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PubMed2002

A unique, bifunctional site-specific DNA recombinase from Mycoplasma pulmonis.

Site-specific DNA invertible elements often control the production of bacterial surface proteins that are subject to phase variation (ON/OFF switching). Inversion of the DNA element occurs as a result of the reciprocal exchange of DNA catalysed by a specialized enzyme (recombinase) that acts at specific sites. By continually switching the orientation of the invertible element in the chromosome, and consequently the production of the variable protein(s), the cell population remains continually responsive to environmental change such as immunological challenge. In addition to phase-variable surface proteins, Mycoplasma pulmonis has a family of phase-variable restriction-modification enzymes. We report here that a single recombinase in M. pulmonis, HvsR, catalyses independent DNA inversions at non-homologous loci, causing variations in surface lipoproteins and in the DNA recognition sequence specificity of restriction enzymes. Thus, HvsR is a site-specific DNA recombinase with dual substrate specificity.

Bacterial Proteins↗
PubMed1995

Pharmacokinetic and pharmacodynamic studies of centrally acting drugs in rat: effect of pentobarbital and chlorpromazine on electroencephalogram in rat.

Electroencephalogram (EEG) alterations in rat after the i.v. administration of pentobarbital (PTB) and chlorpromazine (CPZ) were measured by power spectral analysis. The time courses of PTB concentrations in plasma, cerebrospinal fluid (CSF) and brain were determined after the i.v. administration of PTB (20, 40 mg/kg) by GC-MS. The PTB concentrations in plasma, CSF and brain could be described by a biexponential equation, a CSF model and a blood flow limited model, respectively. The relationship between the alteration of EEG and the PTB concentrations in the CSF or brain or the effect compartment were analyzed using the sigmoid Emax model. The alteration of EEG after PTB administration could be described by the PTB concentration in these compartments using the sigmoid Emax model. These results indicated that the site of action for the alteration of EEG after PTB administration is in instantaneous equilibrium with the CSF, the brain and the effect compartment. Thus, alterations in EEG after PTB administration can be predicted by monitoring the total PTB concentration in plasma. The alteration of EEG after i.v. administration of CPZ (4 mg/kg) showed a two-phase variation. Although the relationship between the alteration of EEG and the CPZ concentrations in CSF or the striatum or the effect compartment (total and free drug) were analyzed using the linear model, the Emax model or the sigmoid Emax model, the two-phase alteration of EEG after CPZ administration could not be described by any of these models. These results indicated that the pharmacokinetic and pharmacodynamic modeling of CPZ during the alteration of EEG may be complicated due to several pharmacokinetic and pharmacodynamic factors, such as an alteration of the free fraction of CPZ in the striatum, the formation of active metabolites, and two different intrinsic effects of CPZ on the EEG (one in an increase and the other in a decrease of the brain's electrical activity.

Animals↗
PubMed2004

Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population.

The extent of genetic variation found in drug metabolism genes and its contribution to interindividual variation in response to medication remains incompletely understood. To better determine the identity and frequency of variation in 11 phase I drug metabolism genes, the exons and flanking intronic regions of the cytochrome P450 (CYP) isoenzyme genes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5 were amplified from genomic DNA and sequenced. A total of 60 kb of bi-directional sequence was generated from each of 93 human DNAs, which included Caucasian, African-American and Asian samples. There were 388 different polymorphisms identified. These included 269 non-coding, 45 synonymous and 74 non-synonymous polymorphisms. Of these, 54% were novel and included 176 non-coding, 14 synonymous and 21 non-synonymous polymorphisms. Of the novel variants observed, 85 were represented by single occurrences of the minor allele in the sample set. Much of the variation observed was from low-frequency alleles. Comparatively, these genes are variation-rich. Calculations measuring genetic diversity revealed that while the values for the individual genes are widely variable, the overall nucleotide diversity of 7.7 x 10(-4) and polymorphism parameter of 11.5 x 10(-4) are higher than those previously reported for other gene sets. Several independent measurements indicate that these genes are under selective pressure, particularly for polymorphisms corresponding to non-synonymous amino acid changes. There is relatively little difference in measurements of diversity among the ethnic groups, but there are large differences among the genes and gene subfamilies themselves. Of the three CYP subfamilies involved in phase I drug metabolism (1, 2, and 3), subfamily 2 displays the highest levels of genetic diversity.

Asia, Southeastern↗
PubMed2005

Analysis of the role of HP0208, a phase-variable open reading frame, and its homologues HP1416 and HP0159 in the biosynthesis of Helicobacter pylori lipopolysaccharide.

The roles of the three ORFs HP0208, HP0159 and HP1416 in the biosynthesis of Helicobacter pylori 26695 LPS were investigated in this study. These ORFs represent a paralogous family of genes with homology to the Salmonella enterica serovar Typhimurium (hereafter referred to as S. typhimurium) waaJ gene, which encodes an alpha-1,2-glycosyltransferase required for core LPS biosynthesis. HP0208 contains multiple tandem repeats of the dimer 5'GA at its 5' end and its expression is predicted to be subject to phase variation. The number of 5'GA repeats present in this ORF was found to be non-permissive for the expression of HP0208 in the majority of H. pylori strains examined. To determine a role for this ORF in LPS biosynthesis a non-phase-variable, constitutively expressed variant of HP0208 was constructed and introduced into the genome of H. pylori 26695. Analysis of the LPS profile of this strain by Tricine-SDS-PAGE and immunoblotting with anti-Lewis Y antigen (Le(y)) mAbs confirmed a role for HP0208 in the biosynthesis of core LPS. A role for HP0159 and HP1416 in the biosynthesis of core LPS was also established. Although homologous to waaJ, H. pylori HP0208, HP0159 and HP1416 failed to complement an S. typhimurium waaJ mutant, suggesting that these ORFs encode functionally different enzymes.

Bacterial Proteins↗
PubMed1977

Prolactin and murine mammary tumorigenesis: a review.

It is unequivocal that prolactin is an influential hormone in murine mammary tumorigenesis. The Berenblum hypothesis (7), a well-known theoretical model of tumorigenesis that depicts this oncogenic process as a two-step mechanism, i.e., initiation and promotion, is a conceptual scheme in which the action of prolactin in mammary tumorigenesis may be understood. According to this conceptual model, prolactin would participate in both the initiation and promotion steps of mammary tumorigenesis, In the initiation phase, variations in prolactin secretion appear to influence the metabolism of the mammary epithelium, so that the epithelium would be either more receptive to or refractory to an initiating agent (e.g., chemical carcinogen, physical carcinogens, oncogenic viruses, ets.) i.e., a permissive action. In the promotion phase, prolactin may act as either a promoter or an antipromoter of the "transformed" mammary epithelium. In promotion, the hormone may either directly or indirectly (via the ovary) stimulate mitotic activity of the "transformed" epithelium. In antipromotion the hormone, in the presence of requisite hormones (e.g., glucocorticoids), may synergistically induce differentiation (e.g., lactation) in the "transformed" epithelium. A tumor would result in the former (promotion) but not in the latter (antipromotion) case. Whether or not prolactin is significantly influential in human breast tumorigenesis remains to be determined. This is an extremely important area of research which is justifiably receiving increased attention. For if prolactin can be shown to influence human breast epithelium in a manner similar to its effect on rodent mammary tissue, then prophylactic and/of chemotherapeutic control of human breast tumorigenesis may be feasible by appropriate drug-mediated prolactin suppression.

Adrenal Glands↗
PubMed1987

Developing antler, a model for endocrine regulation of bone growth. Concentration gradient of T3, T4, and alkaline phosphatase in the antler, jugular, and the saphenous veins.

Thyroxine (T4), triiodothyronine (T3), and alkaline phosphatase (AP) were assayed monthly in white-tailed deer plasma obtained from the antler (A), jugular (J), and the saphenous (S) veins during the period of antler growth and the period of mineralization. The concentrations of T3, T4, and AP in the J and S were not significantly different in any month. During the most intense antler growth period (June and July) AP levels were significantly higher and T3 significantly lower in A as compared to J and S, but no differences were found during the mineralization phase in August. T3 values from all three veins were significantly lower in the mineralization period than J and S values during the growing phase. Variations of T4 levels between A, J, and S as well as differences between months were only negligible. The data indicate that AP is produced in large quantity in the antler tissue during the growth period, but the amount is sharply reduced during the mineralization phase. T3 is utilized in the growing antler; the rate of utilization correlates with the intensity of antler growth. T4 is probably not utilized in the antler bone. Developing antler might be used as a model to study growth and mineralization processes of bony tissues.

Alkaline Phosphatase↗
PubMed2006

Mobile contingency locus controlling Escherichia coli K1 polysialic acid capsule acetylation.

Escherichia coli K1 is part of a reservoir of adherent, invasive facultative pathogens responsible for a wide range of human and animal disease including sepsis, meningitis, urinary tract infection and inflammatory bowel syndrome. A prominent virulence factor in these diseases is the polysialic acid capsular polysaccharide (K1 antigen), which is encoded by the kps/neu accretion domain inserted near pheV at 67 map units. Some E. coli K1 strains undergo form (phase) variation involving loss or gain of O-acetyl esters at carbon positions 7 or 9 of the individual sialic acid residues of the polysialic acid chains. Acetylation is catalysed by the receptor-modifying acetyl coenzyme-A-dependent O-acetyltransferase encoded by neuO, a phase variable locus mapping near the integrase gene of the K1-specific prophage, CUS-3, which is inserted in argW at 53.1 map units. As the first E. coli contingency locus shown to operate by a translational switch, further investigation of neuO should provide a better understanding of the invasive K1 pathotype. Minimal estimates of morbidity and economic costs associated with human infections caused by extraintestinal pathogenic E. coli strains such as K1 indicate at least 6.5 million cases with attendant medical costs exceeding 2.5 billion US dollars annually in the United States alone.

Acetylation↗
PubMed2003

Dynamic optical manipulation with a higher-order fractional bessel beam generated from a spatial light modulator.

Higher-order Bessel beams have been demonstrated to have the ability to trap and rotate low- and high-index particles simultaneously [Phys. Rev. A 66, 063402 (2002)]. The rotation and trapping is caused by the presence of orbital angular momentum arising from its azimuthal phase variation (that changes at integer multiples of 2pi) and the concentric rings of the Bessel mode. We demonstrate for the first time to our knowledge a branch from the family of higher-order Bessel beams that has fractional azimuthal variation at its beam axis. This new family of laser beams has the ability to perform dynamic optical manipulation with dynamic control of a spatial light modulator. Furthermore, we take the opportunity to explore the propagation characteristics of higher-order Bessel beams for which the azimuthal phase changes at noninteger multiples of 2pi.

Journal Article↗
PubMed1998

Differential roles of homologous recombination pathways in Neisseria gonorrhoeae pilin antigenic variation, DNA transformation and DNA repair.

Neisseria gonorrhoeae (Gc) pili undergo antigenic variation when the amino acid sequence of the pilin protein is changed, aiding in immune avoidance and altering pilus expression. Pilin antigenic variation occurs by RecA-dependent unidirectional transfer of DNA sequences from a silent pilin locus to the expressed pilin gene through high-frequency recombination events that occur at limited regions of homology. We show that the Gc recQ and recO genes are essential for pilin antigenic and phase variation and DNA repair but are not involved in natural DNA transformation. This suggests that a RecF-like pathway of recombination exists in Gc. In addition, mutations in the Gc recB, recC or recD genes revealed that a Gc RecBCD pathway also exists and is involved in DNA transformation and DNA repair but not in pilin antigenic variation.

Adenosine Triphosphatases↗
PubMedDate not supplied

Usefulness of the human activity profile, a functional performance measure, in people with chronic obstructive pulmonary disease.

PURPOSE: To further evaluate the usefulness of the Human Activity Profile (HAP) as a functional performance measure for those with chronic obstructive pulmonary disease (COPD). METHODS: Phase 1. The sample consisted of 53 outpatients (51 male) with stable COPD (forced expiratory volume in 1 second% predicted (FEV1% pred) = 38 +/- 14 (mean +/- standard deviation) at a university-affiliated veterans affairs medical center. Variables were functional performance (HAP Maximal Activity Score [MAS], HAP Adjusted Activity Score [AAS]), dyspnea (modified Borg category-ratio scale and Shortness of Breath Questionnaire [SOBQ]), and exercise capacity (6-minute walk distance [6MWD]). Phase 2. The HAP was administered pre-post pulmonary rehabilitation in 48 (14 male) outpatients with stable COPD (FEV1% pred = 35 +/- 15) at an outpatient pulmonary rehabilitation program at a large private hospital. RESULTS: Phase 1. Scores for MAS and AAS were, respectively, 62 +/- 12 and 44 +/- 15. The 6MWD, modified Borg, and SOBQ were, respectively, 1055 +/- 372 ft, 4.1 +/- 1, and 64.4 +/- 22 ft. Correlations of the 6MWD and dyspnea scores with the AAS were strong and explained 40% of the AAS variation. Phase 2. The baseline MAS and AAS scores were 55 +/- 14 and 42 +/- 15, respectively, with 29/48 (60%) classified as "low fitness" on the basis of the AAS. Post-rehabilitation, there was significant improvement in the AAS score (48 +/- 13) and significant reduction for those classified as "low fitness." CONCLUSIONS: The utility of the HAP as a measure of functional performance improvement in COPD is supported by its relationship with both 6MWD and dyspnea and its responsiveness to pulmonary rehabilitation.

Aged↗
PubMed1994

Streptococcus pyogenes type IIa IgG Fc receptor expression is co-ordinately regulated with M protein and streptococcal C5a peptidase.

Streptococcus pyogenes is an important agent of human disease which expresses a variety of proteins and polysaccharides on its surface. Surface molecules M protein and streptococcal C5a peptidase (SCPA) are virulence factors which undergo concurrent phase variation and are under the co-ordinate control of the virR locus. Most opacity factor-positive (OF+) strains of S. pyogenes also express IgG Fc receptor proteins on their surface. These studies were initiated to determine whether the type IIa Fc receptor on the surface of S. pyogenes phase-varies with members of this regulatory circuit. Several methods were applied to M+ and M- variant strains to evaluate this question. (i) Immunoblot assays quantified Fc receptors on whole cells by using human IgG myeloma protein and receptor-specific antibody. M+ strains bound IgG and antibody specific for Fc protein, whereas M- strains did not. (ii) Enzyme-linked immunosorbent assays quantified Fc receptor antigen expression and showed that M+ strains produce more Fc receptor protein than their M- derivatives. (iii) Quantitative RNA dot blots showed that the message for the Fc receptor gene (fcrA) was reduced in M- strains. RNA from M+ strains hybridized to the fcrA probe at a greater dilution than that from their M- counterparts. (iv) Northern hybridization showed that the fcrA transcript is 1200 nucleotides in size and distinct from transcripts for M and SCPA proteins. These data are evidence for the co-ordinate transcriptional control of the Fc receptor, M protein, and SCPA and show that these proteins co-ordinately phase-vary within the same regulatory circuit.

Adhesins, Bacterial↗
PubMed2000

Motion correction and lipid suppression for 1H magnetic resonance spectroscopy.

Spectral/spatial spin-echo pulses with asymmetric excitation profiles were incorporated into a PRESS-based localization sequence to provide lipid suppression while retaining a sufficient amount of water to allow for correction of motion-induced shot-to-shot phase variations. 1H magnetic resonance spectroscopy data were acquired at 1.5 Tesla from a motion phantom and in vivo from the human liver, kidney, and breast. The results demonstrated that lipids in the chemical shift stopband were completely suppressed and that full metabolite signal intensity was maintained after implementation of a regularization algorithm based on phasing the residual water signal. Liver and kidney spectra contained a large resonance at 3.2 ppm that was ascribed to trimethylammonium moieties (betaine plus choline) and a weaker signal at 3.7 ppm that may result from glycogen. A breast spectrum from a histologically proven invasive ductal carcinoma displayed a highly elevated choline signal (3.2 ppm) relative to that from a normal volunteer.

Adult↗
PubMed1998

Phase analysis in high-frequency oscillation.

UNLABELLED: In an oscillating system driven by a sine wave pump, the resonance frequency of the respiratory system can be determined using phase analysis. At resonance frequency, when elastance and inertance cancel out, flow becomes in-phase with resistance. In premature infants with respiratory distress syndrome, owing to surfactant deficiency, localized areas of hyperinflation and collapse develop, resulting in complex changes in overall pulmonary mechanics. We investigated the effect of measuring resonance frequency of the respiratory system by phase analysis at different points of the respiratory cycle: end of inspiration, end of expiration, mid-inspiration and mid-expiration. Ten ventilated premature infants with respiratory distress syndrome were studied, gestational age ranged from 24 to 30 weeks (mean 27.6 weeks) and birth weight ranged from 0.7 to 1.505 kg (mean 0.984 kg). RESULTS: The resonance frequency was consistently higher when measured at the end of inspiration compared with the end of expiration. The expected trend of phase variation, that is, negative below the resonance frequency and positive above, was most consistently found when analysis was done at the end of inspiration. CONCLUSIONS: These findings were most likely a result of the complexity of pulmonary mechanics in the surfactant-deficient lungs, rendering the single compartment model we based our theory on inadequate. However, phase analysis performed at the end of inspiration seemed to produce the most reliable and consistent results.

Biomedical Engineering↗
PubMed1997

Mycoplasma genetic variation and its implication for pathogenesis.

Several pathogenic mycoplasma species are known etiologic agents of diseases in man and animals, which typically involve the respiratory tract, urogenital tract and joints and often show chronicity. Although the basis for this chronicity is not well understood, it is apparent that several species of pathogenic mycoplasmas are endowed with a sophisticated genetic machinery for altering their surface attributes. This surface phenotypic variation is thought to play a key role in the establishment and persistence of mycoplasma infections by enabling evasion of host defences and by ensuring adaptation to the rapidly changing microenvironmental conditions encountered in the host. The variability of mycoplasma surface characteristics results both from reversible ON- and OFF-switching of distinct membrane surface proteins (phase variation), from structural changes of these proteins (size variation) and from changes in their surface presentation (epitope masking and demasking). The majority of these surface proteins that are subject to variation are encoded by multiple variant single-copy genes and are lipid-modified proteins which represent the major coat proteins and surface antigens of several pathogenic mycoplasmas. Variable surface lipoproteins play an important role in the pathogenesis of a mycoplasma infection by providing escape from immune response, and probably by influencing both colonization of and translocation across the mucosal barrier. In this minireview, recent developments regarding the genetic mechanisms and the functional significance of surface lipoprotein variation in the pathogenesis of mycoplasma infections are summarized.

Animals↗
PubMedDate not supplied

Surface plasmon resonance phase-shift interferometry: real-time DNA microarray hybridization analysis.

Surface plasmon resonance (SPR) phase-shift interferometry (PSI) is a novel technique which combines SPR and modified Mach-Zehnder PSI to measure the spatial phase variation caused by biomolecular interactions upon a sensing chip. The SPR-PSI imaging system offers high resolution and high-throughout screening capabilities for microarray DNA hybridization without the need for additional labeling, and provides valuable quantitative information. The SPR-PSI imaging system has an enhanced detection limit of 2.5 x 10(-7) refraction index change, a long-term phase stability of pi/100 in 30 min, and a spatial phase resolution of pi/300 with 100 x 100 microm2 detection area. This study successfully demonstrates the label-free observation of 15-mer DNA microarray.

DNA↗
PubMed2005

Nonlinear phase correction with an extended statistical algorithm.

This paper presents a new magnetic resonance imaging (MRI) phase correction method. The linear phase correction method using autocorrelation proposed by Ahn and Cho (AC method) is extended to handle nonlinear terms, which are often important for polynomial expansion of phase variation in MRI. The polynomial coefficients are statistically determined from a cascade series of n-pixel-shift rotational differential fields (RDFs). The n-pixel-shift RDF represents local vector rotations of a complex field relative to itself after being shifted by n pixels. We have found that increasing the shift enhances the signal significantly and extends the AC method to handle higher order nonlinear phase error terms. The n-pixel-shift RDF can also be applied to improve other methods such as the weighted least squares phase unwrapping method proposed by Liang. The feasibility of the method has been demonstrated with two-dimensional (2-D) in vivo inversion-recovery MRI data.

Algorithms↗
PubMed1996

A newly identified immunodominant membrane protein (pMB67) involved in Mycoplasma bovis surface antigenic variation.

Mycoplasma bovis is a bovine pathogen able to cause systemic disease. It possesses a series of prominent, structurally related yet clearly distinguishable membrane lipoproteins on the cell surface. These variable surface proteins (Vsps) undergo highly dynamic and spontaneous changes in size and expression and are key immunogenic components. They may play a critical role as mediators of adherence to host cells and in escaping immune destruction. In this report, we define a novel, Vsp-unrelated membrane protein also associated with M. bovis surface antigenic variation. This protein has an apparent molecular mass of 67,000 Da in the type strain PG45 and was designated pMB67. Immunological and biochemical characterization of pMB67 demonstrated that it: (i) contains a specific epitope, (ii) is not modified by lipid but does contain cysteine, (iii) does not contain a Vsp-like repetitive periodic protein structure, (iv) is a predominant antigen recognized during M. bovis infections, (v) undergoes a high rate of phase variation in vitro and (vi) is size-variable. These results showed that M. bovis employs two types of specialized membrane proteins for surface diversification. The pMB67 protein may be useful in diagnostic assays and as a vaccine component.

Animals↗
PubMed1998

Pneumococcal trafficking across the blood-brain barrier. Molecular analysis of a novel bidirectional pathway.

Although Streptococcus pneumoniae is a major cause of meningitis in humans, the mechanisms underlying its traversal from the circulation across the blood-brain barrier (BBB) into the subarachnoid space are poorly understood. One mechanism might involve transcytosis through microvascular endothelial cells. In this study we investigated the ability of pneumococci to invade and transmigrate through monolayers of rat and human brain microvascular endothelial cells (BMEC). Significant variability was found in the invasive capacity of clinical isolates. Phase variation to the transparent phenotype increased invasion as much as 6-fold and loss of capsule approximately 200-fold. Invasion of transparent pneumococci required choline in the pneumococcal cell wall, and invasion was partially inhibited by antagonists of the platelet-activating factor (PAF) receptor on the BMEC. Pneumococci that gained access to an intracellular vesicle from the apical side of the monolayer subsequently were subject to three fates. Most opaque variants were killed. In contrast, the transparent phase variants were able to transcytose to the basal surface of rat and human BMEC in a manner dependent on the PAF receptor and the presence of pneumococcal choline-binding protein A. The remaining transparent bacteria entering the cell underwent a previously unrecognized recycling to the apical surface. Transcytosis eventually becomes a dominating process accounting for up to 80% of intracellular bacteria. Our data suggest that interaction of pneumococci with the PAF receptor results in sorting so as to transcytose bacteria across the cell while non-PAF receptor entry shunts bacteria for exit and reentry on the apical surface in a novel recycling pathway.

Adult↗