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PubMed1983

Cellular fatty acid and soluble protein profiles of oral fusobacteria.

We compared the cellular fatty acid and protein content of 43 strains of oral fusobacteria isolated from patients with chronic gingivitis, acute necrotizing ulcerative gingivitis, and juvenile and adult periodontitis, as well as from the stump-tailed macaque, to that of eight reference strains of oral and non-oral Fusobacterium species. A gas-liquid chromatographic examination of trimethylsilyl derivatives of the fatty acid methyl esters revealed n14:0, 3-OH-14:0, n16:0, 16:1, 3-OH-16:0, n18:0, and 18:1 in each of the 51 study strains, and a variable occurrence of 14 other fatty acids. The n16:0 to 3-OH-16:0 ratio distinguished between Fusobacterium nucleatum and the non-oral species Fusobacterium varium, Fusobacterium necrophorum, Fusobacterium russii, Fusobacterium necrogenes, Fusobacterium mortiferum, and Fusobacterium naviforme. The soluble protein content, as determined by polyacrylamide gel electrophoresis, varied considerably among the oral fusobacterial strains studied, and underscored the heterogenous nature of these organisms. "Fingerprinting" of oral fusobacteria may be readily accomplished by polypeptide analysis.

Animals↗

PubMed2006

Regulation of the G1/S phase of the cell cycle and alterations in the RB pathway in human lung cancer.

The retinoblastoma (RB)-Cyclin (CCN)D1-p16 cell cycle pathway has a crucial role in lung tumorigenesis. Impairment of the RB pathway has been shown to occur in almost all lung tumors. A deregulation at any level of this core RB pathway seems to make cells insensitive to the mitogenic signaling that is required for cell cycle progression. To date, almost all participants in this pathway have been shown to be altered to a various degree in lung tumors. Some of the alterations are mutually exclusive, including RB and p16INK4A . In small cell lung cancer, the RB tumor suppressor gene is inactivated in almost 90% of the tumors, whereas in non-small cell lung cancer, the cyclin-dependent kinase (CDK)4 inhibitor p16INK4A is inactivated in 40-60% of the tumors. Many mechanisms may be responsible for activating the RB-Cyclin D1 pathway, including activating (CDK4) and inactivating mutations (p16INK4A ), deletions (RB and p16INK4A ), amplifications (CCND1 and CDK4), silencing methylation (p16INK4A and RB), and hyper-phosphorylation (RB). As some of these alterations, such as p16INK4A methylation, can also be detected in bronchial lavage and serum, they could potentially serve as useful markers for the early detection of lung cancer. This review summarizes recent experiments describing the variable roles of key-player molecules of the RB pathway and different mechanisms by which the RB pathway can be altered in lung cancer.

Animals↗

PubMed2006

Solvent sublation and spectrometric determination of iron(II) and total iron using 3-(2-pyridyl)-5,6-bis(4-phenylsulfonic acid)-1,2,4-triazine and tetrabutylammonium bromide.

Solvent sublation has been studied for the separation and determination of trace iron(II) in various kinds of water samples. A strongly magenta-colored anionic [Fe(FZ)3](4-) complex was formed at pH 5.0 upon adding 3-(2-pyridyl)-5,6-bis(4-phenylsulfonic acid)-1,2,4-triazine (ferrozine, FZ) to the sample solution. Tetrabutylammonium bromide (TBAB) was added in the solution to form the (TBA)4[Fe(FZ)3)] ion pair, and an oleic acid (HOL) surfactant was added. Then, the (TBA)4[Fe(FZ)3] ion pairs were floated by vigorous shaking in the flotation cell and extracted into methyl isobutyl ketone (MIBK) on the surface of the aqueous solution. The iron collected in the MIBK layer was measured directly by spectrophotometry and/or flame atomic-absorption spectrophotometry. Different experimental variables that may affect the sublation efficiency were thoroughly investigated. The molar absorptivity of the (TBA)4[Fe(FZ)3] ion pair was 2.8 x 10(4) l mol(-1) cm(-1) in the aqueous layer. Beer's law held up to 1.0 mg L(-1) Fe(II) in the aqueous as well as in the organic layers. The adopted solvent sublation method was successfully applied for the determination of Fe(II) in natural water samples with a preconcentration factor of 200. The application was extended to determine iron in pharmaceutical samples.

Dose-Response Relationship, Drug↗

PubMed2000

Immunoquantitation of FMO1 in human liver, kidney, and intestine.

To determine the level of FMO1 protein present in human liver tissues, a monospecific antibody was prepared and a sensitive Western blotting procedure with enhanced chemiluminescence detection was developed. Human FMO1, purified from insect cells expressing the recombinant protein, was used as a protein standard for absolute quantification. The average concentrations of FMO1 in microsomes prepared from human liver, kidney, intestine, and fetal liver were found to be <1, 47 +/- 9, 2.9 +/- 1.9, and 14.4 +/- 3.5 pmol/mg, respectively. Quantitation in intestinal microsomes was complicated by variable degrees of proteolytic degradation of FMO1, not seen in microsomes prepared from liver or kidney. Recombinant human FMO1 and detergent-solubilized human duodenal microsomes both metabolized p-tolyl methyl sulfide stereoselectively to the (R)-sulfoxide, indicating the expression of functional FMO1 in human intestine. The relatively high levels of immunoquantifiable FMO1 in human kidney and fetal liver complement our previous catalytic studies in these tissues, which also demonstrated preferential (R)-p-tolyl methyl sulfoxide formation. These data demonstrate a profound ontogenic change in expression of hepatic FMO1 in humans, such that in adult life FMO1 is exclusively an extrahepatic drug-metabolizing enzyme. The marked expression levels of FMO1 found in human kidney coupled to the high catalytic activity of this isoform toward a diverse array of sulfides and tertiary amines suggest the possibility that human renal FMO1 is a significant contributor to the metabolic clearance of drugs and other xenobiotics bearing these functionalities.

Adolescent↗

PubMed1992

Application of neural networks to the interpretation of laboratory data in cancer diagnosis.

Neural networks are a relatively new method of multivariate analysis. The purpose of this study was to investigate the ability of neural networks to differentiate benign from malignant breast conditions on the basis of the pattern of nine variables: patient age, total cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B, albumin, the tumor marker CA15-3, and the Fossel index (measurement of methylene and methyl line-widths in proton NMR spectra). The laboratory analyses were made with blood plasma or serum specimens. The neural network was "trained" with 57 patients: 23 patients with breast malignancies and 34 patients with benign breast conditions. A neural network with nine input neurons, 15 hidden neurons, and two output neurons correctly classified all 57 patients. The ability of the network to predict the diagnoses of patients that it had no encountered in training was tested with a separate group (cross-validation group) of 20 patients. The network correctly predicted the diagnoses for 80% of these patients. For comparison we analyzed the same sets of 57 training patients and 20 cross-validation patients by quadratic discriminant function analysis. The quadratic discriminant function, calculated from the same 57 patients used to train the neural network, correctly classified 84% of the 57 patients, and correctly diagnosed 75% of the 20 cross-validation patients. The results suggest that neural networks are a potentially useful multivariate method for optimizing the diagnostic utility of laboratory data.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed1987

Acyclonucleoside analogues consisting of 5- and 5,6-substituted uracils and different acyclic chains: inhibitory properties vs purified E. coli uridine phosphorylase.

Synthetic procedures are described for the preparation of a variety of pyrimidine acyclonucleoside analogues, in which the aglycones are 5- and 5,6-substituted uracils, and the ribose moiety is replaced by different acyclic chains. These were examined as potential inhibitors of purified E. coli uridine phosphorylase. None of the compounds was a substrate for uridine phosphorylase, or either a substrate or inhibitor of E. coli thymidine phosphorylase. Kinetic measurements were employed to determine inhibition constants, Ki, for inhibition of uridine phosphorylase. One of the more effective of these was 1-(1',3'-dihydroxy-2'-propoxy)methyl-5,6-tetramethyleneuracil, with Ki = 2.7 microM. The same compound was a reasonably good inhibitor of the reverse, synthetic, reaction, with Ki values of 19 microM vs uracil as the variable substrate, and 15 microM vs alpha-D-ribose-1-phosphate as the variable substrate. For one of the analogues, which was a racemate, 1-(2',3'-dihydroxypropyl)-5,6-tetramethyleneuracil, it was shown that only one of the enantiomers (R) was an inhibitor, the (S) enantiomer being totally inactive. For several of the analogues, the corresponding isomeric N(3)-acyclonucleosides were inactive as inhibitors. The results for several of the good inhibitors were compared with those of other observers for inhibition of uridine phosphorylase from mammalian sources. Preliminary measurements with several of our analogues demonstrated that some of them were indeed one to two orders of magnitude more effective against the enzyme from mammalian sources.

Escherichia coli↗

PubMed1996

Exact size and organization of DNA target-recognizing domains of multispecific DNA-(cytosine-C5)-methyltransferases.

A large portion of the sequences of type II DNA-(cytosine-C5)-methyltransferases (C5-MTases) represent highly conserved blocks of amino acids. General steps in the methylation reaction performed by C5-MTases have been found to be mediated by some of these domains. C5-MTases carry, in addition at the same relative location, a region variable in size and amino acid composition, part of which is associated with the capacity of each C5-MTase to recognize its characteristic target. Individual target-recognizing domains (TRDs) for the targets CCGG (M), CC(A/T)GG (E), GGCC (H), GCNGC (F) and G(G/A/T)GC(C/A/T)C (B) could be identified in the C-terminal part of the variable region of multispecific C5-MTases. With experiments reported here, we have established the organization of the variable regions of the multispecific MTases M.SPRI, M.phi3TI, M.H2I and M.rho 11SI at the resolution of individual amino acids. These regions comprise 204, 175, 268 and 268 amino acids, respectively. All variable regions are bipartite. They contain at their N-terminal side a very similar sequence of 71 amino acids. The integrity of this sequence must be assured to provide enzyme activity. Bracketed by 6-10 'linker' amino acids, they have, depending on the enzyme studied, towards their C-terminal end ensembles of individual TRDs of 38 (M), 39 (E), 40 (H), 44 (F) and 54 (B) amino acids. TRDs of different enzymes with equal specificity have the same size. TRDs do not overlap but are either separated by linker amino acids or abut each other.

Amino Acid Sequence↗

PubMed1996

Biological implications of magnesium salts at the molecular level.

The interaction of Mg2+ cations in biological systems is studied by using nucleic acid bases as the biological system. Magnesium salts, such as, MgCl2 6H2O, MgSO4. 7H2O and Mg(ClO4). XH2O have been employed in order to compare their complexation with cytosine and 1-methyl cytosine crystallize in water solutions. The reaction of the above magnesium salts with the two bases has been followed by attempting to crystallization the complexes formed at constant temperature and variable times of crystallization. The water solutions with the above reagents have also been followed by Fourier Transform infrared.

Biological Factors↗

PubMed1988

The sequential hypothesis on sleep function. II. A correlative study between sleep variables and newly synthesized brain DNA.

The information acquired by brain during wakefulness (W) may be processed in two sequential steps occurring during synchronized sleep (SS) and paradoxical sleep (PS), respectively. On the assumption that brain molecules synthesized during the acquisition step undergo a comparable sleep processing, we have designed an experiment aimed at the verification of the sequential hypothesis. Groups of adult female Wistar rats received [3H-methyl] thymidine by intraventricular injection 30 min before being exposed to a 4 hr session of a two-way active avoidance training. Animals failing to achieve the learning criterion were further allowed a period of 3 hr during which they were left free to sleep, or were deprived of PS or of total sleep. Control rats were similarly treated, but were left in their home cages in the same training room during the period of acquisition. The results of correlative study among behavioral, sleep and biochemical variables demonstrate that the specific radioactivity of DNA in the cerebral cortex, cerebellum and brainstem is correlated with several variables of postacquisition sleep, mostly SS parameters. The correlations depend on the previous waking experience of the rats. The data substantiate the two main consequences of the hypothesis, i.e., (1) the involvement of SS in brain information processing; and (2) the dependence of the operations performed by the sleeping brain on the nature of the previous waking experience. The results also provide some insight into the kind of processing which occurs in the sleeping brain.

Animals↗

PubMed1996

The role of N-methyl-D-aspartate (NMDA) receptors in wind-up: a mathematical model.

We present a mathematical model for the phenomenon of wind-up (Mendell, 1966, Exper. Neur. 16,316-22) which occurs in many neurons. We concentrate on its occurrence in the substantia gelatinosa of the dorsal horns of the spinal cord, where it is connected with certain pathological and nonpathological pain states. The model is a development of the model by Britton & Skevington (1989, J. Theor. Biol. 137, 91-105) for Melzack & Wall's gate control theory of pain (1965, Science, New York, 150, 971-9; 1982, The Challenge of Pain, Penguin: Harmondsworth), modified to take account of more recent information. Its variables are the electric potentials of various cells in the midbrain and the spinal cord. Britton & Skevington's original model simulated many of the phenomena observed in acute pain in humans, but not the wind-up mechanism. This is not surprising, since this model did not include the N-methyl-D-aspartate (NMDA) receptors that are now recognized as being crucial to the phenomenon. Here we rectify this omission, and obtain good agreement between the model and experimental data on wind-up. The positive feedback that NMDA receptors exhibit is shown to be the essential feature in producing wind-up. As an independent test of the model we simulate a completely different experimental set-up, and obtain good qualitative agreement with data there. Finally, we present a prediction of the model that has yet to be tested experimentally.

Animals↗

PubMedDate not supplied

AMPA-selective glutamate receptor subtype immunoreactivity in the hippocampal dentate gyrus of patients with Alzheimer disease. Evidence for hippocampal plasticity.

Immunocytochemical techniques were employed in order to examine the distribution and relative intensity of immunolabeling of the alpha-amino-3-hydroxy-5-methyl-4-isoaxolepropionate (AMPA) receptor subunits GluR1 and GluR2/3 within the hippocampal formation of patients with Alzheimer disease (AD). Within sectors of the hippocampus that are particularly vulnerable to AD pathology (i.e., CA1, subiculum), we observed a variable loss of GluR1 and GluR2/3 immunolabeling correlating with the extent of cell loss and neurofibrillary pathology. In contrast, in less vulnerable sectors of the hippocampus (i.e., CA2/3, dentate gyrus), the intensity of immunolabeling was markedly increased in AD cases, particularly in the molecular and polymorphic layers of the dentate gyrus. Importantly, these latter regions correspond to termination zones of glutamatergic perforant pathway axons and mossy fiber collaterals, respectively. The increase in immunolabeling within these projection fields is hypothesized to occur in response to the deafferentation of selected glutamatergic pathways, and suggests a critical role for AMPA receptor subunits in hippocampal plasticity.

Aged↗

PubMed1988

Cobalamin-dependent methionine synthase from Escherichia coli B: electron paramagnetic resonance spectra of the inactive form and the active methylated form of the enzyme.

Cobalamin-dependent methionine synthase (5-methyltetrahydrofolate-homocysteine methyltransferase, EC 2.1.1.13) has been isolated from Escherichia coli B in homogeneous form. The enzyme is isolated in an inactive form with the visible absorbance properties of cob(II)alamin. The inactive enzyme exhibits an electron paramagnetic resonance (EPR) spectrum at 38 K that is characteristic of cob(II)alamin at acid pH, where the protonated dimethylbenzimidazole substituent is not coordinated with the cobalt nucleus (base-off cobalamin). An additional, variable component of the EPR spectrum of the inactive enzyme has the characteristics of a cob(III)alamin-superoxide complex. Previous work by others [Taylor, R.T., & Weissbach, H. (1969) Arch. Biochem. Biophys. 129, 745-766. Fujii, K., & Huennekens, F.M. (1979) in Biochemical Aspects of Nutrition (Yagi, K., Ed.) pp 173-183, Japan Scientific Societies, Tokyo] has demonstrated that the enzyme can be activated by reductive methylation using adenosylmethionine as the methyl donor. We present data indicating that the conversion of inactive to methylated enzyme is correlated with the disappearance of the EPR spectrum as expected for the conversion of paramagnetic cob(II)alamin to diamagnetic methylcobalamin. When the methyl group is transferred from the methylated enzyme to homocysteine under aerobic conditions, cob(II)alamin/cob(III)alamin-superoxide enzyme is regenerated as indicated by the return of the visible absorbance properties of the initially isolated enzyme and partial return of the EPR spectrum. Our enzyme preparations contain copper in approximately 1:1 stoichiometry with cobalt as determined by atomic absorption spectroscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed2025

A comprehensive atlas of full-length Arabidopsis eccDNA populations identifies their genomic origins and epigenetic regulation.

Extrachromosomal circular DNA (eccDNA) has been described in several eukaryotic species and has been shown to impact phenomena as diverse as cancer and herbicide tolerance. EccDNA is thought to arise mainly through transposable element (TE) mobilization. Because studies based on short-read sequencing cannot efficiently identify full-length eccDNA forms generated from TEs, we employed the CIDER-Seq pipeline based on long-read sequencing, to obtain full-length eccDNAs from Arabidopsis. The generated eccDNA datasets identified centromeric/pericentromeric regions as hotspots of eccDNAs with several eccDNA molecules originating from Helitron and LTR TEs. To investigate the role of epigenetic marks on TE-derived eccDNA biogenesis, we studied Arabidopsis methylation mutants dcl3, rdr6, ros1, and ddm1. Contrasting the TE-suppression previously reported in the hypermethylated ros1 mutants, we identified activation of TEs in ros1, specifically of LTR/Gypsy TEs. An enrichment of LTR/Copia elements was identified in actively dividing calli and the shoot apical meristem (SAM). Uncharacterized "variable TEs" with high eccDNA and expression were identified in the SAM, including ATCOPIA58. Together, our study reveals the genomic origins of eccDNAs and delineates the link between epigenetic regulation, transposon mobilization, and eccDNA biogenesis.

Arabidopsis↗

PubMed1987

Retardation of cell cycle progression in yeast cells recovering from DNA damage: a study at the single cell level.

Pedigree analyses of individual yeast cells recovering from DNA damage were performed and time intervals between morphological landmark events during the cell cycle (bud emergence and cell separation), were recorded for three generations. The associated nuclear behavior was monitored with the aid of DAPI staining. The following observations were made: All agents tested (X-rays, MMS, EMS, MNNG, nitrous acid) delayed the first bud emergence after treatment, which indicates inhibition of the initiation of DNA replication. Cells that survived X-irradiation progressed further through the cell cycle in a similar way to control cells. Progress of chemically treated cells became extremely asynchronous because surviving cells stayed undivided for periods of varying length. Prolongation of the time between bud emergence and cell separation was most pronounced for cells treated with the alkylating agents MMS and EMS. This is interpreted as retardation of ongoing DNA synthesis by persisting DNA adducts. Cell cycle prolongation in the second and third generation after treatment was observed only with MMS treated cells. In all experiments, individual cells of uniformly treated populations exhibited highly variable responses.

Cell Cycle↗

PubMed1991

Genotype-treatment interaction between amantadine and chlorpromazine in the mouse.

1. Repeated administration of amantadine prior to chlorpromazine to two different strains of mice altered both locomotor activity, concentrations of brain biogenic amines and selected major metabolites as a function of mouse strain. 2. Amantadine antagonized chlorpromazine effect on motility which was associated with increases in whole brain levels of homovanillic acid in the CDF-1 but not C57BL/6 mice. 3. Conversely, the treatment with amantadine prior to chlorpromazine reduced whole brain normetanephrine and 5-hydroxyindoleacetic acid levels from respective controls in the C57BL/6 and CDF-1 mice, respectively. 4. The results suggest that genetic factors underly differential alteration of brain dopamine and serotonin which may underly the mechanism of amantadine efficacy in neuroleptic-induced extrapyramidal disorders and to the variable responses to amantadine therapy.

Amantadine↗

PubMed1998

[Comparative hemodynamic effects of sevoflurane and halothane at tele-expiratory concentration in intubation of infants].

OBJECTIVE: To compare the cardiovascular changes at the end-tidal concentrations of sevoflurane versus halothane required for tracheal intubation in infants (intubation MAC). STUDY DESIGN: Prospective randomized study. PATIENTS: Thirty-two infants, ASA physical status 1 or 2, scheduled for elective surgery, randomized to receive either halothane or sevoflurane for anaesthetic induction by inhalation. METHODS: Cardiovascular and echocardiographic data were recorded in both groups at baseline, and at the end-tidal concentrations needed for intubation. RESULTS: Intubation MAC was significantly less with sevoflurane than with halothane in infants. Sevoflurane did not change heart rate (HR) and cardiac index (CI) compared to values when awake. Sevoflurane significantly decreased blood pressure, systemic vascular resistance (SVR) and shortening fraction (SF). Myocardial contractility assessed by stress-velocity index (SVI) and stress-shortening index (SSI) decreased significantly at the intubation MAC, but did not fall into the abnormal range. Halothane caused a greater decrease in HR, SF, SSI, and CI than sevoflurane. CONCLUSIONS: Sevoflurane decreases cardiac output less than halothane in infants at the intubation MAC, due to a lower end-tidal concentration at intubation MAC and to less effects on haemodynamic variables.

Anesthetics, Inhalation↗

PubMed2000

Characterization of MLH1 and MSH2 DNA mismatch repair proteins in cell lines of the NCI anticancer drug screen.

PURPOSE AND METHODS: The lack of a functional DNA mismatch repair (MMR) pathway has been recognized as a common characteristic of several different types of human cancers due to mutation affecting one of the MMR genes or due to promoter methylation gene silencing. These MMR-deficient cancers are frequently resistant to alkylating agent chemotherapy such as DNA-methylating or platinum-containing compounds. To correlate drug resistance with MMR status in a large panel of human tumor cell lines, we evaluated by Western blot the cellular levels of the two MMR proteins most commonly mutated in human cancers, MLH1 and MSH2, in the NCI human tumor cell line panel. This panel consists of 60 cell lines distributed among nine different neoplastic diseases. RESULTS: We found that in most of these cell lines both MLH1 and MSH2 were expressed, although at variable levels. Five cell lines (leukemia CCRF-CEM, colon HCT 116 and KM12 and ovarian cancers SK-OV-3 and IGROV-1) showed complete deficiency in MLH1 protein. MSH2 protein was detected in all 57 cell lines studied. Absence of MLH1 protein was always linked to resistance to the methylating chemotherapeutic agent temozolomide. This resistance was independent of cellular levels of O6-alkylguanine DNA alkyltransferase. Based on data available for review in the NCI COMPARE database, cellular levels of MLH1 and MSH2 did not correlate significantly with sensitivity to any standard anticancer drug or with any characterized molecular target already tested against the same panel of cell lines. CONCLUSION: Based on evaluation of 60 tumor cell lines in the NCI anticancer drug screen, MLH1 deficiency was more common than MSH2 deficiency and was always associated with a high degree of temozolomide resistance. These data will enable correlations with other drug sensitivities and molecular targets in the COMPARE database to evaluate linked processes in tumor drug resistance.

Adaptor Proteins, Signal Transducing↗

PubMed1987

Blockade of "NMDA" receptors disrupts experience-dependent plasticity of kitten striate cortex.

Intracortical infusion of the "N-methyl-D-aspartate" (NMDA) receptor blocker D,L-2-amino-5-phosphonovaleric acid (APV) renders kitten striate cortex resistant to the effects of monocular deprivation. In addition, 1 week of continuous APV treatment (50 nanomoles per hour) produces a striking loss of orientation selectivity in area 17. These data support the hypothesis that crucial variables for the expression of activity-dependent synaptic modifications are a critical level of postsynaptic activation and calcium entry through ion channels linked to NMDA receptors.

2-Amino-5-phosphonovalerate↗