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PubMed2002

A 5-HT4 receptor transmembrane network implicated in the activity of inverse agonists but not agonists.

Activation of G protein-coupled receptors is thought to involve disruption of intramolecular interactions that stabilize their inactive conformation. Such disruptions are induced by agonists or by constitutively active mutations. In the present study, novel potent inverse agonists are described to inhibit the constitutive activity of 5-HT(4) receptors. Using these compounds and specific receptor mutations, we investigated the mechanisms by which inverse agonists may reverse the disruption of intramolecular interactions that causes constitutive activation. Two mutations (D100(3.32)A in transmembrane domain (TMD)-III and F275(6.51)A in TMD-VI) were found to completely block inverse agonist effects without impairing their binding properties nor the molecular activation switches induced by agonists. Based on the rhodopsin model, we propose that these mutated receptors are in equilibrium between two states R and R* but are unable to reach a third "silent" state stabilized by inverse agonists. We also found another mutation in TMD-VI (W272(6.48)A) that stabilized this silent state. This mutant remained fully activated by agonists. Molecular modeling indicated that Asp-100, Phe-275, and Trp-272 might constitute a network required for stabilization of the silent state by the described inverse agonists. However, this network is not necessary for agonist activity.

Animals↗
PubMed2003

The effect of inversion on the encoding of normal and "thatcherized" faces.

In the "Thatcher illusion" a face, in which the eyes and mouth are inverted relative to the rest of the face, looks grotesque when shown upright but not when inverted. In four experiments we investigated the contribution of local and global processing to this illusion in normal observers. We examined inversion effects (i.e., better performance for upright than for inverted faces) in a task requiring discrimination of whether faces were or were not "thatcherized". Observers made same/different judgements to isolated face parts (Experiments 1-2) and to whole faces (Experiments 3-4). Face pairs had the same or different identity, allowing for different processing strategies using feature-based or configural information, respectively. In Experiment 1, feature-based matching of same-person face parts yielded only a small inversion effect for normal face parts. However, when feature-based matching was prevented by using the face parts of different people on all trials (Experiment 2) an inversion effect occurred for normal but not for thatcherized parts. In Experiments 3 and 4, inversion effects occurred with normal but not with thatcherized whole faces, on both same- and different-person matching tasks. This suggests that a common configural strategy was used with whole (normal) faces. Face context facilitated attention to misoriented parts in same-person but not in different-person matching. The results indicate that (1) face inversion disrupts local configural processing, but not the processing of image features, and (2) thatcherization disrupts local configural processing in upright faces.

Adult↗
PubMed2005

Evidence for rule-based processes in the inverse base-rate effect.

Three studies provide convergent evidence that the inverse base-rate effect (Medin & Edelson, 1988) is mediated by rule-based cognitive processes. Experiment 1 shows that, in contrast to adults, prior to the formal operational stage most children do not exhibit the inverse base-rate effect. Experiments 2 and 3 demonstrate that an adult sample is a mix of participants relying on associative processes who categorize according to the base-rate and participants relying on rule-based processes who exhibit a strong inverse base-rate effect. The distribution of the effect is bimodal, and removing participants independently classified as prone to rule-based processing effectively eliminates the inverse base-rate effect. The implications for current explanations of the inverse base-rate effect are discussed.

Adult↗
PubMed1996

Interpretation of inverse dose-rate effects for mutagenesis by sparsely ionizing radiation.

An inverse dose-rate effect has sometimes been observed for mutagenesis in cells exposed to gamma-rays. We model such data quantitatively with the key assumption that the effect is caused in cycling cells by correlated variations in sensitivity across the cell cycle, for both mutation and killing. We quantify this approach using the LQR (linear-quadratic + resensitization) formalism, which describes the response to radiation of a heterogeneous cell population. This model is applied to an exponentially growing population. We compare its predictions with dose- and dose-rate dependent mutation data and show that it can well fit the observed inverse dose-rate effect, as well as providing an explanation of why inverse dose-rate effects have been seen in some experiments, but not in others. The actual values of the model parameters emerging from the analysis are reasonable in magnitude, based on their biological interpretations. We conclude that the LQR model can quantify cell-cycle redistribution effects without overparameterization, and that the data favour a correlation explanation of inverse dose-rate effects for mutagenesis by low-LET radiation. It is less clear that this explanation is appropriate to high-LET radiation-induced oncogenic transformation, although all potential explanations of inverse dose-rate effects predict that, at appropriately low doses, no dose-rate effects of any kind are expected.

Cell Cycle↗
PubMed1997

Categorization and perceptual learning: an analogue of the face inversion effect.

This paper reports two experiments that investigate the extent to which it is plausible to suppose that an associatively based mechanism for perceptual learning acts as the basis for the effects of inversion on identification, recognition, matching and discrimination of faces (and certain other stimuli rendered familiar by expertise, e.g. gundogs). In the first experiment, an inversion effect that is contingent both on familiarity with a category and on the category possessing prototypical structure is demonstrated using discrimination learning of chequerboard stimuli. The second experiment demonstrates that the inversion effect found in Experiment 1 can generalize to a recognition paradigm as well. These results are discussed within the framework provided by associative learning theory, and a parallel is drawn with models employing a norm-based coding in similarity space. The conclusion is that it would be remarkable if the inversion effects demonstrated with the abstract categories used in the experiments reported here were not implicated in the inversion effects found with other classes of stimuli, whilst conceding that the analogy is not complete, particularly in the case of faces.

Adolescent↗
PubMed2005

Quantitation of the a priori dosimetric capabilities of spatial points in inverse planning and its significant implication in defining IMRT solution space.

In inverse planning, the likelihood for the points in a target or sensitive structure to meet their dosimetric goals is generally heterogeneous and represents the a priori knowledge of the system once the patient and beam configuration are chosen. Because of this intrinsic heterogeneity, in some extreme cases, a region in a target may never meet the prescribed dose without seriously deteriorating the doses in other areas. Conversely, the prescription in a region may be easily met without violating the tolerance of any sensitive structure. In this work, we introduce the concept of dosimetric capability to quantify the a priori information and develop a strategy to integrate the data into the inverse planning process. An iterative algorithm is implemented to numerically compute the capability distribution on a case specific basis. A method of incorporating the capability data into inverse planning is developed by heuristically modulating the importance of the individual voxels according to the a priori capability distribution. The formalism is applied to a few specific examples to illustrate the technical details of the new inverse planning technique. Our study indicates that the dosimetric capability is a useful concept to better understand the complex inverse planning problem and an effective use of the information allows us to construct a clinically more meaningful objective function to improve IMRT dose optimization techniques.

Algorithms↗
PubMed1973

Gene conversion and transfer of genetic information within the inverted region of inversion heterozygotes.

Prior studies of recombination which monitor exchange events in exceedingly short intervals (i.e., separable sites within a cistron) reveal that the basic event in recombination involves a non-reciprocal transfer of information, termed conversion. As a logical consequence of the model suggested by the work in Drosophila, the present investigation examined recombination between rosy mutant alleles (ry:3-52.0) in Drosophila melanogaster in a paracentric inversion (In(3R)P(18)) heterozygote, which placed the rosy region approximately at the center of the inverted region. Comparison of the results of this study with experiments carried out in standard chromosome homozygotes reveals a dramatic suppression of classical crossovers between the rosy mutant alleles in the inversion heterozygote. However, conversions continue to occur for all rosy mutant alleles in all heterozygous combinations in the inversion heterozygote. Moreover, the order of magnitude of conversion frequencies seen in the inversion heterozygote does not change from that seen in the standard chromosome homozygote study. The significance of these observations with reference to the role of rearrangements as barriers of information transfer is discussed. Particular attention is directed to the elaborate inversion polymorphisms seen in natural populations, and to notions concerning their role in the evolution of adaptive gene complexes.

Animals↗
PubMed1988

Self-reported stressors and hypertension: evidence of an inverse association.

This paper presents an analysis of self-reported stressors and blood pressure in a population of 1,428 San Francisco bus drivers surveyed from 1983 to 1985 as part of an occupational health study. To test the hypothesis of a positive association between psychosocial stressors and hypertension, the authors derived a stressor index from a survey instrument that assessed subjects' appraisal of work-related problems. A logistic regression analysis revealed an unexpected inverse association between the stressor index and hypertension that remained significant after adjustment for 12 potential confounding variables (standardized odds ratio = 0.84, p = 0.038). An analysis restricted to the 1,040 normotensive subjects, with mean blood pressure level as the outcome variable, also yielded inverse findings. To assess whether the results were specific to blood pressure, the authors repeated the multiple logistic analysis for gastrointestinal, respiratory, and musculoskeletal problems. In contrast to the inverse association found for hypertension, highly significant positive associations were found between the stressor index and these health problems. When prevalence of disease was examined by level of stressor score, a significant inverse gradient was observed for hypertension and significant positive gradients were observed for gastrointestinal, respiratory, and musculoskeletal problems (p values less than 0.001). An etiologic implication of these findings is that there may be a direct inverse association between subjective appraisal of stressors and blood pressure. A methodological implication is that subjective appraisal of stressors by persons with heightened blood pressure may be an invalid measure of objective, verifiable stressors.

Blood Pressure↗
PubMedDate not supplied

Reduced binocular depth inversion in patients with alcoholism.

Binocular depth inversion represents an illusion of visual perception, serving to invert the perception of implausible hollow objects, e.g. a hollow face into a normal face. Such inversion occurs frequently, especially when objects with a higher degree of familiarity (e.g. photographs of faces) are displayed. Cognitive factors are assumed to override the binocular disparity cues of stereopsis. The hypothesis was tested that during mild and moderate alcohol withdrawal, and severe and mild alcohol intoxication, the central nervous system is unable to correct implausible perceptual hypotheses. Measurements of binocular depth inversion in perception of three-dimensional objects were performed in 10 patients with severe alcohol intoxication, in 10 subjects with mild alcohol intoxication, in nine patients with moderate alcohol withdrawal treated with carbamazepine, in 10 patients with moderate alcohol withdrawal without any pharmacological treatment, in 11 patients with mild alcohol withdrawal and in 10 healthy volunteers. The binocular depth inversion scores were highly elevated in the severely intoxicated patients group and in the group with moderate withdrawal symptoms without carbamazepine treatment, in comparison to the healthy volunteers. The data demonstrate a strong impairment of binocular depth inversion in moderate alcohol withdrawal and during severe alcohol intoxication. This supports the view that these states may be accompanied by a disorganization of the interaction between sensory input and top-down component. The effects of carbamazepine are discussed.

Adult↗
PubMedDate not supplied

Chromosomal heteromorphisms in Delhi infants. III. Qualitative analysis of C-band inversion heteromorphisms of chromosomes 1, 9, and 16.

Qualitative analysis of C-band heteromorphisms was carried out in 200 infants (100 males and 100 females) in Delhi, India. Partial inversions minor and half inversions were observed as modal levels for chromosomes 1 and 9 in both sexes. No chromosome 16 with a C-band inversion was observed in the present investigation. A significantly higher incidence of percent inversions for chromosomes 1 and 9 was observed in males than in females. The frequency of heterozygous inversion level combinations for chromosome pairs 1 and 9 were remarkably higher than homozygous combinations both in males and females. Our results are compared with the other reported studies, and the possible role of these heteromorphisms in ethnic/racial variation and in developmental disturbances are discussed.

Chromosome Aberrations↗
PubMedDate not supplied

Inversion polymorphism in Drosophila obscura.

The inversion polymorphism of Drosophila obscura Fallen, a European species of the obscura group of the subgenus Sophophora, is described. A total of 21 inversions have been recorded; they are located in the five large chromosomes of the species (a dot chromosome is also present) and form 25 gene arrangements present in the species' natural populations. Strains from five different countries were studied. Two of these inversions were found to be pericentric, and the remaining were paracentric. The presence of "hot" points (multibreaks) was noticed. The distribution of the relative lengths of inversions conformed to the Van Valen-Levins distribution, contrary to what happens in D. subobscura. Observations also showed that there is no crossover inhibition between nonoverlapping inversions. The phylogeny of chromosome C was reconstructed; the existence of several arrangements not found was postulated; and the primitive gene arrangement, linking D. obscura to its closely related species was identified, as well as the primitive gene arrangements of the other chromosomes. Photographic maps of the chromosomes of D. obscura are provided here.

Animals↗
PubMed2002

Chronic infusion of beta-adrenoceptor antagonist and inverse agonists decreases elevated protein kinase A activity in transgenic mice with cardiac-specific overexpression of human beta 2-adrenoceptor.

Neutral antagonists and inverse agonists can produce different cellular responses in some systems. The effects of chronic (14-day) infusion of three ligands, ICI-118,551, carvedilol, and alprenolol were examined in cardiac tissue from wild-type and transgenic mice with cardiac-specific overexpression of the human beta2-adrenoceptor. These ligands vary in their negative efficacy at the human beta2-adrenoceptor, with two (ICI-118,551 and carvedilol) behaving as inverse agonists and one (alprenolol) behaving as a neutral antagonist. Cardiac tissue from the transgenic mice exhibited elevated levels of protein kinase A activity and G protein receptor kinase-2. Fourteen-day infusions of the three ligands lowered the elevated levels of protein kinase A activity of the transgenic hearts to control levels. Alprenolol and carvedilol also decreased G protein receptor kinase-2 amounts to control levels. The left atria from transgenic mice exhibited an impaired inotropic response to histamine relative to responses of wild-type mice atria. Infusions of the inverse agonists and a neutral antagonist at the beta2-adrenoceptor significantly restored the impaired histamine response. Restoration of protein kinase A activity and the impaired histamine responses in the atria from transgenic mice can be observed following 14-day infusions of both a neutral antagonist and inverse agonists. The reversal of the effects of the transgene by both inverse agonists and a neutral antagonist suggests that agonist occupancy, and not spontaneous activity, of the beta2-adrenoceptor is producing the elevated protein kinase A activity and the impaired histamine response.

Adrenergic beta-Agonists↗
PubMed2006

Impact of inversion of the CD4/CD8 ratio on the natural history of HIV-1 infection.

BACKGROUND: HIV-1 infection is characterized by an inverted CD4/CD8 T-cell ratio, but the distribution of inversions over time after seroconversion and whether delay of inversion is associated with a favorable prognosis are not known. METHODS: T-cell counts and clinical outcomes among men in the Multicenter AIDS Cohort Study who had incident HIV-1 infection before December 31, 1995 were analyzed by Kaplan-Meier and Cox proportional hazards methods. Results were also analyzed by time-dependent multivariate methods to adjust for CD4 lymphocyte counts, viral loads, age, race, and polymorphisms in host chemokine receptor genes (CCR5-Delta32 and CCR2-64I). RESULTS: Among 424 cases whose date of seroconversion was known to within +/-4.5 months, 317, 52, and 55 inverted their CD4/CD8 ratio within less than 1, 1 to 2, and more than 2 years of seroconversion, respectively. Longer time to inversion was significantly associated with longer time to AIDS, even after adjusting for CD4 lymphocyte count and viral load at the first seropositive visit and over the first 3 seropositive visits. Of the 6 seroconverters who had more than 500 CD4 lymphocytes 10 years after seroconversion without receiving highly active antiretroviral therapy, 5 took more than 2 years to invert their CD4/CD8 ratio. CONCLUSIONS: Time from HIV-1 seroconversion to inversion of the CD4/CD8 ratio independently predicted time to AIDS. Early measurements of the CD4/CD8 ratio until inversion occurs may identify people likely to become long-term nonprogressors or slow progressors, thus facilitating detailed studies of the mechanism of HIV-1 disease progression.

Adult↗
PubMed2003

Effects of asymmetric salt and a cylindrical macroion on charge inversion: electrophoresis by molecular dynamics simulations.

The charge inversion phenomenon is studied by molecular dynamics simulations, focusing on size and valence asymmetric salts, and a threshold of surface charge density for charge inversion. The charge inversion criteria by the electrophoretic mobility and the radial distribution functions of ions coincide except around the charge inversion threshold. The reversed electrophoretic mobility increases with the ratio of coion to counterion radii, a(-)/a(+), while it decreases with the ratio of coion to counterion valences, Z(-)/Z(+). The monovalent salt enhances charge inversion of a strongly charged macroion at small salt ionic strength, while it reduces reversed mobility otherwise. A cylindrical macroion is more persistent to monovalent salt than a spherical macroion of the same radius and surface charge density.

Journal Article↗
PubMed2004

Robustness of the inverse cascade in two-dimensional turbulence.

We study quasisteady inverse cascades in unbounded and bounded two-dimensional turbulence driven by time-independent injection and dissipated by molecular viscosity. It is shown that an inverse cascade that carries only a fraction r of the energy input to the largest scales requires the enstrophy-range energy spectrum to be steeper than k(-5) (ruling out a direct cascade) unless 1-r<<1. A direct cascade requires the presence of an inverse cascade that carries virtually all energy to the largest scales (1-r<<1). These facts underlie the robustness of the Kolmogorov-Kraichnan k(-5/3) inverse cascade, which is readily observable in numerical simulations without an accompanying direct enstrophy cascade. We numerically demonstrate an instance where the k(-5/3) inverse-cascading range is realizable with 79% of the energy injection dissipated within the energy range and virtually all of the enstrophy dissipated in the vicinity of the forcing region. As equilibrium is approached, the respective logarithmic slopes -alpha and -beta of the ranges of wave numbers lower and higher than the forcing wave number satisfy alpha+beta approximately 8. These results are consistent with recent theoretical predictions.

Journal Article↗
PubMed2005

Inverse structure functions.

While the ordinary structure function in turbulence is concerned with the statistical moments of the velocity increment Deltau measured over a distance r , the inverse structure function is related to the distance r where the turbulent velocity exits the interval Deltau. We study inverse structure functions of wind-tunnel turbulence which covers a range of Reynolds numbers Re(lambda) = 400-1100. We test a recently proposed relation between the scaling exponents of the ordinary structure functions and those of the inverse structure functions [S. Roux and M. H. Jensen, Phys. Rev. E 69, 16309 (2004)]. The relatively large range of Reynolds numbers in our experiment also enables us to address the scaling with Reynolds number that is expected to highlight the intermediate dissipative range. While we firmly establish the (relative) scaling of inverse structure functions, our experimental results fail both predictions. Therefore, the question of the significance of inverse structure functions remains open.

Journal Article↗
PubMed1967

Effect of Inversion on Growth and Movement of Indole-3-acetic Acid in Coleoptiles.

The effect of a 180 degrees displacement from the normal vertical orientation on longitudinal growth and on the acropetal and basipetal movement of (14)C-IAA was investigated in Avena sativa L. and Zea mays L. coleoptile sections. Inversion inhibits growth in intact sections (apex not removed) and in decapitated sections supplied apically with donor blocks containing auxin. Under aerobic conditions, inversion inhibits basipetal auxin movement and promotes acropetal auxin movement, whereas under anaerobic conditions, it does not influence the movement of auxin in either direction. Inversion retards the basipetal movement of the peak of a 30-minute pulse of auxin in corn.The inversion-induced inhibition of basipetal auxin movement is not explained by an effect of gravity on production, uptake, destruction, exit from sections, retention in tissue, or purely physical movement of auxin. It is concluded that inversion (a) inhibits basipetal transport, the component of auxin movement that is metabolically dependent, and as a result (b) inhibits growth and (c) promotes acropetal auxin movement.

Journal Article↗
PubMed2005

Bayesian solutions and performance analysis in bioelectric inverse problems.

In bioelectric inverse problems, one seeks to recover bioelectric sources from remote measurements using a mathematical model that relates the sources to the measurements. Due to attenuation and spatial smoothing in the medium between the sources and the measurements, bioelectric inverse problems are generally ill-posed. Bayesian methodology has received increasing attention recently to combat this ill-posedness, since it offers a general formulation of regularization constraints and additionally provides statistical performance analysis tools. These tools include the estimation error covariance and the marginal probability density of the measurements (known as the "evidence") that allow one to predictively quantify and compare experimental designs. These performance analysis tools have been previously applied in inverse electroencephalography and magnetoencephalography, but only in relatively simple scenarios. The main motivation here was to extend the utility of Bayesian estimation techniques and performance analysis tools in bioelectric inverse problems, with a particular focus on electrocardiography. In a simulation study we first investigated whether Bayesian error covariance, computed without knowledge of the true sources and based on instead statistical assumptions, accurately predicted the actual reconstruction error. Our study showed that error variance was a reasonably reliable qualitative and quantitative predictor of estimation performance even when there was error in the prior model. We also examined whether the evidence statistic accurately predicted relative estimation performance when distinct priors were used. In a simple scenario our results support the hypothesis that the prior model that maximizes the evidence is a good choice for inverse reconstructions.

Algorithms↗