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PubMedDate not supplied

Human dopamine transporter gene not linked to schizophrenia in multigenerational pedigrees.

A large body of data suggests that perturbations in brain dopaminergic transmission play a role in the pathogenesis of schizophrenia. Recently, the gene for the human dopamine transporter has been cloned and polymorphisms have been identified. Because mutations of the dopamine transporter gene might underlie the cause of schizophrenia in a subset of families, we undertook a linkage analysis between schizophrenia in 9 families and a dopamine transporter gene polymorphism. Evidence of linkage was not found in most families assuming autosomal dominant or recessive inheritance.

Carrier Proteins↗
PubMed2004

Urotensin II promotes hypertrophy of cardiac myocytes via mitogen-activated protein kinases.

Urotensin II and its receptor are coexpressed in the heart and up-regulated during cardiac dysfunction. In cultured neonatal cardiomyocytes, we mimicked this up-regulation using an adenovirus to increase expression of the urotensin receptor. In this model system, urotensin II promoted strong hypertrophic growth and phenotypic changes, including cell enlargement and sarcomere reorganization. Urotensin II potently activated the MAPKs, ERK1/2 and p38, and blocking these kinases with PD098059 and SB230580, respectively, significantly inhibited urotensin II-mediated hypertrophy. In contrast, urotensin II did not activate JNK. The activation of ERK1/2 and p38 as well as cellular hypertrophy was independent of protein kinase C, and calcium and phosphoinositide 3-kinase, yet dependent on the capacity of the urotensin receptor to trans-activate the epidermal growth factor receptor. Urotensin II promoted the tyrosine phosphorylation of epidermal growth factor receptors, which was inhibited by the selective epidermal growth factor receptor kinase inhibitor, AG1478. These data indicate that perturbations in cardiac homeostasis, which lead to up-regulation of urotensin II receptors, promote urotensin II-mediated cardiomyocyte hypertrophy via ERK1/2 and p38 signaling pathways in an epidermal growth factor receptor-dependent manner.

Adenoviridae↗
PubMed2003

Competitive transport of cadmium and lead through a natural porous medium: influence of the solid/liquid interface processes.

Contaminated groundwater typically contains different metal contaminants which may compete with each other for the same adsorption sites. Understanding the fate of these micro-pollutants is of primary importance for the assessment of the risk associated with their dispersion in the environment and for the evaluation of the most appropriate remediation technology. In this regard, column techniques can be considered as useful tools both to perform transport experiments and to obtain equilibrium adsorption data without any perturbation of the actual solid/liquid interface. Cd and Pb monocomponent step column experiments were used to obtain adsorption isotherms on a natural aquifer material. A General Composite approach was used to define the equilibrium adsorption model characterized by two types of sites (ion-exchange and surface complexation sites). Coupling the adsorption model with the Advection-Dispersion equation (by IMPACT code) allowed us to well represent the monocomponent step experiments. The model was successfully used to predict the competitive Cd and Pb transport behaviour. Cd peaks of concentration due to Pb competition were experimentally observed and simulated by the model. This behaviour can be described only by an accurate modelling of the interaction and cannot be predicted by simple isotherms (such as Langmuir or Freundlich type).

Adsorption↗
PubMed1991

Accumulation of CHO cells in G2 phase following exposure to WR-1065.

The radioprotector WR-1065 (2-[(aminopropyl)amino]ethanethiol) is known to protect mammalian cells from the cytotoxic and mutagenic effects of radio- and chemotherapeutic agents, but the exact mechanisms involved in this protection are not fully known. To help determine the effects of WR-1065 alone on cells, we examined its effect on a variety of cellular processes. Incubation of AA8 cells in 4 mM WR-1065 did not significantly affect the rate of DNA synthesis. Autoradiographic analysis of heavily labeled (S-phase population) nuclei of AA8 cells showed no significant difference in the S-phase population of WR-1065-treated versus control cells for up to 3 h. An examination of the effect of WR-1065 on repair synthesis, as measured by unscheduled DNA synthesis (UDS) in cells exposed to 15 Gy, showed no difference between treated and sham-treated cells for up to 2 h exposure. A significant reduction in the amount of UDS was seen in cells treated with the protector for 2.5 and 3 h. Incubation of cells in WR-1065 did alter the cell cycle distributions. An increase in the G2-phase population with a corresponding decrease in the G1-phase population was observed in cells incubated up to 3 h in the presence of 4 mM WR-1065. After the removal of WR-1065 at 3 h, a redistribution of the cells throughout the cell cycle occurred as has been observed in cells treated with other synchronization agents. These data suggest that perturbations in cell cycle progression, rather than direct effects on the rate of DNA synthesis, could play a role in the increased survival and reduced mutation frequencies observed in the presence of WR-1065.

Animals↗
PubMed1990

Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells.

Elevated blood levels of homocysteine are associated with atherosclerosis and thrombotic disease. We previously reported that treatment of cultured endothelial cells with homocysteine increased endogenous factor V activity by activation of the cofactor. Because endothelial cell-associated factor Va would be regulated by the protein C mechanism, the ability of homocysteine-treated arterial and venous endothelial cells to activate protein C was investigated. Both arterial and venous endothelial cells activated protein C; 0.6 mmol/L homocysteine reduced endothelial cell protein C activation by 12%. Maximal inhibition (90%) of protein C activation occurred with 7.5 to 10 mmol/L homocysteine after 6 to 9 hours of incubation. Metabolism of homocysteine was not accelerated by cultured endothelial cells. Investigation of the mechanism(s) by which homocysteine reduced protein C activation indicated that the metabolite did not induce an inhibitor to activated protein C, but in low concentrations acted as a competitive inhibitor to thrombin. These data suggest that perturbation of the vascular endothelial cell protein C mechanism by homocysteine may contribute to the thrombotic tendency seen in patients with elevated blood levels of this metabolite.

Cells, Cultured↗
PubMed1990

Pristane induced changes in rat lymphocyte membrane fluidity.

The ability of pristane (2,6,10,14-tetramethylpentadecane) to act as a membrane perturbant was examined. Data obtained from rats treated with pristane by either intraperitoneal injection or the diet indicated there were significant increases over normal in the amount of pristane in lymphoid cells; 50-89% was incorporated into the plasma membranes. Fluorescence polarization analyses, using 1,6-diphenyl-1,3,5-hexatriene, of normal plasma membrane isolates demonstrated that splenic and Peyer's patch lymphocytic membranes were more viscous than those of the thymus, mesenteric lymph nodes or peripheral blood. Studies to assess the effects of pristane on membrane viscosity demonstrated that there were significant differences in the viscosities of plasma membrane isolates from lymphocytes of normal versus pristane treated rats. The observed changes were dependent on route of administration, length of exposure and the lymphoid organ examined.

Animals↗
PubMed1985

Treatment of baboon with vinblastine: insights into the mechanisms of pharmacologic stimulation of Hb F in the adult.

Vinblastine was administered to anemic baboons to test whether stimulation of Hb F takes place following distortion of erythropoiesis by an M-stage-specific compound. The treatments elicited erythroid cell cytoreduction followed by regeneration. During the phase of reticulocyte reduction, gamma/gamma + beta biosynthetic ratios increased without increment in F reticulocytes, suggesting that there was increased production of Hb F per F cell. The phase of reticulocyte regeneration was associated with sharp increments in relative (percentage) and absolute F reticulocytes. These data suggest that perturbations of erythropoiesis underlie the stimulation of Hb F synthesis by vinblastine. Accelerated or abnormal precursor maturation may account for the release of shift F reticulocytes with higher Hb F content, during the reduction phase. Accelerated total erythroid differentiation/maturation may account for the increment in F reticulocyte numbers during the phase of regeneneration.

Anemia↗
PubMed1989

Interaction of plasma clotting factors with vascular endothelial cells in hemostasis and thrombosis with special reference to endothelial cell tissue factor.

The interaction of plasma clotting factors with vascular endothelial cells was investigated. Human umbilical cord vein endothelial cells generated tissue factor activity after treatment with various stimulators including IL-1. Cycloheximide inhibited production of the tissue factor in the cells, but did not affect the expression of the tissue factor activity on the surface of endothelial cells. Endotoxin-treated vascular endothelial cells activated Factor X in the presence of Factor VII and calcium ion. Activation of Factor X by endothelial cells with Factor VII was enhanced by the presence of both Factors VIII and IX. Binding study revealed that endotoxin-treated endothelial cells bound Factor IX. These data suggest that perturbed vascular endothelium expresses tissue factor activity on the cell surface, binds factor IX and in the presence of Factor VII, activates not only factor X but also Factor IX.

Blood Coagulation Factors↗
PubMed1979

Modulation of thymocyte membrane potential by concanavalin A.

Binding of convanavalin A, a potent mitogenic lectin, to thymocyte surface membrane causes depolarization of membrane potential. The effect is suppressed by alpha-methyl-D-glucoside, a haptenic inhibitor of this lectin, or by low temperature. Colchicine and cytochalasin B aslso suppress the change. These data indicate that perturbation of thymocyte surface membrane receptors induced by concanavalin A might be linked to change in the functional state of cellular cytoskeletal systems in turn causing depolarization of thymocyte surface membrane. The initial event generated by receptor-ligand interaction on the outer surface could be translated into cellular interior action only under highly fluid conditions of membrane lipid. Depolarization of thymocyte plasma membrane may be involved in the triggering mechanism of metabolic burst associated with blastoid transformation.

Animals↗
PubMed1977

Pertechnetate distribution in man after intravenous infusion: a compartmental model.

Using a primed infusion technique, distribution of pertechnetate was monitored in normal volunteer subjects over an 8-hr period. Two groups of subjects were studied, during hours 0-4 (n = 8) and hours 4-8 (n = 7), respectively, of the infusion. At 6.5 hr a large dose of NaI (1000 mg) was administered intravenously to the second group. Plasma, salivary, and urinary radioactivities were assayed, and external counts were made of radioactivities over the neck, thigh, and right upper abdomen. A kinetic model was developed for pertechnetate based upon the distribution data, the iodide perturbation, and known physiology for pertechnetate and iodide. The model has three major subsystems: (1) the thyroid trap; (2) a whole-body distribution, containing plasma and two extravascular compartments; and (3) the gastrointestinal tract, including the salivary, stomach (including upper small intestine), and two lower intestinal compartments. One of the latter, which turns over very slowly, is believed to represent bowel wall. The large NaI dose markedly reduced transport into compartments of the thyroid trap, the saliva, and the stomach and small intestine. This study shows that, in most respects, pertechnetate is distributed qualitatively but not quantitatively like iodide but that, unlike iodide, large bowel distribution plays an important role, especially in long-term studies.

Adult↗
PubMed2003

Influence of the particle porosity on chromatographic band profiles.

The mass transfer kinetics of butyl benzoate, eluted on a monolithic RPLC column with methanol-water (65:35, v/v) as the mobile phase was investigated, using the perturbation method to acquire isotherm data and the mobile phase velocity dependence of the height equivalent to a theoretical plate of perturbation peaks to acquire kinetics data. The equilibrium isotherm of butyl benzoate is accounted for by the liquid-solid extended multilayer BET isotherm model. The total porosity of the column varies much with the butyl benzoate concentration, influencing strongly the parameters of its mass transfer kinetics and the profiles of the breakthrough curves. Using all these parameters, the general rate model of chromatography predicts band profiles and Van Deemter curves that are in excellent agreement with experimental results provided the influence of concentration on the porosity is properly taken into account. This agreement confirms the validity of the models selected for the isotherm and for the mass transfer kinetics.

Chromatography, Liquid↗
PubMed2004

Measurement of the generalized forward spin polarizabilities of the neutron.

The generalized forward spin polarizabilities gamma(0) and delta(LT) of the neutron have been extracted for the first time in a Q2 range from 0.1 to 0.9 GeV2. Since gamma(0) is sensitive to nucleon resonances and delta(LT) is insensitive to the Delta resonance, it is expected that the pair of forward spin polarizabilities should provide benchmark tests of the current understanding of the chiral dynamics of QCD. The new results on delta(LT) show significant disagreement with chiral perturbation theory calculations, while the data for gamma(0) at low Q2 are in good agreement with a next-to-leading-order relativistic baryon chiral perturbation theory calculation. The data show good agreement with the phenomenological MAID model.

Journal Article↗
PubMed2025

BMDx2: A Tool for Integrating Toxicogenomics-Based Dose-Dependency Analysis and AOP-Based Mechanistic Insights.

Despite the advent of mechanistic toxicology using omics data to link molecular perturbations with systemic outcomes, regulatory toxicology still lacks the application of mechanism-anchored metrics from such data. This is partially because traditional gene-centric analysis often falls short of linking molecular changes to adverse outcomes. To address this gap, BMDx2, an open-source tool that transforms multi-dose toxicogenomics datasets into quantitative, mechanistic evidence for human chemical safety assessment is developed. BMDx2 couples benchmark-dose modeling with Adverse Outcome Pathway (AOP) enrichment to derive transcriptomic-based points of departure, enabling potency ranking, chemical prioritization, and mechanistically anchored explanations of the effect of chemical exposures. BMDx2 can process a broad range of data, including DNA microarray and RNA sequencing studies. Here, case studies are used to illustrate the versatility of BMDx2 in characterizing the mechanism of action of chemicals. An initial case study on carbon nanotubes exposure applies integrative analysis of transcriptomics and genome-wide DNA methylation data, uncovering cellular reprogramming processes underlying fibrosis. A second case study on bleomycin exposure demonstrate how transcriptomic data alone can be mapped to fibrosis-related AOPs in a standardized, regulatory appropriate manner. Together, these examples show how BMDx2 supports the regulatory application of toxicogenomics and accelerates mechanism-based chemical safety evaluation.

Toxicogenetics↗
PubMed2000

Structure-fluorescence correlations in a single tryptophan mutant of carp parvalbumin: solution structure, backbone and side-chain dynamics.

Heterogeneous fluorescence intensity decays of tryptophan in proteins are often rationalized using a model which proposes that different rotameric states of the indole alanyl side-chain are responsible for the observed fluorescence lifetime heterogeneity. We present here the study of a mutant of carp parvalbumin bearing a single tryptophan residue at position 102 (F102W) whose fluorescence intensity decay is heterogeneous and assess the applicability of a rotamer model to describe the fluorescence decay data. We have determined the solution structure of F102W in the calcium ligated state using multi-dimensional nuclear magnetic resonance (NMR) and have used the minimum perturbation mapping technique to explore the possible existence of multiple conformations of the indole moiety of Trp102 of F102W and, for comparison, Trp48 of holo-azurin. The maps for parvalbumin suggest two potential conformations of the indole side-chain. The high energy barrier for rotational isomerization between these conformers implies that interwell rotation would occur on time-scales of milliseconds or greater and suggests a rotamer basis for the heterogeneous fluorescence. However, the absence of alternate Trp102 conformers in the NMR data (to within 3 % of the dominant species) suggests that the heterogeneous fluorescence of Trp102 may arise from mechanisms independent of rotameric states of the Trp side-chain. The map for holo-azurin has only one conformation, and suggests a rotamer model may not be required to explain its heterogeneous fluorescence intensity decay. The backbone and Trp102 side-chain dynamics at 30 degrees C of F102W has been characterized based on an analysis of (15)N NMR relaxation data which we have interpreted using the Lipari-Szabo formalism. High order parameter (S(2)) values were obtained for both the helical and loop regions. Additionally, the S(2) values imply that the calcium binding CD and EF loops are not strictly equivalent. The S(2) value for the indole side-chain of Trp102 obtained from the fluorescence, NMR relaxation and minimum perturbation data are consistent with a Trp moiety whose motion is restricted.

Amino Acid Substitution↗
PubMed1999

Interaction between voluntary and postural motor commands during perturbed lifting.

STUDY DESIGN: An experimental study was conducted to evaluate the effect of an unexpected postural perturbation during a lifting task. OBJECTIVES: To investigate electromyographic responses in the erector spinae to a postural perturbation, simulating slipping, during an ongoing voluntary lifting movement. It was hypothesized that specific combinations of voluntary movement and postural perturbation present a situation in which injury caused by a rapid switch between conflicting motor commands can occur. SUMMARY OF BACKGROUND DATA: Studies of postural perturbations have mainly focused on behavior during static tasks such as quiet, upright standing. To date, there are no published studies of the effect of a perturbation during an ongoing voluntary lifting movement. METHODS: Subjects standing on a movable platform were exposed to random perturbations while lifting a 20-kg load. Muscle activity was recorded from flexor and extensor muscles of the trunk and hip. Trunk flexion angle in the sagittal plane was recorded with a video system. RESULTS: Perturbations forward were followed by an increased activity in erector spinae superimposed on the background activation present during the lift, indicating that both the voluntary and postural motor programs caused an activation of erector spinae. During backward perturbation, however, there was a sudden cessation of erector spinae activity followed by an extended period of rapid electromyographic amplitude fluctuations while the trunk was flexing, indicating an eccentric contraction of the erector spinae. CONCLUSIONS: This erratic behavior with large electromyographic amplitude fluctuations in the erector spinae after a backward slip during lifting may indicate a rapid switch between voluntary and postural motor programs that require conflicting functions of the back muscles. This may cause rapid force changes in load-carrying tissue, particularly in those surrounding the spine, thus increasing the risk of slip-and-fall-related back injuries.

Adult↗
PubMed2001

Tomography of joint P-wave traveltime and polarization data: a simple approach for media with low to moderate velocity gradients.

An elastic wave tomography method utilizing joint traveltime and polarization data is proposed that is computationally simpler than the existing methods [Hu and Menke, Geophys. J. Int. 110, 63 (1992); Farra and Begat, Geophys. J. Int. 121, 371 (1995)]. In the linearization problem for the use of polarization data, we start with ray perturbation theory and assume that the medium is weakly inhomogeneous. Then the problem formulation for polarization data is approximately expressed as a linear integral of the gradient of the medium slowness perturbation along a reference ray. We call this a quasi-linear approximation which ignores the effect of the perturbation of the ray position on the first-order perturbation of the ray slowness vector. To efficiently obtain the solution for multi-data sets, a quadratic objective functional is constructed by including the data misfit terms and a model constraint term. Then a new conjugate gradient type of iterative reconstruction algorithm is developed to solve this minimization problem. This algorithm is also an extension of the conjugate gradient approach for standard least-squares problems. The feasibility and capability of the proposed tomography method is illustrated by conducting both noise-free and noisy synthetic experiments in a cross-hole geometry. The numerical results demonstrate that the additional use of polarization data not only improves the image quality, but also has a stabilizing effect on the iterative tomography solution. However, the limitation of the method is that it becomes inaccurate if the velocity variations in the medium change rapidly with position.

Journal Article↗
PubMed1988

Proton NMR studies of human hemoglobin variants modified in the proximal side of beta heme pocket. Implications for the affinity control and cooperative mechanism.

Using high resolution proton NMR spectroscopy, we have investigated 10 human hemoglobin variants modified in the proximal side of the heme pocket in beta subunits. Comparative observation of several resonances in the spectra of liganded and unliganded hemoglobins allowed us to characterize the localization and nature of the structural perturbations induced by amino acid substitutions or chemical modification. The present data indicate that the structural perturbations are localized in the beta subunits, mainly in the tertiary domain surrounding the modification site. Analysis of the aromatic region of the liganded hemoglobin spectra gives substantial information for the assignment of the His-beta 97 C-2H resonance. Correlation of the spectroscopic observations with the functional characteristics of the studied hemoglobins demonstrates that structural factors localized in the proximal side of the heme pocket can control the ligand-iron interaction taking place on the other heme side. The structural perturbations induced by the modifications in the F or FG segments of the beta subunits do not extend to the distal side but rather to the alpha 1 beta 2 interface. This argues the existence of a gradient of tertiary structural stability, indicating a possible structural pattern of heme-heme interaction in the cooperativity control.

Amino Acids↗
PubMed2005

Influence diagnostics for two-component Poisson mixture regression models: applications in public health.

In many medical and health applications, Poisson mixture regression models are commonly used to analyse heterogeneous count data. Motivated by two data sets drawn from public health studies, influence diagnostics are proposed for assessing the sensitivity of the fitted two-component Poisson mixture regression models. Under various perturbations of the observed data or model assumptions, influence assessments based on the local influence approach are developed for detecting clusters and/or individual observations that impact on the estimation of model parameters. Results from studies on recurrent urinary tract infections and maternity length of stay illustrate the usefulness of the influence diagnostics.

Cluster Analysis↗