Biomedical subjects

Dennis K Pearl

Publications and source records attributed to Dennis K Pearl.

7 recordsLinked to original sources

PubMed2005

Taxonomic utility of a phylogenetic analysis of phosphoglycerate kinase proteins of Archaea, Bacteria, and Eukaryota: insights by Bayesian analyses.

We studied 131 protein sequences of the essentially ubiquitous glycolytic enzyme 3-phosphoglycerate kinase (3-PGK) by Bayesian analyses in three Domains: 15 Archaea, 83 Bacteria, and 33 Eukaryota. The posterior distribution of phylogenetic trees developed were based on a uniform prior, the WAG model of protein evolution, Metropolis-Hastings sampling in a Markov chain Monte Carlo analysis, and a package of diagnostics to critically evaluate the validity of the analyses. The 15 Archaea separated with high posterior probability. The archaean Phyla Euryarchaeota and the apparently Euryarchaeota derived Crenarchaeota were monophyletic. The 33 Eukaryota separated into two main groups: the non-chlorophyllous forms with coherent sub-groupings of Euglenozoa, Alveolata, Fungi, and Metazoa and all the chlorophyllous species studied: the Plantae (Viridaeplantae), chlorophyllous Stramenopiles, and the chlorophyllous Bacteria. This association supports other opinions concerning the related lineage of cyanobacteria and the Plantae. The 3-PGK sequences from 83 Bacteria in almost every instance associated by their recognized taxal group: alpha-, beta-, gamma-, epsilon-proteobacteria, Chlamydia, Actinobacteridae, and Firmicutes. Firmicutes sequences were subdivided into three apparently monophyletic groups: the anaerobic Clostridia, the spore-forming Bacillales and a group containing the Mollicutes, Lactobacillales and non-spore-forming Bacillales. The 3-PGK-gene tree assemblage was notable both for its pervasive clustering in three Domains according to recognized taxonomic groupings of Class, Order, Family, and Genus. The 3-PGK enzyme or 3-PGK-like activity may have played a central role in the metabolism of the Universal Ancestor.

Archaea↗

PubMed2005

Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines.

Sphingosine-1-phosphate is a bioactive lipid that is mitogenic for human glioma cell lines by signaling through its G protein-coupled receptors. We investigated the role of sphingosine-1-phosphate receptors and the enzymes that form sphingosine-1-phosphate, sphingosine kinase (SphK)-1, and -2 in human astrocytomas. Astrocytomas of various histologic grades expressed three types of sphingosine-1-phosphate receptors, S1P1, S1P2, and S1P3; however, no significant correlation with histologic grade or patient survival was detected. Expression of SphK1, but not SphK2, in human astrocytoma grade 4 (glioblastoma multiforme) tissue correlated with short patient survival. Patients whose tumors had low SphK1 expression survived a median 357 days, whereas those with high levels of SphK1 survived a median 102 days. Decreasing SphK1 expression using RNA interference or pharmacologic inhibition of SphK significantly decreased the rate of proliferation of U-1242 MG and U-87 MG glioblastoma cell lines. Surprisingly, RNA interference to knockdown SphK2 expression inhibited glioblastoma cell proliferation more potently than did SphK1 knockdown. SphK knockdown also prevented cells from exiting G1 phase of the cell cycle and marginally increased apoptosis. Thus, SphK isoforms may be major contributors to growth of glioblastoma cells in vitro and to aggressive behavior of glioblastoma multiforme.

Adult↗

PubMed2003

The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan.

The inverse relationship between serum albumin concentration and its half-life suggested to early workers that albumin would be protected from a catabolic fate by a receptor-mediated mechanism much like that proposed for IgG. We show here that albumin binds FcRn in a pH dependent fashion, that the lifespan of albumin is shortened in FcRn-deficient mice, and that the plasma albumin concentration of FcRn-deficient mice is less than half that of wild-type mice. These results affirm the hypothesis that the major histocompatibility complex-related Fc receptor protects albumin from degradation just as it does IgG, prolonging the half-lives of both.

Animals↗

PubMed2002

Estimation of evolutionary parameters with phylogenetic trees.

An important issue in the phylogenetic analysis of nucleotide sequence data using the maximum likelihood (ML) method is the underlying evolutionary model employed. We consider the problem of simultaneously estimating the tree topology and the parameters in the underlying substitution model and of obtaining estimates of the standard errors of these parameter estimates. Given a fixed tree topology and corresponding set of branch lengths, the ML estimates of standard evolutionary model parameters are asymptotically efficient, in the sense that their joint distribution is asymptotically normal with the variance-covariance matrix given by the inverse of the Fisher information matrix. We propose a new estimate of this conditional variance based on estimation of the expected information using a Monte Carlo sampling (MCS) method. Simulations are used to compare this conditional variance estimate to the standard technique of using the observed information under a variety of experimental conditions. In the case in which one wishes to estimate simultaneously the tree and parameters, we provide a bootstrapping approach that can be used in conjunction with the MCS method to estimate the unconditional standard error. The methods developed are applied to a real data set consisting of 30 papillomavirus sequences. This overall method is easily incorporated into standard bootstrapping procedures to allow for proper variance estimation.

Animals↗

PubMed2002

Molecular markers that identify human astrocytomas and oligodendrogliomas.

The classification of human gliomas is currently based solely on neuropathological criteria. Prognostic and therapeutic parameters are dependent upon whether the tumors are deemed to be of astrocytic or oligodendroglial in origin. We sought to identify molecular reagents that might provide a more objective parameter to assist in the classification of these tumors. In order to identify mRNA transcripts for genes normally transcribed exclusively by oligodendrocytes. Northern blot analysis was carried out on RNA samples from 138 human gliomas. Transcripts encoding the myelin basic protein (MBP) were found in an equally high percentage of tumors that by neuropathological criteria were either astrocytic or oligodendroglial. In contrast, proteolipid protein (PLP) and cyclic nucleotide phosphodiesterase (CNP) mRNA molecules were found significantly more often in oligodendrogliomas than in astrocytomas. The strongest association with histological typing was found with the transcript for the myelin galactolipid biosynthetic enzyme UDP-galactose: ceramide galactosytransferase (CGT), which was about twice as frequently detected in tumors of oligodendroglial type. Results of glycolipid analyses were previously reported on a subset of the tumors studied herein. Statistical analyses of both molecular and biochemical data on this subset of astrocytomas, oligoastrocytomas, and oligodendrogliomas were performed to determine if a panel of markers could be used to separate astrocytic and oligodendroglial tumors. The presence of asialo GM1 (GA1) and the absence of paragloboside occurred most frequently in oligodendrogliomas. Ceramide monohexoside (CMH) levels correlated highly with the expression of mRNA for 4 myelin proteins: CGT, MBP, CNP, and PLP. The best combination of 2 markers of oligodendroglial tumors was CGT and GA1; the best combination of 3 markers was the presence of CGT, GA1, and the absence of paragloboside. We conclude that this combination of markers could be useful in distinguishing between astrocytic and oligodendroglial tumors.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2002

Combination of drugs and drug-resistant reverse transcriptase results in a multiplicative increase of human immunodeficiency virus type 1 mutant frequencies.

Replication of drug-resistant human immunodeficiency virus type 1 (HIV-1) in the presence of drug can lead to the failure of antiretroviral drug treatment. Drug failure is associated with the accumulation of drug resistance mutations. Previous studies have shown that 3'-azido-3'-deoxythymidine (AZT), (-)2',3'-dideoxy-3'-thiacytidine (3TC), and AZT-resistant HIV-1 reverse transcriptase (RT) can increase the virus in vivo mutation rate. In this study, the combined effects of drug-resistant RT and antiretroviral drugs on the HIV-1 mutant frequency were determined. In most cases, a multiplicative effect was observed with AZT-resistant or AZT/3TC dually resistant RT and several drugs (i.e., AZT, 3TC, hydroxyurea, and thymidine) and led to increases in the odds of recovering virus mutants to over 20 times that of the HIV-1 mutant frequency in the absence of drug or drug-resistance mutations. This observation indicates that HIV-1 can mutate at a significantly higher rate when drug-resistant virus replicates in the presence of drug. These increased mutant frequencies could have important implications for HIV-1 population dynamics and drug therapy regimens.

Animals↗

PubMedDate not supplied

Chemoprevention of oral cancer by black raspberries.

Oral cavity cancers represent 2.5% of the cancers that occur in the United States and are ranked sixth worldwide. Since current therapeutic protocols are relatively ineffective, alternative strategies for prevention need to be developed and tested in appropriate animal models. In the study reported herein, the hamster cheek pouch (HCP) was used to evaluate the ability of black raspberries to inhibit oral cavity tumors. Male Syrian Golden hamsters, 3-4 weeks of age, were fed 5% and 10% lyophilized black raspberries (LBR) in the diet for two weeks prior to treatment with 0.2% 7,12-dimethylbenz(a) anthracene in dimethylsulfoxide and for 10 weeks thereafter. HCPs were painted 3X/week for eight weeks. The animals were sacrificed 12-13 weeks from the beginning of DMBA treatment and the number and volume of tumors (mm3) determined. There was a significant difference (p = 0.02) in the number of tumors between the 5% LBR and control groups (27 tumors/14 animals and 48 tumors/15 animals, respectively) and an intermediate number of tumors in the 10% berry-treated animals (39 tumors/15 animals). These experiments support previous studies from our laboratories showing the chemopreventive activity of black raspberries and show, for the first time, that dietary black raspberries will inhibit tumor formation in the oral cavity.

9,10-Dimethyl-1,2-benzanthracene↗