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B A Williams

Publications and source records attributed to B A Williams.

At least 55 records · Page 3Linked to original sources
PubMed1997

Adenosine acts through a novel extracellular receptor to inhibit granule exocytosis by natural killer cells.

Adenosine concentrations in solid tumors are elevated as a result of altered metabolism by hypoxic cancer cells within the tumor microenvironment. In this study we show that adenosine inhibits mouse natural killer (NK) cell function by interfering with the process of granule exocytosis. Adenosine, at concentrations ranging from 5-25 microM, had a marked inhibitory effect on granule exocytosis by mouse spleen cells stimulated with phorbol myristate acetate and ionomycin. Selective depletion of spleen cell subsets by antibody and complement treatments established that granule exocytosis was mediated by NK cells. Blocking the cellular uptake of adenosine with NBTI or dilazep failed to prevent the inhibitory effect of adenosine, indicating the involvement of a cell-surface receptor. However, adenosine-induced inhibition of granule exocytosis was not blocked by the nonselective A1 and A2 receptor antagonists theophylline and 8-phenyltheophylline, the A1 receptor antagonist DPCPX, or the A2 receptor antagonist DMPX. In addition, the A3 receptor agonists APNEA and NECA failed to affect granule exocytosis. Taken together, these data provide evidence that adenosine inhibits NK cell granule exocytosis by interacting with a novel extracellular receptor. A similar inhibitory effect of tumor-elaborated adenosine on the function of NK cells and other cytotoxic lymphocytes may contribute to tumor survival in the face of host cell-mediated immune defenses.

Adenosine↗
PubMed1997

Anthropoid origins.

Recent fossil discoveries have greatly increased our knowledge of the morphology and diversity of early Anthropoidea, the suborder to which humans belong. Phylogenetic analysis of Recent and fossil taxa supports the hypotheses that a haplorhine-strepsirrhine dichotomy existed at least at the time of the earliest record of fossil primates (earliest Eocene) and that eosimiids (middle Eocene, China) are primitive anthropoids. Functional analysis suggests that stem haplorhines were small, nocturnal, arboreal, visually oriented insectivore-frugivores with a scurrying-leaping locomotion. A change from nocturnality to diurnality was the fundamental adaptive shift that occurred at the base of the tarsier-eosimiid-anthropoid clade. Stem anthropoids remained small diurnal arborealists but adopted locomotor patterns with more arboreal quadrupedalism and less leaping. A shift to a more herbivorous diet occurred in several anthropoid lineages.

Adaptation, Biological↗
PubMed1997

Histone H1 in Saccharomyces cerevisiae.

The existence of histone H1 in the yeast, Saccharomyces cerevisiae, has long been debated. In this report we describe the presence of histone H1 in yeast. YPL127c, a gene encoding a protein with a high degree of similarity to histone H1 from other species was sequenced as part of the contribution of the Montreal Yeast Genome Sequencing Group to chromosome XVI. To reflect this similarity, the gene designation has been changed HHO1 (Histone H One). The HHO1 gene is highly expressed as poly A+ RNA in yeast. Although deletion of this gene had no detectable effect on cell growth, viability or mating, it significantly altered the expression of beta-galactosidase from a CYC1-lacZ reporter. Fluorescence observed in cells expressing a histone H1-GFP protein fusion indicated that histone H1 is localized to the nucleus.

Amino Acid Sequence↗
PubMed1997

Magnesium shifts voltage dependence of activation of delayed rectifier I(K) in guinea pig ventricular myocytes.

The sensitivity of the delayed rectifier K+ current (I(K)) to intracellular Mg2+ was investigated in guinea pig ventricular myocytes using the whole cell patch-clamp technique. An increase in free intracellular Mg2+ concentration ([Mg2+]i) led to a dose-dependent decrease in I(K) with a half-maximal effect of approximately 20 nM. Activation of I(K) was shifted toward more positive voltages on increasing [Mg2+]i, but little effect was observed on activation and deactivation kinetics. Isoproterenol increased I(K) and was partially reversible in both control and 100 nM [Mg2+]i. The antiarrhythmic drug dofetilide was used to separate I(K) into its two components, rapidly activating (I(Kr)) and slowly activating (I(Ks)). The magnitude of both components decreased to a similar extent with an increase in [Mg2+]i. As [Mg2+]i was reduced, however, the number of experiments in which the dofetilide-sensitive current I(Kr) displayed inward rectification was reduced. In contrast to results previously reported for frog myocytes, it is unlikely that Mg2+ effects on guinea pig I(K) are mediated by a protein phosphatase.

Animals↗
PubMed1997

Emergence of determined myotome precursor cells in the somite.

Myotome and sclerotome precursor cells are derived, respectively, from cells in the dorsomedial and ventromedial regions of the somite. To assay changes in the specification of myotomal precursor cells during somite maturation, we implanted dorsomedial quadrant fragments, from staged quail somites, next to the notochords of host chick embryos, and superimposed two additional notochords on these implants. In this notochord signalling environment, dorsomedial quadrant cells that are developmentally plastic are expected to differentiate as cartilage, while cells determined to a myogenic fate are expected to differentiate as skeletal muscle. Large numbers of differentiated chondrocytes developed from dorsomedial quadrant grafts of all stages of paraxial mesoderm development tested, indicating that persistent chondrogenic potential in cells fated to form muscle and dermis can be elicited by notochord signals. Differentiated myocytes, however, appeared in two somite-stage-dependent phases. In the first phase, dorsomedial quadrants from segmental plate and early stage somites (II and IV) form small, disorganized clusters of individual myocytes. The frequency of first-phase myocluster formation increases as myogenic factor expression begins in the dorsomedial quadrant, indicating that myogenic determination assayed by this method is closely linked to the expression of myogenic factors in the dorsomedial quadrant. In the second phase, dorsomedial quadrants from somite stages XI-XIII consistently form morphologically organized muscle tissue containing large numbers of parallel-oriented, multinucleated myotubes. Mitotic labelling demonstrated that muscle precursors were determined to the muscle phenotype prior to withdrawal from the cell cycle. Thus, myogenic determination in cells of the dorsomedial quadrant is acquired at earlier stages of somite maturation than the ability to proliferate and form muscle tissue. These results are consistent with the hypothesis that successive lineages of myotome precursor cells with different mitotic and morphogenetic properties arise in the dorsomedial quadrant during somite maturation.

Animals↗
PubMed1997

Conditioned reinforcement dynamics in three-link chained schedules.

In two experiments rats were trained on three-link concurrent-chains schedules of reinforcement. In Experiment 1, additional entries to one terminal link were added during one of the middle links to a baseline schedule that was otherwise equal for the two chains, and, depending on the condition, these additional terminal-link presentations ended either in food or in no food. When food occurred, preference was always in favor of the chain with the additional terminal-link presentations (which also entailed a higher rate of reinforcement). When no food occurred at the end of the additional terminal links, the outcome depended on the nature of the stimuli associated with these additional terminal links. When stimuli different from the reinforced baseline terminal links were used for the no-food terminal links, preference was against the choice alternative that led to the extra periods of extinction. When the same stimulus was used for the two kinds of terminal links, preference was near indifference, that is, significantly greater than when different stimuli were used. In Experiment 2, rats learned repeated reversals of a simultaneous discrimination under a three-link concurrent-chains schedule, in which the food or no-food choice outcomes were delayed until the end of the chain. Different conditions were defined by the point in the chain at which differential stimuli occurred. When the middle and terminal links provided no differential stimuli, discrimination was acquired more slowly than when differential stimuli occurred in both links. When differential stimuli occurred in the middle but not the terminal links, acquisition rates were intermediate. Both experiments together show that the effects of stimuli in a chain schedule are due partly to the time to food correlated with the stimuli and partly to the time to the next conditioned reinforcer in the sequence.

Animals↗
PubMed1996

Glial cell-specific differences in repair of O6-methylguanine.

Normal and malignant cells of the oligodendrocyte lineage show increased sensitivity to alkylating agents compared to astrocytes. One of the most mutagenic DNA lesions formed following exposure to alkylating agents is O6-alkylguanine. To determine whether the increased sensitivity to nitrosoureas seen in oligodendrocytes is due to decreased repair capacity for O6-alkylguanine, removal of this lesion from DNA was assessed in primary cultures of rat oligodendrocytes, astrocytes, and microglia. Glial cells were exposed to 1 mM N-methyl-N-nitrosourea for 1 h and allowed 8 or 24 h for repair. Repair was evaluated using an immunoslot blot technique and a monoclonal antibody which recognizes O6-methylguanine (O6MeGua). Astrocytes removed O6MeGua more efficiently (approximately 80% in 24 h) than either oligodendrocytes (approximately 20%) or microglia (approximately 4%). Determination of O6-alkylguanine-DNA-alkyltransferase (AT) activity revealed that astrocytes contain 0.4 pmol/mg protein, which is average by comparison to other cell types. Both oligodendrocytes and microglia exhibited very low levels of AT (oligodendrocytes, 0.08; microglia, 0.01 pmol/mg protein). These data are the first to show that within different populations of glial cells, O6MeGua adduct removal is substantially reduced in both oligodendrocytes and microglia. Rapid removal of O6MeGua in astrocytes coupled with persistence of this mutagenic lesion in oligodendrocytes following exposure of the developing central nervous system to nitrosoureas could contribute to the observed formation of oligodendrogliomas. Inefficient removal of O6MeGua in oligodendrogliomas might also account for their response to chemotherapeutic regimens involving alkylating agents such as procarbazine, lomustine, and carmustine. The lack of repair of O6MeGua in microglia suggests that primary lymphomas of the central nervous system might be sensitive to treatment with alkylating drugs whose toxicity depends on repair of this adduct.

Alkylating Agents↗
PubMed1996

Isolation by genetic complementation of two differentially expressed genes for beta-isopropylmalate dehydrogenase from Aspergillus niger.

We have constructed an Aspergillus niger cDNA library with a yeast expression vector. The library DNA complemented a leucine auxotroph of Saccharomyces cerevisiae (strain BWG1-7a) at a frequency of 4x10(-4). Plasmids rescued from the yeast prototrophs also complemented Escherichia coli (strain MC1066) deficient in leucine biosynthesis. Sequence determination of the rescued plasmids revealed two genes for beta-isopropylmalate dehydrogenase, which we called leu2A and leu2B. Genomic-blot analysis suggested that both leu2A and leu2B were derived from single-copy genes. Northern-blot hybridization showed that in nutrient-rich medium a leu2A transcript accumulated during germination and log-phase growth while the leu2B transcript appeared late in the growth phase. In minimal medium, only leu2A expression was greatly stimulated. We examined the codon preference of these two genes. Whereas leu2A shows a bias in codon usage typical of A. niger genes, leu2B does not. These results indicate the presence in A. niger of two highly divergent, differentially regulated, isozymes for beta-isopropylmalate dehydrogenase.

3-Isopropylmalate Dehydrogenase↗
PubMed1996

Rate-dependent effects of sematilide on ventricular monophasic action potential duration and delayed rectifier K+ current in rabbits.

Our objective was to define the actions of sematilide in rabbits and to assess the contribution of the delayed rectifier (IK) to rate dependence of action potential duration (APD) in rabbit ventricular myocardium. In studies in vivo, New Zealand White rabbits were used to obtain dose/response curves of the effects of sematilide on APD from contact monophasic action potentials (MAP), ventricular effective refractory period (VERP), and ECG. Sematilide or placebo was administered as an i.v. bolus followed by a 45-min infusion in the following cumulative manner: infusion 1 (1 mg/kg bolus + 8 micrograms/kg/min); infusion 2 (2 mg/kg + 20 micrograms/kg/min); and infusion 3 (7 mg/kg + 68 micrograms/kg/min). At each infusion level, VERP and APD at 75% repolarization (APD75) were measured during cardiac pacing between 200- and 400-ms cycle length (CL). Serum sematilide levels were analyzed by high-performance liquid chromatography (HPLC). In studies in vitro, sematilide's effects on the delayed rectifier were assessed in isolated rabbit ventricular myocytes by using patch-clamp techniques. Sematilide infusion in vivo resulted in stable serum levels of 1.3 +/- 0.5, 3.7 +/- 1.4, and 13.4 +/- 1.8 micrograms/ml during infusions 1, 2, and 3, respectively. Maximal effects occurred at infusion 2, such that at 400 ms CL, sematilide widened predrug APD75 (145 +/- 5 ms) by 27 +/- 4% (p < 0.001 vs. placebo), and at 200-ms CL, sematilide prolonged predrug APD75 (115 +/- 10 ms) by only 18 +/- 4% (p < 0.001 vs. placebo; p < 0.05 vs. 400-ms CL). Similar effects were observed in VERP. Sematilide enhanced rate dependence of APD and produced the same degree of APD prolongation at a given CL, during accommodation to and recovery from rapid pacing. Rabbit ventricular myocytes appeared to have at least two types of delayed rectifier. Sematilide selectively blocked IKr, and block was not relieved by repetitive stimulation. In conclusion, the APD-widening effect of sematilide was independent of previous pacing history. Sematilide had little influence on background processes likely responsible for shortening APD because of rapid repetitive stimulation.

Action Potentials↗
PubMed1996

Changeover behavior and preference in concurrent schedules.

Pigeons were trained on a multiple schedule of reinforcement in which separate concurrent schedules occurred in each of two components. Key pecking was reinforced with milo. During one component, a variable-interval 40-s schedule was concurrent with a variable-interval 20-s schedule; during the other component, a variable-interval 40-s schedule was concurrent with a variable-interval 80-s schedule. During probe tests, the stimuli correlated with the two variable-interval 40-s schedules were presented simultaneously to assess preference, measured by the relative response rates to the two stimuli. In Experiment 1, the concurrently available variable-interval 20-s schedule operated normally; that is, reinforcer availability was not signaled. Following this baseline training, relative response rate during the probes favored the variable-interval 40-s alternative that had been paired with the lower valued schedule (i.e., with the variable-interval 80-s schedule). In Experiment 2, a signal for reinforcer availability was added to the high-value alternative (i.e., to the variable-interval 20-s schedule), thus reducing the rate of key pecking maintained by that schedule but leaving the reinforcement rate unchanged. Following that baseline training, relative response rates during probes favored the variable-interval 40-s alternative that had been paired with the higher valued schedule. The reversal in the pattern of preference implies that the pattern of changeover behavior established during training, and not reinforcement rate, determined the preference patterns obtained on the probe tests.

Journal Article↗
PubMed1995

A robotic dissolution system with on-line fiber-optic UV analysis.

An automated, robotic system has been developed with on-line UV fiber optics for real time dissolution analysis of solid dosage forms. The system is comprised of "off-the-shelf" hardware including a UV-Vis diode array spectrophotometer, fiber optic coupler, immersion probe, robot, and dissolution apparatus. The software system is modular with the functionalities of control, data acquisition, and spectral analysis separated into three Windows applications with communications performed via Dynamic Data Exchange (DDE). The fiber optic spectrophotometer collects a full spectrum over the range of 190-810 nm. Single wavelength UV analysis is performed on dosage forms in six dissolution vessels. The robotic system automates all facets of the analyses: measuring, degassing, and dispensing of the media; thermostating the media to physiologic temperature; dropping the dosage forms into the vessels; immersing the fiber optic probe at the appropriate time intervals; initiating the data acquisition, analyses, and reporting; and emptying and washing of the vessels prior to the next automated run. As a representative dosage form, 10 mg active tablets were selected and analyzed by this method. This fiber optic system has significantly improved the throughput of the robotic systems by eliminating the need for time consuming off-line HPLC or UV analyses. In addition, with the exception of system calibration, it is no longer necessary for laboratory personnel to come in contact with samples.

Chemistry, Pharmaceutical↗
PubMed1994

New early eocene anaptomorphine primate (Omomyidae) from the Washakie Basin, Wyoming, with comments on the phylogeny and paleobiology of anaptomorphines.

Recent paleontological collecting in the Washakie Basin, southcentral Wyoming, has resulted in the recovery of over 100 specimens of omomyid primates from the lower Eocene Wasatch Formation. Much of what is known about anaptomorphine omomyids is based upon work in the Bighorn and Wind River Basins of Wyoming. This new sample documents greater taxonomic diversity of omomyids during the early Eocene and contributes to our understanding of the phylogeny and adaptations of some of these earliest North American primates. A new middle Wasatchian (Lysitean) anaptomorphine, Anemorhysis savagei, n. sp., is structurally intermediate between Teilhardina americana and other species of Anemorhysis and may be a sister group of other Anemorhysis and Trogolemur. Body size estimates for Anemorhysis, Tetonoides, Trogolemur, and Teilhardina americana indicate that these animals were extremely small, probably less than 50 grams. Analysis of relative shearing potential of lower molars of these taxa indicates that some were primarily insectivorous, some primarily frugivorous, and some may have been more mixed feeders. Anaptomorphines did not develop the extremes of molar specialization for frugivory or insectivory seen in extant prosimians. Incisor enlargement does not appear to be associated with specialization in either fruits or insects but may have been an adaptation for specialized grooming or food manipulation.

Adaptation, Physiological↗
PubMed1994

The role of probability of reinforcement in models of choice.

A general account of choice behavior in animals, the cumulative effects model, has been proposed by Davis, Staddon, Machado, and Palmer (1993). Its basic assumptions are that choice occurs in an all-or-none fashion for the response alternative with the highest probability of reinforcement and that the probability of reinforcement for each response alternative is calculated from the entire history of training (total number of reinforced responses/total number of reinforced and nonreinforced responses). The model's reliance on probability of reinforcement as the fundamental variable controlling choice behavior subjects the cumulative effects model to the same criticisms as have been directed toward other related models of choice, notably melioration theory. Several different data sets show that the relative value of a response alternative is not predicted by the obtained probability of reinforcement associated with that alternative. Alternative approaches to choice theory are considered.

Animals↗
PubMed1994

Block of ATP-sensitive K+ channels in isolated mouse pancreatic beta-cells by 2,3-butanedione monoxime.

1. The patch-clamp technique has been used to examine the action of the chemical phosphatase 2,3-butanedione monoxime (BDM) on ATP-sensitive K+ channels (KATP-channels) from mouse isolated pancreatic beta-cells in the absence of ATP and Mg2+. 2. BDM reversibly inhibited whole-cell KATP-currents with a concentration for half maximal inhibition (K(i)) of 15 +/- 1 mM and a Hill coefficient (n) of 2.5 +/- 0.2 (n = 4). 3. In outside-out patches, external BDM reversibly reduced the activity of single KATP-channels with an affinity similar to that observed in whole-cell recordings (K(i) = 11 +/- 3 mM, n = 2.0 +/- 0.3, n = 7). In inside-out patches, internally applied BDM also reversibly blocked the activity of KATP-channels (K(i) = 31 +/- 2 mM, n = 2.2 +/- 0.4, n = 8). In both excised patch configurations, BDM decreased the mean open life-time and the burst duration, thereby producing a decrease in the channel open probability. The drug had no effect on the short intraburst closed times. 4. BDM had no effect on the single-channel current amplitude. 5. The results suggest that BDM blocks the KATP-channel directly, by mechanisms independent of channel dephosphorylation.

Adenosine Triphosphate↗
PubMed1994

The respiratory response of healthy term infants to breath-by-breath alternations in inspired oxygen at two postnatal ages.

We have studied the reflex respiratory responses to breath-by-breath alternations in fractional inspired oxygen in a group of healthy term infants at two ages, 43 +/- 7 h (study 1) and 47 +/- 3 d (study 2). Respiration was measured noninvasively using inductance plethysmography. Responses to alternations of fractional inspired oxygen between 0.16 and 0.21 (test runs) were compared with responses to alternating the inspired gas between two lines each containing a fractional inspired oxygen concentration of 0.21 (control runs). The respiratory response was measured as the mean percentage breath-by-breath alternation for inspiratory tidal volume (VTI), expiratory tidal volume (VTE), inspiratory time (TI), expiratory time (TE), frequency (f), mean inspiratory flow (VTI/TI), mean expiratory flow (VTE/TE), timing (TI.f), and ventilation. A significant chemoreflex response was present in the infants at the time of study 1, as shown by test runs that were significantly different from control for TI, TE, f, mean inspiratory flow, mean expiratory flow, timing, and ventilation (p < 0.05), and at study 2 for VTI, VTE, TE, f, mean inspiratory flow, mean expiratory flow, timing, and ventilation (p < 0.05). When control and test runs were compared separately with respect to age, there were no significant differences for any respiratory variable between study 1 and study 2. Thus, we did not observe significant maturation of respiratory chemoreflex responses to hypoxia after an age at which we could detect an established response, and this suggests that the "resetting" of chemoreceptor responses to hypoxia is essentially complete within approximately 24-48 h of birth in humans.

Age Factors↗
PubMed1994

Absence of ventilatory responses to alternating breaths of mild hypoxia and air in infants who have had bronchopulmonary dysplasia: implications for the risk of sudden infant death.

Infants who have had bronchopulmonary dysplasia (BPD) are at an increased risk of sudden infant death syndrome. Because failure of the cardiorespiratory response to hypoxia is suggested to play a key role in sudden infant death syndrome, we tested the hypothesis that infants who have had BPD have a reduced respiratory chemoreflex response to hypoxia. We examined the reflex respiratory responses to breath-by-breath alternations in fractional inspired oxygen concentration in eight infants who had had BPD (mean gestation = 27 wk, mean postnatal age = 93 d) who were no longer on supplemental oxygen and compared the responses with those of 12 preterm infants who had not required supplemental oxygen or been mechanically ventilated since birth (mean gestation = 30 wk, mean postnatal age = 38 d). For test runs we alternated fractional inspired oxygen concentration through two gas delivery lines between 0.21 and 0.16 on a breath-by-breath basis, and for control runs we alternated the inspirate between the two gas lines with a fractional inspired oxygen concentration of 0.21 in each. Respiration was measured using inductance plethysmography infants with BPD showed no significant differences between test and control responses for any respiratory variable. In contrast, all respiratory variables in the preterm infants showed test responses significantly greater than control. We speculate that the "blunted" chemoreflex respiratory response seen in infants with BPD may predispose them to subsequent respiratory failure, but we do not known which component of the chemoreflex is impaired.

Bronchopulmonary Dysplasia↗
PubMed1994

Pax-3 expression in segmental mesoderm marks early stages in myogenic cell specification.

Specification of the myogenic lineage begins prior to gastrulation and culminates in the emergence of determined myogenic precursor cells from the somites. The myoD family (MDF) of transcriptional activators controls late step(s) in myogenic specification that are closely followed by terminal muscle differentiation. Genes expressed in myogenic specification at stages earlier than MDFs are unknown. The Pax-3 gene is expressed in all the cells of the caudal segmental plate, the early mesoderm compartment that contains the precursors of skeletal muscle. As somites form from the segmental plate and mature, Pax-3 expression is progressively modulated. Beginning at the time of segmentation, Pax-3 becomes repressed in the ventral half of the somite, leaving Pax-3 expression only in the dermomyotome. Subsequently, differential modulation of Pax-3 expression levels delineates the medial and lateral halves of the dermomyotome, which contain precursors of axial (back) muscle and limb muscle, respectively. Pax-3 expression is then repressed as dermomyotome-derived cells activate MDFs. Quail-chick chimera and ablation experiments confirmed that the migratory precursors of limb muscle continue to express Pax-3 during migration. Since limb muscle precursors do not activate MDFs until 2 days after they leave the somite, Pax-3 represents the first molecular marker for this migratory cell population. A null mutation of the mouse Pax-3 gene, Splotch, produces major disruptions in early limb muscle development (Franz, T., Kothary, R., Surani, M. A. H., Halata, Z. and Grim, M. (1993) Anat. Embryol. 187, 153-160; Goulding, M., Lumsden, A. and Paquette, A. (1994) Development 120, 957-971). We conclude, therefore, that Pax-3 gene expression in the paraxial mesoderm marks earlier stages in myogenic specification than MDFs and plays a crucial role in the specification and/or migration of limb myogenic precursors.

Animals↗