affected an early step in the repair pathway. Thus, a true mutator phenotype exists in a subset of tumor cells, the responsible defect is likely to cause transitions and transversions in addition to microsatellite alterations, and a biochemical basis for this phenotype has been identified.

Base Sequence↗
PubMed1993

WAF1, a potential mediator of p53 tumor suppression.

The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. Introduction of WAF1 cDNA suppressed the growth of human brain, lung, and colon tumor cells in culture. Using a yeast enhancer trap, a p53-binding site was identified 2.4 kb upstream of WAF1 coding sequences. The WAF1 promoter, including this p53-binding site, conferred p53-dependent inducibility upon a heterologous reporter gene. These studies define a gene whose expression is directly induced by p53 and that could be an important mediator of p53-dependent tumor growth suppression.

Amino Acid Sequence↗
PubMed1993

Medical care and case fatality from myocardial infarction and coronary death in Newcastle and Perth.

Coronary mortality rates are significantly higher in Newcastle than Perth. In this paper we examine the extent to which this might be due to differences in medical treatment and case fatality. Population-based disease registers were used to identify all cases of non-fatal definite myocardial infarction (MI) and coronary death in people aged 25-64 years in the study populations between July 1988 and June 1990. Case fatality (at 28 days from onset of symptoms) was not significantly different between the centres. Thrombolytic therapy was used for one third of all hospitalised events in both centres. Other drugs of proven benefit were, however, used more often in Perth than in Newcastle. For example, during hospitalisation 74% of patients in Perth received beta-blockers compared with 41% in Newcastle (difference = 33%, 95% confidence interval (CI): 28%, 37%) and 85% of patients in Perth compared with 72% in Newcastle received aspirin (difference = 13%, 95% CI: 9%, 17%). Median lengths of stay in a coronary care unit (CCU) and total hospital stay were one day shorter in Perth. As case fatality was similar, the differences in mortality rates can be attributed mainly to differences in attack rates. Greater use of cardio-active drugs in Perth apparently did not result in improved short-term outcome although potential long-term benefits cannot be judged yet.

Adult↗
PubMed1993

Genetic algorithms for DNA sequence assembly.

This paper describes a genetic algorithm application to the DNA sequence assembly problem. The genetic algorithm uses a sorted order representation for representing the orderings of fragments. Two different fitness functions, both based on pairwise overlap strengths between fragments, are tested. The paper concludes that the genetic algorithm is a promising method for fragment assembly problems, achieving usable solutions quickly, but that the current fitness functions are flawed and that other representations might be more appropriate.

Algorithms↗
PubMed1992

Spacing is crucial for coordination of domain functions within the simian virus 40 core origin of replication.

The simian virus 40 core origin of replication is composed of distinct domains that are bracketed by DNA spacers. We created a matched set of insertion mutations in spacer sites to study the spatial relationships among origin domains. Insertions larger than a single base pair severely inhibit replication regardless of the helical phasing between domains. Replication-defective mutations reduce T-antigen binding and T-antigen-induced KMnO4 modifications of DNA to various extents. Mutations in the early half of the origin reduce T-antigen functions in the entire origin, whereas mutations in the late half reduce functions only in that half. Surprisingly, some mutations that severely inhibit DNA replication reduce T-antigen-induced melting and other structural changes within origin DNA to only a limited extent. In contrast, all replication-defective origin mutations prevent T antigen from extending the primary replication bubble beyond the limits of the core origin of replication. We conclude, therefore, that T-antigen-induced events within the core origin must be spatially coordinated for conversion of T-antigen hexamers bound to the core origin into mobile helicase units.

Base Sequence↗
PubMed1992

Successful managed care: serving four masters.

Successful managed care requires serving four masters: the consumer, the employer, the hospital, and the physician. Managed care organizations that deal with these key issues effectively are more likely to achieve success (see Table 1). Managed care entities must recognize and respond to the needs of the four masters. While it is true that no one plan can provide everything for each party, each managed care entity can and should determine those aspects that are of greatest importance to them (see Table 2).

Consumer Behavior↗
PubMed1990

Effects of cromakalim, pinacidil and nicorandil on cardiac refractoriness and arterial pressure in open-chest dogs.

The cardiac electrophysiologic effects of the potassium channel activators cromakalim, pinacidil and nicorandil were determined in anesthetized open-chest normotensive dogs using conventional surface electrogram recording techniques. Intravenous administration of cromakalim (0.025-0.5 mg/kg), pinacidil (0.1-2.0 mg/kg) and nicorandil (0.1-2.5 mg/kg) produced large dose-dependent decreases in arterial blood pressure accompanied by smaller reductions of atrial and ventricular effective refractory periods. The shortening of refractoriness was more pronounced in the atrium than in the ventricle and was similar for all three compounds at a given level of hypotension. Effects on other electrophysiological parameters were minimal. Atrial arrhythmias could be induced during electrical pacing at doses of cromakalim and pinacidil producing excessive (greater than or equal to 40%) decreases in mean arterial pressure. No arrhythmias were observed with nicorandil. Induction of the arrhythmias appeared to be closely coupled to the extrastimuli (S2) used to determine refractory periods and was associated with a significant reduction in atrial refractory period (greater than or equal to 30%). No ventricular arrhythmias were observed in this study with any of the compounds tested. Although the plasma levels reached in this study are likely to be higher than those seen clinically, the results nevertheless suggest the potential for cardiac electrophysiologic effects by these agents.

Animals↗
PubMed1990

Three domains in the simian virus 40 core origin orchestrate the binding, melting, and DNA helicase activities of T antigen.

The simian virus 40 (SV40) core origin of replication consists of three functional domains. The sequence 5'-CACTACTTCTGGAATAG-3' with an imperfect inverted repeat (underlined), a palindrome with four 5'-GAGGC-3' pentanucleotide repeats, and a 17-base-pair A + T-rich segment. We have been able to assign primary functions to each domain. Remarkably, SV40 large T antigen melted the inverted repeat domain in the complete absence of other origin sequences. Presumably, this protein-DNA interaction initiates a replication bubble that leads to daughter strand DNA synthesis. The pentanucleotide domain alone docked and arranged T antigen at the origin. The A + T-rich domain had no independent function, but, in the presence of the other two domains, allowed bound T antigen to extend the replication bubble. Thus, three domains of the origin coordinate the binding, melting, and DNA helicase activities of T antigen in an ordered sequence of events to initiate DNA replication.

Antigens, Polyomavirus Transforming↗
PubMed1990

Tarsal tunnel syndrome. Comprehensive review of 87 cases.

The results of the study indicate that tarsal tunnel syndrome is a pathologic condition in which there are multiple etiologies, which in some cases are poorly defined. In order to arrive at a definitive diagnosis, all available tests, including pathology reports, are important. Where proper diagnosis is made and followed with appropriate adjunctive care, the probability of recurrence will be minimized. Statistical information in itself is of some value, because it may help the podiatrist to more clearly diagnose and treat the patients in whom vague or general symptoms may exist.

Female↗
PubMed1989

The zinc finger region of simian virus 40 large T antigen.

Simian virus 40 large T antigen contains a single sequence element with an arrangement of cysteines and histidines that is characteristic of a zinc finger motif. The finger region maps from amino acids 302 through 320 and has the sequence Cys-302LeuLysCys-305IleLysLysGluGlnProSerHisTyrLysTyrHis- 317GluLysHis-320. In a conventional representation, the binding of zinc to the cysteines and histidines at positions 302, 305, 317, and 320 would form two minor loops and one major loop from the intervening amino acids. We made single amino acid substitutions at every position in the finger to identify possible functional elements within the putative metal-binding domain. Amino acids in the zinc finger could be divided into three classes characterized by distinct roles in DNA replication and transformation. Class 1 consisted of amino acids in the two minor loops of the finger and in the amino-terminal part of the major loop. Mutations here did not affect either replication or transformation. Class 2 consisted of the SerHisTyrLysTyr amino acids located in the carboxy terminus of the major loop of the finger. Mutations in this contiguous region reduced replication of the mutant viruses to different degrees. This clustering suggested that the region is an active site important for a specific function in DNA replication. With the exception of a mutation in the histidine at position 313, these mutations had no effect on transformation. Class 3 consisted of the proposed zinc-binding amino acids at positions 302, 305, 317, and 320 and the histidine at position 313 in the major loop of the finger. Mutations in these amino acids abolished the viability of the virus completely and had a distinctive effect on the transforming functions of the protein. Thus, the five cysteines and histidines of class 3 may play an important role in determining the overall structure of the protein. The histidine at position 313 may function both in the active site where it is located and in cooperation with the proposed zinc-binding ligands.

Amino Acid Sequence↗
PubMed1987

Frankia vesicles provide inducible and absolute oxygen protection for nitrogenase.

When Frankia HFPCcI3 was grown in culture at oxygen O(2) levels ranging from 2 to 70 kilopascals O(2), under nitrogen fixing conditions, nitrogenase activity adapted to ambient pO(2) and showed a marked optimum close to growth pO(2). Vesicles were thin walled at low pO(2) and very thick walled at high pO(2). Freeze fracture transmission electron microscopy confirmed that Frankia produces vesicles with outer walls thickened by multiple lipid-like monolayers, in proportion to ambient pO(2).

Journal Article↗