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Biomedical subjects

J B Moore

Publications and source records attributed to J B Moore.

At least 37 records · Page 2Linked to original sources
PubMed1994

Identification and sequencing of the Thermotoga maritima lacZ gene, part of a divergently transcribed operon.

The lacZ gene encoding a beta-galactosidase (beta Gal) from the hyperthermophile Thermotoga maritima was cloned on an 11-kb fragment by complementation of an Escherichia coli lacZ deletion stain. The nucleotide sequence of the structural gene and two other ORFs found within a 6317-bp region were determined. The deduced amino acid (aa) sequence of the Tt. maritima beta Gal predicts a 1037-aa polypeptide with a calculated M(r) of 122,312. The translated sequence is 30% similar to nine other beta Gal sequences from bacteria and one yeast. Alignment of the Tt. maritima beta Gal with these other sequences reveals that the residues responsible for Mg2+ binding, catalysis and substrate recognition are conserved in the thermophilic enzyme. Sequence analysis also revealed the presence of a divergently transcribed operon containing at least two other genes 5' to lacZ. These ORFs encode proteins homologous to a second family of beta Gal found in Bacillus species and to an ATP-dependent family of bacterial oligopeptide transport proteins.

Amino Acid Sequence↗
PubMed1994

Deletion of fowlpox virus homologues of vaccinia virus genes between the 3 beta-hydroxysteroid dehydrogenase (A44L) and DNA ligase (A50R) genes.

A fragment of 4156 bp of fowlpox virus (FPV) genomic DNA contains homologues of vaccinia virus 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD; A44L) and DNA ligase (A50R) genes. The FPV locus has clearly been rearranged relative to that of vaccinia virus as homologues of genes A45R to A49R, including the thymidylate kinase and a gene with homology to superoxide dismutase, are deleted. The deleted genes are replaced by two open reading frames: for a serine proteinase inhibitor with homology to vaccinia virus gene K2L and for a protein with no significant homology to proteins in the databases. In addition, the FPV homologues of A44L and A50R are in the same polarity in FPV whereas they are in opposite polarities in vaccinia virus. Increased 3 beta-HSD activity has been demonstrated in cells infected with either of two different strains of FPV or with canarypox virus.

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

Measurement of regional blood oxygenation and cerebral hemodynamics.

An echo planar linewidth mapping technique, Shufflebutt, has allowed temporal measurements of changes in linewidth caused by static inhomogeneities (delta LWSI) and transverse relaxation rate (delta R2) in models of hypoxia and hypercapnia. We demonstrate these changes are due to intravascular susceptibility differences/(delta chi) between the blood and tissue. Contrast agent injections at a delta chi equivalent to that of deoxygenated blood showed a twofold difference between the contrast agent and physiological anoxia values. Hypercapnia decreased both delta LWSI and delta R2 consistent with an increase in blood oxygenation. We attribute these findings to constant oxygen extraction during an increase in blood flow, resulting in less deoxygenated venous blood and thus reduced delta chi. For in vivo perturbations we found that delta R2/delta R2' approximately 0.33, a ratio much different from that measured in whole blood phantoms (delta R2/delta R2' approximately 2). This demonstrates that signal changes in these studies are produced predominantly by dephasing of extravascular protons due to field inhomogeneities produced by intravascular deoxygenated hemoglobin (deoxyHb).

Animals↗
PubMed1993

RWJ-22108--a novel airway tissue--selective calcium channel blocker.

RWJ-22108 is a novel calcium entry blocker that has potential therapeutic use as an antiasthmatic agent. Although displaying typical potent inhibition of 45Ca uptake into aortic rings (IC50 = 7.1 nM) and displacement of [3H]nitrendipine from cardiac membranes (IC50 = 137 nM), RWJ-22108 demonstrates tissue selectivity in the inhibition of KCl-induced contractions. RWJ-22108 inhibits the calcium-dependent contraction of canine bronchiolar smooth muscle with an IC50 of 5.7 nM. The IC50 femoral artery/IC50 bronchiolar ratios are 2.85, 8.02, 1.47 and 1.96 for nifedipine, RWJ-22108, verapamil, and gallopamil, respectively. Furthermore, this selectivity ratio (range 2.8-5.5) of RWJ-22108 is also observed when inhibition of other pulmonary and cardiovascular smooth muscles are compared. Using canine tracheal muscle and rabbit aortae, the IC50 aorta/IC50 trachea ratio is 1.75 for RWJ-22108 compared to approximately 0.5 for several calcium blocker standards. These results indicate that in vitro RWJ-22108 is a bronchoselective calcium channel blocker.

Animals↗
PubMed1993

Alterations of highly conserved residues in the regulatory domain of nitrogen regulator I (NtrC) of Escherichia coli.

Transcription of many nitrogen-regulated (Ntr) genes requires the phosphorylated form of nitrogen regulator I (NRI, or NtrC), which binds to sites that are analogous to eukaryotic enhancers. A highly conserved regulatory domain contains the site of phosphorylation and controls the function of NRI. We analyzed the effects of substitutions in highly conserved residues that are part of the active site of phosphorylation of NRI in Escherichia coli. Fourteen substitutions of aspartate 54, the site of phosphorylation, impaired the response to nitrogen deprivation. Only one of these variants, NRI D-54-->E (NRI-D54E), could significantly stimulate transcription from glnAp2, the major promoter of the glnALG operon. Cells with this variant grew with arginine as a nitrogen source. Experiments with purified components showed that unphosphorylated NRI-D54E stimulated transcription. In contrast, substitutions at aspartate 11 were not as deleterious as those at aspartate 54. Finally, we showed that NRI-K103R, in which arginine replaces the absolutely conserved lysine, is functionally active and efficiently phosphorylated. This substitution appears to stabilize the phosphoaspartate of NRI. The differences between our results and those from study of homologous proteins suggest that there may be significant differences in the way highly conserved residues participate in the transition to the activated state.

Aspartic Acid↗
PubMed1993

Experimental antiasthmatic activity of RWJ 22108: a bronchoselective calcium entry blocker.

RWJ 22108 (N-benzyl-N-methylaminoethyl 9-(2-chloro-6-fluorophenyl)-2,3,4,5,6,9-hexahydro-7-methyl-1, 1-dioxothiacyclohepteno-[3,2-b]pyridine-8-carboxylate) is a new bronchoselective calcium entry blocker with potential use as an antiasthmatic agent. Previous studies have shown that RWJ 22108 is a potent calcium entry blocker in vitro and demonstrates tissue selectivity for airway smooth muscle over vascular smooth muscle. The current study demonstrates the in vivo activity of RWJ 22108 in several different models of airway obstruction and asthma. RWJ 22108 relaxes preconstricted airways in dogs with little effect on blood pressure when administered by aerosol. In addition, it inhibits airway obstruction induced by antigen, histamine and exogenous leukotriene D4 in guinea pigs. In a conscious sheep model of allergic asthma, aerosol RWJ 22108 inhibits antigen-induced early and late phase airway obstruction and also the cellular infiltration associated with late phase. Total leukotrienes production is decreased in the guinea pig model probably as a result of fewer inflammatory cells infiltrating the lungs as shown in the sheep model of late phase. These data suggest that RWJ 22108 may have pharmacological potential in the clinical management of asthma.

Airway Obstruction↗
PubMed1993

RWJ 26629, a new potassium channel opener and vascular smooth muscle relaxant: a potential antihypertensive and antianginal agent.

The effects of trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-7H- thieno[3,2-b]pyran (RWJ 26629) were compared with those of the standard potassium channel opener cromakalim and several standard calcium channel blockers. RWJ 26629 lowered the mean arterial blood pressure in conscious spontaneously hypertensive (ED30 = 10 micrograms/kg p.o. or 8 micrograms/kg i.v.) and renal hypertensive (15 micrograms/kg p.o.) rats, conscious renal hypertensive (ED20 = 4 micrograms/kg p.o.) and normotensive (ED20 = 5 micrograms/kg p.o. or 2 micrograms/kg i.v.) dogs and anesthetized rhesus monkeys (ED20 = 6 micrograms/kg i.v.). RWJ 26629 was more potent than cromakalim and had a maximal activity greater than the calcium channel blockers. At antihypertensive doses, RWJ 26629 had no significant effect on cardiac force, cardiac output, stroke volume or stroke work in dogs and had little or no effect on renal, carotid or femoral blood flow or vascular resistance. RWJ 26629 was also selective for antihypertensive activity in rats compared with its ability to inhibit intestinal motility. However, RWJ 26629 did relax contracted pulmonary smooth muscle in vivo at antihypertensive doses. All compounds tested caused reflex tachycardia in conscious dogs, although this effect was lowest for RWJ 26629. Most importantly, RWJ 26629 potently and selectively increased coronary blood flow with a potency and duration of action greater than that of cromakalim or nifedipine without affecting contractile force. In vitro, RWJ 26629 selectively relaxed precontracted coronary arteries compared with its effect on femoral arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1993

Predictors of children's self-care performance: testing the theory of self-care deficit.

Orem's theory of self-care deficit proposes relationships between self-care performance and (a) basic conditioning factors, (b) self-care agency, and (c) dependent-care agent performance. The purpose of this study was to examine these proposed relationships in children. The study sample was composed of 414 students in grades 4 through 12, ages 9 through 18 years. Using regression analyses, study findings were that the variables chosen to represent the basic conditioning factors together accounted for 19% of the variance in children's self-care performance. Separately, both age and health state were significant predictors. Additionally, when self-care agency was added to the regression model, the combination accounted for 36% of the variance. A correlational analysis showed a moderate relationship between a child's self-care performance and her or his mothers' dependent-care agent performance. Future research should continue to investigate Orem's theories and the operationalization of the concepts.

Adolescent↗
PubMed1992

Thiophene systems. 14. Synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxythieno[3,2-b]pyrans and related compounds as new potassium channel activators.

The synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxy-5,5-dimethylthieno[3,2-b]pyrans and related compounds are described. The compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats (SHR) and selected compounds were evaluated in vitro for increases in 86Rb efflux in rabbit isolated mesenteric arteries. The effects on activity in SHR of lactam ring size, the presence of heteroatoms in the lactam ring, the relative stereochemistry at C-6 and C-7, and the substituents on the thiophene ring are examined. The best racemic compound in this series is 32, trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-5H- thieno[3,2-b]pyran, which is 10-fold more potent than cromakalim with an ED30 = 0.015 mg/kg in SHR. Compound 32 could be resolved and the antihypertensive activity determined to reside primarily in the (6S,7S)-(-)-enantiomer 41. Surprisingly, the elimination of water to give the enamides 50-52, thiophene isosteres of bimakalim, diminishes activity significantly.

Animals↗
PubMed1992

Steroid hormone synthesis by a vaccinia enzyme: a new type of virus virulence factor.

Vaccinia virus open reading frame (ORF) SalF7L has 31% amino acid identity to human 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD). Here we show that SalF7L encodes an active 3 beta-HSD, by the conversion of pregnenolone to the steroid hormone progesterone. The gene is transcribed early during infection into a 1.4 kb mRNA from an initiation site 12 bp upstream of the ORF. An antiserum raised against bacterially expressed SalF7L immunoprecipitated a 38 kDa polypeptide from infected cells, but not from mock infected cells or from cells infected with a mutant virus from which the SalF7L ORF had been removed. Deletion of the gene had no effect on virus replication in CV-1 cells in culture, yet the deletion mutant was attenuated when intranasally inoculated into mice. This steroid hormone synthesizing enzyme is a novel type of virus virulence factor.

3-Hydroxysteroid Dehydrogenases↗
PubMed1992

Heteroatom analogues of bemoradan: chemistry and cardiotonic activity of 1,4-benzothiazinylpyridazinones.

A series of close analogues of the potent, long-acting cardiotonic bemoradan (2a) was synthesized and examined in both in vitro and in vivo test systems. Changing the oxygen heteroatom at the 1-position of the benzoxazine ring of bemoradan to sulfur gave 4a, a more potent enzyme inhibitor and in vivo cardiotonic compound by the iv route. Intraduodenal administration of bemoradan, however, showed a superior response compared to its sulfur analogue, possibly due to oxidation of sulfur followed by a facile Pummerer rearrangement. Model studies were performed to examine the effect of the oxidation state of sulfur. Lack of a heteroatom at the 1-position, 3a (Y-590), afforded a compound with activity and potency very similar to those of bemoradan while the 1-selena compound gave a much less potent analogue 5. Analogues having a methyl group on the 4-nitrogen (2b, 3b, and 4b) were less potent than the desmethyl compounds, but all of these compounds have potent PDE III inhibiting activity and the ability to increase cardiac force in an anesthetized dog preparation when given iv.

Animals↗
PubMed1992

Children's one-hand catching as a function of age, gender, and ball location.

A sizable body of literature exists on the product characteristics and developmental sequence for two-hand catching, but to date there is no description of the developmental characteristics of simple one-hand catching in young children. This study investigated the influence of age, gender, and ball location on children's one-hand catching. Boys and girls (N = 240) ranging in age from 5 to 12 years attempted to catch a total of 24 tennis balls, tossed from a 9-ft distance. Tosses were directed to four locations: (a) Waist, (b) Shoulder, (c) Above-the-Head, and (d) Out-to-the-Side. Descriptive data consisted of the percentage of successful catches at each ball location, and the hand-arm orientation selected by the child as a function of ball location. Results revealed that catching performance improved with age, boys caught more balls than girls, ball location influenced catching success, and, in general, the location of the toss constrained the child's selection of an appropriate hand-arm orientation. With the possible exception of the Shoulder location for girls, even very young children are sensitive to the perceptual aspects of the toss and respond with an appropriate orientation.

Age Factors↗
PubMed1991

Adaptive processing techniques based on hidden Markov models for characterizing very small channel currents buried in noise and deterministic interferences.

Techniques for characterizing very small single-channel currents buried in background noise are described and tested on simulated data to give confidence when applied to real data. Single channel currents are represented as a discrete-time, finite-state, homogeneous, Markov process, and the noise that obscures the signal is assumed to be white and Gaussian. The various signal model parameters, such as the Markov state levels and transition probabilities, are unknown. In addition to white Gaussian noise, the signal can be corrupted by deterministic interferences of known form but unknown parameters, such as the sinusoidal disturbance stemming from AC interference and a drift of the base line owing to a slow development of liquid-junction potentials. To characterize the signal buried in such stochastic and deterministic interferences, the problem is first formulated in the framework of a Hidden Markov Model and then the Expectation Maximization algorithm is applied to obtain the maximum likelihood estimates of the model parameters (state levels, transition probabilities), signals, and the parameters of the deterministic disturbances. Using fictitious channel currents embedded in the idealized noise, we first show that the signal processing technique is capable of characterizing the signal characteristics quite accurately even when the amplitude of currents is as small as 5-10 fA. The statistics of the signal estimated from the processing technique include the amplitude, mean open and closed duration, open-time and closed-time histograms, probability of dwell-time and the transition probability matrix. With a periodic interference composed, for example, of 50 Hz and 100 Hz components, or a linear drift of the baseline added to the segment containing channel currents and white noise, the parameters of the deterministic interference, such as the amplitude and phase of the sinusoidal wave, or the rate of linear drift, as well as all the relevant statistics of the signal, are accurately estimated with the algorithm we propose. Also, if the frequencies of the periodic interference are unknown, they can be accurately estimated. Finally, we provide a technique by which channel currents originating from the sum of two or more independent single channels are decomposed so that each process can be separately characterized. This process is also formulated as a Hidden Markov Model problem and solved by applying the Expectation Maximization algorithm. The scheme relies on the fact that the transition matrix of the summed Markov process can be construed as a tensor product of the transition matrices of individual processes.

Algorithms↗
PubMed1991

Bemoradan--a novel inhibitor of the rolipram-insensitive cyclic AMP phosphodiesterase from canine heart tissue.

Canine cardiac muscle contains a type IV cyclic AMP (cAMP) phosphodiesterase (PDE) that is composed of two subtypes. One subtype is sensitive to rolipram inhibition (RSPDE), whereas the other is not inhibited significantly by rolipram (RIPDE). The RIPDE is inhibited by several cardiotonic agents operating by a PDE-inhibitory mechanism. Bemoradan [RWJ-22867; 7-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-2H-1,4-benzoxazin -3(4H)-one], a novel, potent positive inotropic agent, demonstrated biphasic inhibition of the fraction III enzyme from canine cardiac muscle. Inhibition by rolipram of the RSPDE converted the IC50 curves of bemoradan, indolidan, pimobendan, and imazodan to sigmoidal, monophasic curves. Lineweaver-Burk analysis yielded competitive inhibition KI values of 0.023, 0.09, 0.065 and 0.60 microM, respectively, for these compounds. The cardiotonic compounds, however, were not potent inhibitors of the Type I and Type II cAMP PDEs found in canine ventricular muscle. The order of potency for inhibiting the RIPDE cAMP PDE subtype was bemoradan greater than pimobendan greater than indolidan greater than imazodan. Bemoradan is, therefore, a potent inhibitor of the cardiac muscle cAMP PDE which could, in part, be responsible for its cardiotonic activity.

3',5'-Cyclic-AMP Phosphodiesterases↗