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At least 631 records · Page 35Linked to original sources
PubMed2003

Constitutive coupling of a chimeric dopamine D2/alpha 1B receptor to the phospholipase C pathway: inverse agonism to silent antagonism by neuroleptic drugs.

Neuroleptic drugs have been suggested to act as inverse agonists at the dopamine D2 receptor, but no link between therapeutic efficacy and ligand's intrinsic activity could be determined. Since the resolving capacity to monitor inverse agonism at dopamine D2 receptors is limited, we speculated that receptor constitutive activation could be enhanced by constructing chimeric D2/alpha 1B receptors. Marked inverse agonist responses with a series of dopamine antagonists were obtained by: 1) exchange of the D 2short receptor's 3ICL by that of the alpha 1B-adrenoceptor, 2) incorporation of an activating mutation (Ala 279 Glu) in the distal portion of its 3ICL, and 3) coexpression with a G alpha11 protein. This chimeric D2/alpha 1B receptor construct displayed a ligand binding profile comparable to that of the wild-type (wt) D 2short receptor and an effector activation profile close to that of the wt alpha 1B-adrenoceptor. Most of the dopamine antagonists attenuated by -54 to -59% basal inositol phosphates (IP) formation, thus clearly acting as inverse agonists. Ziprasidone behaved as a silent antagonist (+5% versus basal IP level) and antagonized both dopamine-mediated (pK B, 7.61) and tropapride-mediated (pK B, 8.52) IP responses. Clozapine, olanzapine, and raclopride displayed partial inverse agonist properties (-31, -67, and -71% versus tropapride, respectively), whereas bromerguride (+63%) and cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino tetralin) [(+)-UH 232] (+88%) demonstrated positive agonism. In conclusion, analyses with the chimeric D2/alpha 1B Ala 279 Glu 3ICL receptor construct suggest that neuroleptic drugs can be differentiated on the basis of their intrinsic activity, as they can either activate, inhibit, or be silent at this receptor construct.

Animals↗
PubMed2004

Inverse agonist activity of selected ligands of the cysteinyl-leukotriene receptor 1.

Cysteinyl leukotrienes (CysLTs) are associated with several inflammatory processes, including asthma. Due to this association, considerable effort has been invested in the development of antagonists to the CysLT receptors (CysLT(1)R). Many of these molecules have been shown to specifically interact with CysLT(1)R, but little is known about their impact on the conformation of the receptor and its activity. We were especially interested in possible inverse agonist activity of the antagonists. Using a constitutively active mutant (N106A) of the human CysLT(1)R and the wild-type (WT) receptor coexpressed with the G(alphaq) subunit of the trimeric G protein, we were able to address this issue with ligands commonly used in therapy. We demonstrated that some of these molecules are inverse agonists, whereas others act as partial agonists. In cells expressing the CysLT(1)R mutant N106A exposed to Montelukast, Zafirlukast, or 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), the basal inositol phosphate production was reduced by 53 +/- 6, 44 +/- 3, and 54 +/- 4%, respectively. On the other hand, 6(R)-(4-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid (BayU9773) and 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazole-5-YL)-butoxy]-phenyl ethanone] (LY171883) acted as partial agonists and alpha-pentyl-3-[2-quinolinylmethoxy] benzyl alcohol (REV 5901) as a neutral antagonist. However, in cells expressing CysLT(1)R and G(alphaq), all antagonists used had inverse agonist activity. The decrease in basal inositol phosphate production by ligands with inverse agonist activity could be inhibited by a more neutral antagonist, confirming the specificity of the reaction. We demonstrate here that Montelukast, MK571, and Zafirlukast can act as inverse agonists on the human CysLT(1) receptor.

Acetates↗
PubMed2004

Renal D-amino acid oxidase mediates chiral inversion of N(G)-nitro-D-arginine.

N(G)-nitro-d-arginine (d-NNA), i.v. injected into rats, produced a pressor response, and was presumed to act via chiral inversion into N(G)-nitro-l-arginine (l-NNA), an inhibitor of nitric oxide synthase. We examined the possible role of renal d-amino acid oxidase (DAAO) in the chiral inversion of d-NNA to l-NNA. In pentobarbital-anesthetized rats, l-NNA was detected via capillary electrochromatography in the blood immediately after i.v. injection of d-NNA. The time course of appearance of l-NNA paralleled the increase in blood pressure elicited by d-NNA. Unilateral renal ligation partially, and bilateral ligation completely, blocked the pressor response as well as the conversion of d-NNA to l-NNA. Furthermore, injection into conscious rats of sodium benzoate, a selective DAAO inhibitor, completely blocked the pressor response to naive d-NNA, but not pressor response to d-NNA preincubated with homogenates of the kidney. Homogenates of the kidneys, liver (lesser degree), and brain (much lesser degree) converted d-NNA to l-NNA, and the chiral inversion was blocked by the addition of benzoate. Moreover, d-NNA chiral inversion correlates with the activity of DAAO. Our results reveal a novel pathway of chiral inversion of d-amino acids where the renal DAAO plays an essential role that accounts for the biological activity of d-NNA.

Animals↗
PubMed2001

Inverse agonist activity at the alpha(2A)-adrenergic receptor.

Constitutive activation of G protein-coupled receptors (GPCRs) is now well recognized and many classical GPCR antagonists have been found to be inverse agonists. For the alpha(2A)-adrenergic receptor (AR) we determine the relative inverse efficacies of a series of antagonists and utilize the extended ternary complex model to estimate the fraction of constitutively active mutant (CAM) receptors in the active state. Stable Chinese hamster ovary cell lines expressing the porcine alpha(2A)-AR in its wild-type (WT) and constitutively activated (CAM-T373K) form were isolated. Activation of both G(i) and G(s) was enhanced for CAM receptors. cAMP production was suppressed in cells with the CAM alpha(2A)-AR and this suppression was reversed by alpha(2)-adrenergic antagonists with an order of inverse efficacy of rauwolscine > yohimbine > RX821002 > MK912, whereas phentolamine and idazoxan were essentially neutral antagonists. This striking difference in inverse efficacy between idazoxan and RX821002 may account for in vivo pharmacological differences between these two alpha(2)-adrenergic antagonists. Agonist binding affinity to the non-G protein-coupled CAM receptor was 3- to 9-fold higher than to WT, whereas binding of the most efficacious inverse agonists, yohimbine and rauwolscine, was 1.7- and 2.1-fold weaker. Analysis of this difference by the extended ternary complex model indicates that approximately 50% of the CAM alpha(2A)-AR is in the active (R*) state although there is no detectable constitutive activity of the WT receptor in the absence of agonist.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2004

Inverse agonists: tools to reveal ligand-specific conformations of G protein-coupled receptors.

G protein-coupled receptors (GPCRs) traverse the plasma membrane seven times and produce intracellular effects through interaction with G proteins. Three classes of ligands bind and regulate the activity of GPCRs: agonists, antagonists, and inverse agonists. To describe the activity of these ligands at GPCRs, a two-state receptor model has been proposed in which receptors exist in an equilibrium between inactive (R) and active (R*) states. Agonists preferentially bind and stabilize the active (R*) state. This results in an enrichment of the proportion of active receptors, producing an increase in receptor activity. In contrast, inverse agonists preferentially bind and stabilize receptors in the inactive (R) state. This results in an enrichment of the proportion of inactive receptors, producing a reduction in spontaneous receptor activity. Neutral antagonists have equal preferences for both R and R* states, lack any intrinsic activity, and are able to block actions produced by either agonists or inverse agonists. Exciting observations reported in two recent manuscripts by Gbahou et al. and Azzi et al. indicate that some inverse agonists act not only in opposition to agonists by suppressing constitutive receptor activity, but may also initiate unique signal transduction cascades as well. Specifically, it is proposed that these unique ligands are able to enrich several distinct active receptor conformations, each demonstrating a preference for regulation of a discrete intracellular effector. This suggests that inverse agonists are not merely "the opposite of agonists," but instead may serve as useful tools to investigate ligand-specific conformations of GPCRs.

Animals↗
PubMed1979

Inversion in the lactose region of Escherichia coli K-12.

A spontaneous mutant of Escherichia coli K-12, strain SY99, with an inversion in the lactose region was isolated and partially characterized. The inversion was detected due to inverse chromosomal conjugational transfer after introduction of an F42 (F'lac) episome. The termini of the inversion are between proAB and lac on one side and lac and proC on the other. The inverse conjugational transfer in SY99 did not appear to be absolute but was always accompanied by a residual "normal" counterclockwise mobilization. This residual transfer was further shown to be caused by the intrinsic instability of this region (at least in the line W3110). The possible involvement of IS3 elements flanking the lactose operon is discussed.

Chromosomes, Bacterial↗
PubMed1970

Electrocardiogram in corrected transposition of the great vessels of the bulbo-ventricular inversion type.

Twenty cases of corrected transposition of the great vessels of the bulbo-ventricular inversion type, either lone or combined with other intracardiac anomalies, were analysed. Rhythm and/or atrio-ventricular conduction disturbances were common to all groups of cases. QRS pattern changes were found to be related both to ventricular inversion and to ventricular hypertrophy. Isolated corrected transposition and corrected transposition with systemic ventriculo-atrial regurgitation give rise to tracings suggestive of systemic ventricular hypertrophy.Corrected transposition of the great vessels with pulmonary stenosis or pulmonary artery hypertension is usually accompanied by the electrocardiographic signs of a venous-ventricular hypertrophy, with a characteristic inversion of the normal praecordial pattern. The conventional criteria of ventricular hypertrophy may be applied in corrected transposition of the great vessels but are less reliable than in cases without ventricular inversion. The so-called electrocardiographic pattern of ;ventricular inversion' in this anomaly is related not only to the inverted position of the ventricles but to a greater extent to the predominant, anatomically left, venous-ventricular hypertrophy which re-establishes the normal weight ratio between the anatomically right and anatomically left ventricles.

Adolescent↗
PubMed2004

Inverse agonism: more than reverting constitutively active receptor signaling.

Seven-transmembrane receptors constitute one of the major families of proteins encoded by the genome. This type of receptor is one of the most important targets of the pharmaceutical industry, and many of the drugs with significant therapeutic action have been shown to be inverse agonists. Concepts regarding the mechanisms by which ligands activate and inactivate receptors are thought to be far more complex that a simple on-off switch. For both drug design and pharmacology principles, it is important to understand the mechanisms by which these drugs achieve their effects. Recent studies have demonstrated intriguing actions of inverse agonists. They have been shown not only to block constitutive responses of receptors but also to activate and regulate seven-transmembrane receptor signaling and trafficking. The activation of pathways by inverse agonists was shown to occur mainly via G-protein-independent mechanisms. These findings emphasize the importance of inverse agonism as a principle of receptor regulation. In this paper, we will review the evidence supporting inverse agonist promoted signaling and trafficking.

Ligands↗
PubMed1979

Exercise-induced U-wave inversion as a marker of stenosis of the left anterior descending coronary artery.

The prevalence and cineangiographic correlates of exercise-induced inversion of U waves were studied in 248 patients. Exercise-induced U-wave inversion was observed in 36 patients (15%), of whom 35 had greater than or equal to 75% stenosis in one or more of the major coronary arteries. The proximal left anterior descending or left main coronary artery was involved in 33 of these patients, including 24 patients with no electrocardiographic evidence of anterior myocardial infarction. Exercise-induced U-wave inversion was observed in the absence of an abnormal resting 12-lead ECG. Only one of the 82 patients (1.2%) without significant coronary artery disease demonstrated exercise-induced U-wave inversion, and this patient had a primary cardiomyopathy. We conclude that exercise-induced inversion of the U-wave is highly predictiveof significant coronary artery disease and, more specifically, of disease of the proximal left anterior descending coronary artery.

Adult↗
PubMedDate not supplied

Electromyographic latency changes in the ankle musculature during inversion moments.

Ten uninjured subjects (ages 18 to 30 years) had electromyographic testing of the peroneus longus, peroneus brevis, and tibialis anterior muscles in response to inversion moments at two speeds (50 and 200 deg/sec) and two joint angles (neutral and 20 degrees of plantar flexion) using a hydraulically controlled tilt platform. Subjects underwent 10 trials of each type of inversion moment on Day 1 testing, which included both legs. On Day 2, subjects again underwent 10 trials of each type of inversion moment, but only on one leg. Reliability was assessed by comparing left and right leg data within muscle groups for Day 1 testing. Repeatability was assessed by comparing Day 1 with Day 2 data. The latency measurements (the time between the beginning of the inversion moment and the onset of first motor response) for the peroneus brevis and tibialis anterior muscles were found to be reliable and repeatable with no significant differences between the same muscle groups. The peroneus longus muscle had a significant difference between legs but was found to be highly repeatable. Speed of inversion moment and plantar flexion angle both caused significant changes in latency response of the peroneus muscles, with increased speed producing a shorter latency response and increased angle causing a longer latency response. Our results indicate a loss of protective reflexes with increasing plantar flexion.

Adolescent↗
PubMedDate not supplied

Ankle sensorimotor control and eversion strength after acute ankle inversion injuries.

We performed this study to monitor changes in ankle eversion strength and sensorimotor control functions after acute ankle inversion injury. Forty-four patients with clinical grade II to III first-time ankle inversion sprains were tested for 1) pathologic talar tilt and anterior talar translation at 1 and 12 weeks after injury; 2) isometric eccentric ankle eversion strength and 3) peroneal reaction time to sudden ankle inversion at 3, 6, and 12 weeks after injury; and 4) accuracy of inversion position assessment 1, 3, 6, and 12 weeks after injury. Not all patients could perform all tests at the early follow-up visits. There was mechanical instability in 19 of 40 tested patients at 1 week and in 4 patients at 12 weeks after injury. Eversion strength was 88% of the contralateral side 3 weeks after injury, rising to 96% after 12 weeks. The magnitude of error of inversion position sense was 190% of the contralateral side 1 week after injury; this was still affected after 12 weeks, but fell to 133%. Patients with pathologic talar tilt or anterior talar translation, or both, at 1 week after injury did not show significantly greater error in position assessment or reduction in eversion strength when compared with patients with ankles that remained stable after injury.

Acute Disease↗
PubMed2001

Estimation of intra-cranial neural activities by means of regularized neural-network-based inversion techniques.

Artificial neural networks can be exploited to solve inverse problems arising from the estimation of neural activities in the brain. In this paper, we review the network inversion techniques for solving inverse problems with special attention directed towards electroencephalographic dipole localization and the improvement of positron emission tomography. In our regularized network inversion technique, for stabilizing the solution, we explicitly include the a priori knowledge by adding penalty terms to the energy function and/or build this knowledge into the architecture of the multi-layered neural networks that are used as an inverse problem solver. In the electroencephalogram analysis, the consensus term added to the energy function facilitated 3-dipole localization for visually evoked potentials. Effectiveness of our regularization is shown in improving the positron emission tomographic images and for generating metabolic images of the brain, under the constraints given by the a priori knowledge inherent to the measurement systems and physiological rules.

Algorithms↗
PubMedDate not supplied

A rapid method for computing the inverse of the gametic covariance matrix between relatives for a marked quantitative trait locus.

The inverse of the gametic covariance matrix between relatives, G(-1), for a marked quantitative trait locus (QTL) is required in best linear unbiased prediction (BLUP) of breeding values if marker data are available on a QTL. A rapid method for computing the inverse of a gametic relationship matrix for a marked QTL without building G itself is presented. The algorithm is particularly useful due to the approach taken in computing inbreeding coefficients by having to compute only few elements of G. Numerical techniques for determining, storing, and computing the required elements of G and the nonzero elements of the inverse are discussed. We show that the subset of G required for computing the inbreeding coefficients and hence the inverse is a tiny proportion of the whole matrix and can be easily stored in computer memory using sparse matrix storage techniques. We also introduce an algorithm to determine the maximum set of nonzero elements that can be found in G(-1) and a strategy to efficiently store and access them. Finally, we demonstrate that the inverse can be efficiently built using the present techniques for very large and inbred populations.

Algorithms↗
PubMed2006

Influence of head models on neuromagnetic fields and inverse source localizations.

BACKGROUND: The magnetoencephalograms (MEGs) are mainly due to the source currents. However, there is a significant contribution to MEGs from the volume currents. The structure of the anatomical surfaces, e.g., gray and white matter, could severely influence the flow of volume currents in a head model. This, in turn, will also influence the MEGs and the inverse source localizations. This was examined in detail with three different human head models. METHODS: Three finite element head models constructed from segmented MR images of an adult male subject were used for this study. These models were: (1) Model 1: full model with eleven tissues that included detailed structure of the scalp, hard and soft skull bone, CSF, gray and white matter and other prominent tissues, (2) the Model 2 was derived from the Model 1 in which the conductivity of gray matter was set equal to the white matter, i.e., a ten tissuetype model, (3) the Model 3 consisted of scalp, hard skull bone, CSF, gray and white matter, i.e., a five tissue-type model. The lead fields and MEGs due to dipolar sources in the motor cortex were computed for all three models. The dipolar sources were oriented normal to the cortical surface and had a dipole moment of 100 microA meter. The inverse source localizations were performed with an exhaustive search pattern in the motor cortex area. A set of 100 trial inverse runs was made covering the 3 cm cube motor cortex area in a random fashion. The Model 1 was used as a reference model. RESULTS: The reference model (Model 1), as expected, performed best in localizing the sources in the motor cortex area. The Model 3 performed the worst. The mean source localization errors (MLEs) of the Model 3 were larger than the Model 1 or 2. The contour plots of the magnetic fields on top of the head were also different for all three models. The magnetic fields due to source currents were larger in magnitude as compared to the magnetic fields of volume currents. DISCUSSION: These results indicate that the complexity of head models strongly influences the MEGs and the inverse source localizations. A more complex head model performs better in inverse source localizations as compared to a model with lesser tissue surfaces.

Action Potentials↗
PubMed1999

Actomyosin contraction of the posterior hemisphere is required for inversion of the Volvox embryo.

During inversion of a Volvox embryo, a series of cell shape changes causes the multicellular sheet to bend outward, and propagation of the bend from the anterior to the posterior pole eventually results in an inside-out spherical sheet of cells. We use fluorescent and electron microscopy to study the behavior of the cytoskeleton in cells undergoing shape changes. Microtubules are aligned parallel to the cell's long axis and become elongated in the bend. Myosin and actin filaments are arrayed perinuclearly before inversion. In inversion, actin and myosin are located in a subnuclear position throughout the uninverted region but this localization is gradually lost towards the bend. Actomyosin inhibitors cause enlargement of the embryo. The bend propagation is inhibited halfway and, as a consequence, the posterior hemisphere remains uninverted. The arrested posterior hemisphere will resume and complete inversion even in the presence of an actomyosin inhibitor if the anterior hemisphere is removed microsurgically. We conclude that the principal role of actomyosin in inversion is to cause a compaction of the posterior hemisphere; unless the equatorial diameter of the embryo is reduced in this manner, it is too large to pass through the opening defined by the already-inverted anterior hemisphere.

Actomyosin↗
PubMed1981

Inverse solution of ST vector as a single unfixed location dipole in patients with acute myocardial infarction.

For the quantitative assessment of infarct site and size in patients with acute myocardial infarction, an attempt was made to solve the inverse problem, that is, to characterize ST vector in the infarcted myocardium from ST segment deviations in 29 precordial leads and their sterical positions A simple inverse model was employed, assuming that the source origin of ST segment displacement in surface electrocardiograms was a single unfixed dipole embedded in the homogeneous infinite medium. The magnitude, direction and position of ST vector were calculated as an inverse solution by computer. The direction of ST vector determined by this inverse problem was well in accord with infarct site assessed by left ventriculography or myocardial scintigraphy carried out later. However, the magnitude of ST vector was poorly correlated (r = 0.47, p less than 0.005, n = 17) with infarct size estimated from serum creatine phosphokinase, although a good correlation (r = 0.74) was obtained when 3 cases with extremely large infarction were excluded. These results suggest that our inverse solution of ST vector is useful for prediction of the site and size of acute myocardial infarction.

Aged↗
PubMed2006

Individual differences in children's understanding of inversion and arithmetical skill.

UNLABELLED: Background and aims. In order to develop arithmetic expertise, children must understand arithmetic principles, such as the inverse relationship between addition and subtraction, in addition to learning calculation skills. We report two experiments that investigate children's understanding of the principle of inversion and the relationship between their conceptual understanding and arithmetical skills. SAMPLE: A group of 127 children from primary schools took part in the study. The children were from 2 age groups (6-7 and 8-9 years). METHODS: Children's accuracy on inverse and control problems in a variety of presentation formats and in canonical and non-canonical forms was measured. Tests of general arithmetic ability were also administered. RESULTS: Children consistently performed better on inverse than control problems, which indicates that they could make use of the inverse principle. Presentation format affected performance: picture presentation allowed children to apply their conceptual understanding flexibly regardless of the problem type, while word problems restricted their ability to use their conceptual knowledge. Cluster analyses revealed three subgroups with different profiles of conceptual understanding and arithmetical skill. Children in the 'high ability' and 'low ability' groups showed conceptual understanding that was in-line with their arithmetical skill, whilst a 3rd group of children had more advanced conceptual understanding than arithmetical skill. CONCLUSIONS: The three subgroups may represent different points along a single developmental path or distinct developmental paths. The discovery of the existence of the three groups has important consequences for education. It demonstrates the importance of considering the pattern of individual children's conceptual understanding and problem-solving skills.

Age Factors↗
PubMed2006

Improved inverse PCR scheme for metagenome walking.

Inverse PCR has been used for the recovery of genome regions flanking a known sequence, although its application to metagenome walking is limited due to inefficient amplification from low copy number fragments. Here we present an improved inverse PCR scheme that enables walking of rare fragments in environmental metagenomes. Our scheme includes the following steps: (i) inverse PCR in which one primer is connected to an affinity tag; (ii) affinity purification of PCR products for removing background metagenome; and (iii) nested PCR to recover target flanking regions (IAN-PCR). In a model experiment, flanking regions of a gene fragment in Ralstonia eutropha were recovered from mixtures of Ralstonia and Escherichia genomes by standard inverse PCR, inverse PCR coupled to nested PCR (IN-PCR), and IAN-PCR, showing that they were recovered when ratios of Ralstonia genome to the background Escherichia genome were greater than 10(-1), 10(-3), and 10(-5), respectively. The utility of IAN-PCR was also examined by recovering flanking regions of PCR-amplified putative chitinase gene fragments from a groundwater metagenome, showing that IAN-PCR obtained flanking regions for more diverse gene fragments than IN-PCR. Since rare sequences are a critical element of natural genetic diversity, IAN-PCR enables access to undiscovered diverse genes in the environment.

Amino Acid Motifs↗