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At least 1,009 records · Page 56Linked to original sources
PubMed2001

Allosteric effects of G protein overexpression on the binding of beta-adrenergic ligands with distinct inverse efficacies.

Allosteric models of G protein-coupled receptors predict that G protein influences the spontaneous isomerization between inactive (R) and active (R*) conformations. Since inverse agonists have been proposed to preferentially bind to the inactive and uncoupled form(s), changes in the G protein content should influence the binding properties of these ligands. To test this hypothesis, we systematically assessed the effect of G proteins on the binding of beta(2)-adrenergic ligands with distinct levels of inverse efficacy. Recombinant baculoviruses encoding the human beta(2)-adrenoreceptor (beta(2)AR) were expressed alone or in combination with G protein subunits in Sf9 cells. Coexpression with the G protein alpha s beta 1 gamma 2 did not influence the relative efficacy of the ligands to inhibit the adenylyl cyclase but induced considerable decrease in number of sites detected by [(3)H]ICI 118551, [(3)H]propranolol, and (125)I-cyanopindolol. This loss was proportional to the inverse efficacy of the ligand used as the radiotracer in the assay. The addition of Gpp(NH)p inhibited the effects of G protein overexpression indicating that the G proteins acted allosterically. Consistent with this notion, Western blot analysis revealed that coexpression with the G proteins was not accompanied by a loss of immunoreactive beta(2)AR. Such allosteric effects of the G proteins were also observed in mammalian cells expressing endogenous level of G proteins indicating that the phenomenon is not unique to overexpression systems. Taken together, these results demonstrate that the apparent receptor number detected by radiolabeled inverse agonists is affected by the content in G proteins as a result of their influence on R/R* isomerization.

Allosteric Regulation↗
PubMed2001

Agonism, inverse agonism, and neutral antagonism at the constitutively active human neurotensin receptor 2.

Two G protein-coupled neurotensin (NT) receptors, termed NTR1 and NTR2, have been identified so far. In contrast to the NTR1, which has been extensively studied, little is known about the pharmacological and biological properties of the NTR2. In the course of characterizing NT analogs that exhibited binding selectivity for the NTR2, we discovered that this receptor constitutively activated inositol phosphate (IP) production. Here, we report on the constitutive activity of the human NTR2 (hNTR2) transfected in COS cells and on compounds that exhibit agonism, inverse agonism, and neutral antagonism at this receptor. IP levels increased linearly with time, whereas they remained constant in mock-transfected cells. Furthermore, IP production was proportional to the amount of hNTR2 present at the cell membrane. SR 48692, a nonpeptide antagonist of the NTR1, stimulated IP production, whereas levocabastine, a nonpeptide histamine H1 antagonist that binds the NTR2 but not the NTR1, behaved as a weak partial inverse agonist. NT analogs modified at position 11 of the NT molecule, in particular by the introduction of bulky aromatic D amino acids, exhibited binding selectivity at the hNTR2 and also behaved as partial inverse agonists, reversing constitutive IP production up to 50%. Finally, NT barely affected constitutive IP production but antagonized the effects of both agonist and inverse agonist compounds, thus behaving as a neutral antagonist. The unique pharmacological profile of the hNTR2 is discussed in the light of its sequence similarity with the NTR1 and the known binding site topology of NT and SR 48692 in the NTR1.

Amino Acid Sequence↗
PubMed1987

Role of the response oscillator in inverse responses of Halobacterium halobium to weak light stimuli.

Under certain conditions Halobacterium halobium organisms respond to a weak attractant light stimulus with a repellent response and to a weak repellent stimulus with an attractant response. The appearance of inverse responses depends on the stimulus strength, on the interval length between spontaneous reversals, and on the moment of stimulation during the interval. Although the cells are absolutely refractory to repellent stimuli for 500 ms after a reversal, repellent responses can be evoked even during that period if they are inverse responses to weak attractant stimuli. Simultaneous attractant and repellent stimuli cancel each other even when one of them leads to an inverse response, indicating that normal cellular signals occur at the site of signal integration. We postulate that the inverse responses are caused by certain properties of a cellular oscillator for which we previously postulated a role in response regulation and sensory control in halobacteria (A. Schimz and E. Hildebrand, Nature [London] 317:641-643, 1985).

Halobacterium↗
PubMed1982

Serum retinol and the inverse relationship between serum cholesterol and cancer.

Several human studies have shown an inverse relation between vitamin A intake (and serum concentrations of retinol and carotene) and cancer. Serum cholesterol concentrations have also been reported in inverse relation to cancer. In a study of 3102 people in Evans County, Georgia, who were followed for over 12-14 years to assess the incidence of cancer there was an inverse association between the risk of cancer and both serum retinol and serum cholesterol concentrations. The data also showed an unexpectedly strong correlation between serum retinol and total cholesterol concentrations. The inverse relationship with cancer was stronger with serum retinol than with cholesterol, which suggested that the association with cholesterol might be secondary. This suggestion may also explain the cholesterol-cancer association reported in several other cohort studies. Further studies of the relation between serum concentrations of cholesterol, retinol, and carotene and the incidence of cancer are needed.

Cholesterol↗
PubMed1970

Ventricular inversion without transposition of the great vessels in situs inversus.

A classification of one type of congenital malformation previously reported (de la Cruz et al., 1967) is based on the integration of an embryological theory for ventricular inversions with the embryological concepts of trunco-conal malformations (de la Cruz and da Rocha, 1956). In that classification we consider that in each situs, either solitus or inversus ventricular inversions may be associated with: (a) normally arranged great vessels (not transposed); (b) transposition of the great vessels; (c) persistent truncus arteriosus. The patients had ventricular inversion without transposition of the great vessels in situs inversus.THE CORRECT ANATOMICAL DIAGNOSIS WAS NOT FORESEEN BUT THE PHYSIOPATHOLOGICAL DIAGNOSIS WAS CORRECT: pulmonary ischaemia associated with septal defects. In one case these facts were substantiated by catheterization and by angiocardiographic findings which led us to advise surgery. Haemodynamically isolated inversion of the ventricles is as severe a malformation as complete (not corrected) transposition of the great vessels. However, an operation of the anastomotic type between a systemic vessel and the narrow pulmonary artery seemed justified in these cases, as a means to convey more blood to the lungs and improve the saturation of the arterial blood. It was unsuccessfully carried out in one patient.The anatomical, radiological, and electrocardiographic features which might aid in the diagnosis are analysed.

Adult↗
PubMed1983

U wave inversion during attacks of variant angina.

Sequential 12 lead electrocardiograms were recorded during angina pectoris induced by ergonovine maleate in 38 patients with variant angina. Transient U wave inversion was observed in 17 patients with ST segment elevation in anterior chest leads, but in only three of 21 patients with ST segment elevation in the inferior leads associated with right coronary artery spasm. In the 17, all of whom had spasm of the left anterior descending coronary artery, the sensitivity of ST segment elevation in V5 was only 41%, and that of U wave inversion 71%. U wave inversion without ST segment elevation occurred during attacks in 35% of patients. During the recovery phase, the sensitivity of U wave inversion was 82% in V4 and 65% in V5, though ST segment elevation was absent in both V4 and V5. Thus, inverted U waves without ST segment elevation often appear in marginal ischaemic zones or during the time of recovery from temporary ischaemia. Detection of inverted U waves should aid in the diagnosis of variant angina when only lead V5 is used as a monitor and when electrocardiograms are recorded only during the recovery phase.

Adult↗
PubMed2004

Myocardial infarction: optimization of inversion times at delayed contrast-enhanced MR imaging.

Seventeen patients underwent magnetic resonance (MR) imaging for myocardial viability with a protocol approved by the institutional review board and gave written informed consent. Breath-hold cine inversion-recovery segmented k-space true fast imaging with steady-state precession sequence, referred to as inversion time (TI) mapping, was performed to determine optimal TI for myocardial infarction inversion-recovery imaging. From TI mapping, optimal TI was 180-315 msec 10-15 minutes after administration of 0.15 mmol/kg of gadolinium-based contrast material. At that optimal TI, relative signal intensity of infarcted myocardium compared with uninfarcted myocardium was maximal (mean +/- standard deviation, 297.8% +/- 86.5), whereas signal-to-noise ratio of uninfarcted myocardium was minimal (4.5 +/- 1.2). When applied to conventional myocardial infarction inversion-recovery imaging, optimal TI resulted in nulling of signal intensity of uninfarcted myocardium in all patients and in excellent conspicuity of infarcted myocardium in all nine patients with visible infarction.

Adult↗
PubMed2001

Infinite number of solutions to the hemodynamic inverse problem.

Investigators have had much success solving the "hemodynamic forward problem," i.e., predicting pressure and flow at the entrance of an arterial system given knowledge of specific arterial properties and arterial system topology. Recently, the focus has turned to solving the "hemodynamic inverse problem," i.e., inferring mechanical properties of an arterial system from measured input pressure and flow. Conventional methods to solve the inverse problem rely on fitting to data simple models with parameters that represent specific mechanical properties. Controversies have arisen, because different models ascribe pressure and flow to different properties. However, an inherent assumption common to all model-based methods is the existence of a unique set of mechanical properties that yield a particular pressure and flow. The present work illustrates that there are, in fact, an infinite number of solutions to the hemodynamic inverse problem. Thus a measured pressure-flow pair can result from an infinite number of different arterial systems. Except for a few critical properties, conventional approaches to solve the inverse problem for specific arterial properties are futile.

Animals↗
PubMed1987

Inverse modeling of dog airway and respiratory system impedances.

Mechanical parameters of the respiratory system are often estimated from respiratory impedances using lumped-element inverse models. One such six-element model is composed of an airway branch [with a resistance (Raw) and inertance (Iaw)] separated from a tissue branch [with a resistance (Rt), inertance (It), and compliance (Ct)] by a shunt compliance representing alveolar gas compression (Cg). Even though the airways are known to have frequency-dependent resistance and inertance, these inverse models have been composed of linear frequency-independent elements. In this study we investigated the use of inverse models where the airway branch was represented by a frequency-independent Raw and Iaw, a Raw that is linearly related to frequency and an Iaw that is independent of frequency, and a system of identical parallel tubes the impedance of which was computed from the tube radius and length. These inverse models were used to analyze airway and respiratory impedances between 2 and 1,024 Hz that were predicted from an anatomically detailed forward model. The forward model represented the airways by an asymmetrically branched network with a terminal impedance representative of known Cg, Rt, It, and Ct. For respiratory impedances between 2 and 128 Hz, all models fit the data reasonably well, and reasonably accurate estimates of Cg, Rt, It, and Ct were extracted from these data. For data above 200 Hz, however, only the multiple-tube model accurately fitted respiratory impedances (Zrs). This model fitted the Zrs data best when composed of 27 tubes, each having a radius of 0.148 cm and a length of 16.5 cm.

Animals↗
PubMed1987

Forward and inverse electrocardiographic calculations using resistor network models of the human torso.

An automated method of modelling the electrical properties of the human thorax from horizontal section data such as computerized tomographic scans has been used to develop both forward and inverse transformations between epicardial and body surface potential distributions. Eleven torso models with varying geometry and organ configurations have been studied. For the forward calculations, a standard dipole-like source is placed along the axis of the heart. Inverse calculations are performed using a measured body surface potential distribution and are based on a division of the surface of the heart into 25 source regions, producing epicardial potentials on these regions. A regularization method is used to stabilize the inverse solutions. Both forward and inverse solutions show substantial differences between models. These findings imply that matching models with patient geometry may be necessary in order to use such solutions in a clinical setting.

Electrocardiography↗
PubMed1985

Prior inverse filtering for the improvement of axial resolution.

A prior inverse filtering technique is applied to improve the axial resolution in ultrasonic imaging. The ultrasound transducer is excited by a synthesized signal corresponding to the impulse response of the inverse filter. The diffraction effects of the transducer and the observed scatterer, which limit the performance of the inverse filter, are examined experimentally as well as theoretically. Using a B-scan image of a tissue-equivalent phantom, we demonstrate the possibility of applying the prior inverse filtering method to improve medical ultrasound images.

Models, Structural↗
PubMed1992

Inverse scattering scheme based on the moment method in the spectral domain, Part I: Theory.

Recently, electromagnetic and ultrasonic imaging of inhomogeneous objects by applying the moment-method procedures of forward scattering problems in the reverse sequence have been developed. In this paper, the inverse scattering formulation has been modified to be applicable in the spectral domain. Compared to previous schemes, the suggested formulation illustrates clearly the actual mechanism of the inverse scattering process by explicit separation of the contributions from several variables, such as the measurement location, basis function, and geometry of objects. The ill-posedness inherent in inverse scattering problems was also explained easily in this spectral scheme by the exponentially-decaying behavior of high-frequency spectral components of the scattered field. It implies that enlargement of the discretized cell size is a key factor in regularizing the ill-posedness. In particular, since the singular kernel to be integrated on each cell became regular in the modified scheme, various types of basis functions instead of pulse function were adopted without additional difficulties. This advantage is expected to play an important role in regularizing the noise effect by selecting polynomial basis function on the enlarged cells of discretization in the spectral inverse scattering scheme.

Algorithms↗
PubMedDate not supplied

Inversion and eversion strengths in the weightbearing ankle of young women. Effects of plantar flexion and basketball shoe height.

Maximum isometric ankle inversion and eversion muscle strengths were measured under full unipedal weightbearing in 20 healthy young adult women. When the women wore a low-top shoe, the mean (standard deviation) maximum external eversion moments resisted with the foot in 0 degrees and 32 degrees of ankle plantar flexion were 24.1 (7.6) and 24.1 (8.1) N x m, respectively, while the corresponding values for maximum inversion moments resisted were 14.7 (6.8) and 17.4 (6.4) N x m, respectively. Both shoe height and ankle plantar flexion affected the overall inversion moment resisted by 17% (P = 0.03) at 0 degrees of ankle plantar flexion to 11.9% (P = 0.003) at 32 degrees of ankle plantar flexion. However, neither shoe height nor ankle plantar flexion significantly affected the maximum eversion moment resisted. Although eversion muscle strength of the young women averaged 39% less than the corresponding value found in young men, the sex difference was not significant when ankle strengths were normalized by body size (body weight x height). Thus, when data from healthy young men and women were averaged, eversion and inversion strengths averaged 1.6% and 2.7%, respectively, of body weight x height.

Adult↗
PubMed2005

Intrinsic risk factors for inversion ankle sprains in male subjects: a prospective study.

BACKGROUND: Many variables have been retrospectively associated with ankle sprains. However, very little is known about factors predisposing people to these injuries. HYPOTHESIS: Measurable intrinsic factors might predispose male athletes to ankle sprains. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 241 male physical education students were evaluated for possible intrinsic risk factors for inversion sprains at the beginning of their academic study. The evaluated intrinsic risk factors included anthropometrical characteristics, functional motor performances, ankle joint position sense, isokinetic ankle muscle strength, lower leg alignment characteristics, postural control, and muscle reaction time during a sudden inversion perturbation. Subjects were followed prospectively for 1 to 3 years. RESULTS: A total of 44 (18%) of the 241 male subjects sustained an inversion sprain; 4 sprained both ankles. Cox regression analysis revealed that male subjects with slower running speed, less cardiorespiratory endurance, less balance, decreased dorsiflexion muscle strength, decreased dorsiflexion range of motion, less coordination, and faster reaction of the tibialis anterior and gastrocnemius muscles are at greater risk of ankle sprains. CONCLUSION: Based on our findings, it is suggested that running speed, cardiorespiratory endurance, balance, dorsiflexion strength, coordination, muscle reaction, and dorsiflexion range of motion at the ankle are associated with the risk of ankle inversion sprains in male subjects.

Adolescent↗
PubMedDate not supplied

Basketball shoe height and the maximal muscular resistance to applied ankle inversion and eversion moments.

To determine if the height of a basketball shoe alters the maximal inversion and eversion moment that can be actively resisted by the ankle in the frontal plane, we tested 20 healthy, young adult men with no recent ankle injuries. Subjects underwent unipedal functional ankle strength testing under weightbearing conditions at 0 degrees, 16 degrees, and 32 degrees of ankle plantar flexion using a specially designed testing apparatus. Testing was performed with the subject wearing either a low- or a three quarter-top basketball shoe. Shoe height did not significantly affect an individual's ability to actively resist an eversion moment at any angle of ankle plantar flexion. However, tests at 0 degrees of ankle plantar flexion demonstrated that the three quarter-top basketball shoe we tested significantly increased the maximal resistance to an inversion moment by 29.4%. At 16 degrees of ankle plantar flexion, inversion resistance was also significantly improved by 20.4%. These results show that athletic shoe height can significantly increase the active resistance to an inversion moment in moderate ankle plantar flexion. The findings apply to a neutral foot position in the frontal plane, an orientation equivalent to the early phase of a potential ankle sprain.

Adult↗
PubMedDate not supplied

What best protects the inverted weightbearing ankle against further inversion? Evertor muscle strength compares favorably with shoe height, athletic tape, and three orthoses.

We measured the maximal isometric eversion moment developed under full weightbearing in 20 healthy adult men (age, 24.4 +/- 3.4 years; mean +/- SD) with their ankles in 15 degrees of inversion. Tests were performed at both 0 degree and 32 degrees of ankle plantar flexion in low- and in three-quarter-top shoes with and without adhesive athletic tape or one of three proprietary ankle orthoses. At 0 degree of ankle plantar flexion, the mean maximal voluntary resistance of the unprotected ankle to an inversion moment was 50 +/- 8 N-m; this increased by an average of 12% (or 6 N-m) when the subject wore a three-quarter-top basketball shoe. The maximal voluntary resistances to inversion moments developed with the ankles further protected by athletic tape or any of three orthoses were not significantly different. Biomechanical calculations suggest that at 15 degrees of inversion the fully active ankle evertor muscles isometrically developed a moment up to six times larger than that developed when an athlete wears a three-quarter-top shoe alone and more than three times larger than that developed passively when the athlete has tape or an orthosis worn inside a three-quarter-top shoe. We conclude that fully activated and strong ankle evertor muscles are the best protection for a near-maximally inverted ankle at footstrike.

Adult↗
PubMed2006

Bioluminescence resonance energy transfer as a screening assay: Focus on partial and inverse agonism.

The reported data for compound screening with the bioluminescence resonance energy transfer (BRET2) assay is very limited, and several questions remain unaddressed, such as the behavior of agonists. Eleven beta2 adrenergic receptor (beta2-AR) agonists were tested for full or partial agonism in an improved version of the receptor/beta-arrestin2 BRET2 assay and in 2 cyclic adenosine monophosphate (cAMP) assays (column cAMP assay and ALPHAscreen cAMP assay). Tested in the highly sensitive ALPHAscreen cAMP assay, all selected agonists behaved as full agonists, using isoproterenol as a reference compound. In the less sensitive column cAMP assay, ephedrine and dopamine had a clear partial response. For the BRET2 assay, a highly graded picture was obtained. Moreover, beta2-AR antagonists were tested for inverse agonism. Pronounced inverse agonism was detected in the ALPHAscreen cAMP assay. Only marginal inverse agonistic responses were seen for alprenolol and pindolol in the column cAMP assay, and no inverse agonism was seen in the BRET2 assay. For the beta2-AR, the BRET2 assay may be superior for secondary screening of agonists where a separation of full and partial agonists is needed and the ALPHAscreen cAMP assay may be preferred for primary screening of agonists where all receptor activating compounds are desired.

Adrenergic beta-2 Receptor Agonists↗
PubMed1996

Inverse agonism of amino-terminally truncated parathyroid hormone (PTH) and PTH-related peptide (PTHrP) analogs revealed with constitutively active mutant PTH/PTHrP receptors.

Inverse agonists, ligands that suppress spontaneous receptor signaling activity, have been described for a growing number of G protein-coupled receptors; however, none have been reported for the PTH/calcitonin/secretin receptor family. We took advantage of the constitutive signaling activity of two mutant forms of the PTH/PTH-related peptide (PTHrP) receptor, recently identified in patients with Jansen's metaphyseal chondrodysplasia, to screen for PTH and PTHrP analogs with inverse agonist activity. Two antagonist peptides, [Leu11, D-Trp12]hPTHrP(7-34)NH2 and [D-Trp12, Tyr34]bPTH-(7-34)NH2, displayed inverse agonist activity and reduced cAMP in COS-7 cells expressing either mutant receptor by 30-50% (EC50 approximately 50 nM). These data demonstrate that the concept of inverse agonism can be extended to this distinct family of G protein-coupled receptors and their cognate antagonist peptide ligands. Such ligands shall be useful probes of the multi-state conformational equilibria proposed for these receptors and could lead to new approaches for treating human diseases caused by receptor activating mutations.

Cell Line↗