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Results for “Inverse design”

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PubMed2005

The ratio of constitutive androstane receptor to pregnane X receptor determines the activity of guggulsterone against the Cyp2b10 promoter.

Guggulsterone is the active ingredient in gugulipid, an organic extract of the Commiphora mukul plant. Gugulipid has been used for nearly 3000 years in Ayurvedic medicine, mainly as a treatment for arthritis. Herbal practitioners currently use gugulipid therapy in conditions as diverse as rheumatism, coronary artery disease, arthritis, hyperlipidemia, acne, and obesity. The active ingredient in gugulipid is guggulsterone, a plant sterol compound recently identified as a pregnane X receptor (PXR; NR1I2) ligand. We show herein that guggulsterone treatment represses the expression of cytochrome P450 2b10 (Cyp2b10) gene expression by inhibiting constitutive androstane receptor (CAR; NR1I3) activity in hepatocytes lacking functional PXR (PXR-knockout). We also show that PXR-CAR cross-talk determines the net activity of guggulsterone treatment toward Cyp2b10 gene expression. Using mammalian two-hybrid assays, we show that treatment with guggulsterone differentially affects protein cofactor recruitment to these two nuclear receptors. These data identify guggulsterone as an inverse agonist of the nuclear receptor CAR. When viewed together with the data showing that PXR and CAR expression is highly variable in different ethnic populations and that CAR expression is under the control of a circadian rhythm, our data provide important insight into the molecular mechanism of interindividual variability of drug metabolism. These data, together with the recent resolution of the crystal structures of PXR and CAR, will likely aid in the rational design of more specific CAR inverse agonists that are currently viewed as potential antiobesity drugs.

Animals↗

PubMedDate not supplied

Designing novel polymers with targeted properties using the signature molecular descriptor.

A method for solving the inverse quantitative structure-property relationship (QSPR) problem is presented which facilitates the design of novel polymers with targeted properties. Here, we demonstrate the efficacy of the approach using the targeted design of polymers exhibiting a desired glass transition temperature, heat capacity, and density. We present novel QSPRs based on the signature molecular descriptor capable of predicting glass transition temperature, heat capacity, density, molar volume, and cohesive energies of linear homopolymers with cross-validation squared correlation coefficients ranging between 0.81 and 0.95. Using these QSPRs, we show how the inverse problem can be solved to design poly(N-methyl hexamethylene sebacamide) despite the fact that the polymer was used not used in the training of this model.

Algorithms↗

PubMed1998

Association of environmental tobacco smoke exposure with socioeconomic status in a population of 7725 New Zealanders.

OBJECTIVE: To test the hypothesis that environmental tobacco smoke (ETS) exposure is inversely associated with socioeconomic status. DESIGN: Survey. SETTING: General community, New Zealand. PARTICIPANTS: 7725 non-smoking adults (volunteer sample of a multi-industry workforce, n = 5564; and a random sample of urban electoral rolls, n = 2161), including 5408 males; mean age 45 years. MAIN OUTCOME MEASURES: ETS exposure was assessed as self-reported number of hours per week spent near someone who is smoking, and as prevalence of regular exposure to some ETS. Socioeconomic status was assessed as educational level, occupational status, and median neighbourhood household income. RESULTS: Both measures of ETS exposure were steeply and inversely associated with all three indicators of socioeconomic status (all p < 0.0001). Geometric mean ETS exposure ranged from 16 minutes per week among university-educated participants to 59 minutes per week in the second lowest occupational quintile (95% confidence intervals: 14-18 minutes per week and 54-66 minutes per week). The associations with occupational status and educational level were steeper than those with neighbourhood income. The socioeconomic gradients of ETS exposure were steeper among participants aged less than 35 years than among participants aged over 50 years, among men than women, and among Maori than Europeans. CONCLUSIONS: In this study population, ETS exposure was inversely associated with socioeconomic status. Greater ETS exposure might therefore contribute to the higher risks of disease and death among low socioeconomic groups. These results provide a further rationale for targeting tobacco control measures to people in low socioeconomic groups.

Adult↗

PubMed1991

Stimulus intensity and experimental design effects on motor response processing.

Experimental design effects and range effects may have influenced previous studies on motor response processing (Grice & Hunter, 1964; Grice, Nullmeyer, & Schnizlein, 1979; Poulton, 1973). This investigation was conducted concurrently with two experiments. First, Erlebacher's (1977) more powerful analysis of variance (ANOVA) model, which allows for the testing of the independent variable (stimulus intensity effect), the experimental design effect (between-subjects [BS] vs. within-subjects [WS]), and the important interaction between independent variable and experimental design was utilized to clarify if the nature of the experimental design (BS, WS) biases motor response processing. Second, Erlebacher's (1977) ANOVA model was used to determine if motor response processing was affected by stimulus intensity and experimental design when different ranges of auditory stimuli were compared. Results indicate motor response processing was inversely affected by increasing stimulus intensity. Experimental design effects and range effects did not appear to bias motor response processing. We conclude stimulus intensity effects on motor response processing appear to be the result of true neuromotor functioning and not artifacts of experimental design or of range effects.

Acoustic Stimulation↗

PubMed2004

Fruit and vegetable consumption and LDL cholesterol: the National Heart, Lung, and Blood Institute Family Heart Study.

BACKGROUND: An elevated LDL-cholesterol concentration is associated with an increased risk of cardiovascular disease. The association between fruit and vegetable consumption and LDL has been inconsistent. OBJECTIVE: The objective was to determine whether a high intake of fruit and vegetables is inversely associated with LDL concentrations. DESIGN: We used data collected from 4466 subjects in the National Heart, Lung, and Blood Institute Family Heart Study to study the association between fruit and vegetable consumption and serum LDL. We used a food-frequency questionnaire to assess fruit and vegetable intakes and regression models to estimate adjusted mean LDL according to fruit and vegetable consumption. RESULTS: The mean (+/-SD) age of the men (n = 2047) was 51.5 +/- 14.0 y and that of the women (n = 2419) was 52.2 +/- 13.7 y. The average daily serving of fruit and vegetables was 3.2 +/- 1.7 for men and was 3.5 +/- 1.8 for women. Fruit and vegetable consumption was inversely related to LDL: in the categories 0-1.9, 2.0-2.9, 3.0-3.9, and > or = 4 servings/d, multivariate-adjusted mean (95% CI) LDL concentrations were 3.36 (3.28, 3.44), 3.35 (3.27, 3.43), 3.26 (3.17, 3.35), and 3.17 (3.09, 3.25) mmol/L, respectively, for men (P for trend < 0.0001) and 3.35 (3.26, 3.44), 3.22 (3.14, 3.30), 3.21 (3.13, 3.29), and 3.11 (3.04, 3.18), respectively, for women (P for trend < 0.0001). This association was observed across categories of age, education, smoking status, physical activity, and tertiles of Keys score. Exclusion of subjects with prevalent diabetes mellitus or coronary artery disease did not alter these results significantly. CONCLUSION: Consumption of fruit and vegetables is inversely related to LDL in men and women.

Body Mass Index↗

PubMed2003

A meta-analysis of the association between childhood type 1 diabetes and atopic disease.

OBJECTIVE: To review the published literature and perform a meta-analysis summarizing the evidence in support of an inverse association between type 1 diabetes and the atopic disorders: asthma, eczema, and allergic rhinitis in children. RESEARCH DESIGN AND METHODS: MEDLINE, Web of Science, and PubMed were searched to identify relevant studies. These were assessed on quality criteria, and odds ratios (ORs) and 95% CIs were calculated for each study from the reported prevalences of atopy in children with diabetes and in control children. Meta-analysis was then used to derive a combined OR and test for heterogeneity in findings between studies. RESULTS: Twenty-five studies were identified. Heterogeneity in the findings from different studies was evident but was considerably reduced when the asthma and rhinitis analyses were restricted to those studies judged to be of adequate design. The meta-analysis revealed an inverse association between asthma and type 1 diabetes, but the finding only attained significance when analysis was restricted to the studies of adequate design (OR 0.82, 95% CI 0.68-0.99). In this subset an association of similar magnitude was observed between eczema and type 1 diabetes (0.82, 0.62-1.10) although this failed to attain statistical significance, and heterogeneity between studies was still present. There was little evidence of an association between rhinitis and type 1 diabetes (0.97, 0.82-1.16) in this subset of studies. CONCLUSIONS: Our analysis suggests that there is a small but significant reduction in the prevalence of asthma in children with type 1 diabetes, but the findings for the other atopic diseases are less conclusive.

Asthma↗

PubMed2002

Study of disabling T-cell activation and inhibiting T-cell-mediated immunopathology reveals a possible inverse agonist activity of CD4 peptidomimetics.

We designed a new class of aromatically modified exocyclic peptides based on the structure of CD4 by engineering one of the cysteine residues in a peptidomimetic derived from the CDR3 region of the CD4 molecule. All three species mediate inhibition of T-cell proliferation at concentrations ranging from 10 to 100 microM. The mimetics CD4-Cys and CD4-Met bind to sCD4 with affinities ranging from 1 to 2 microM, while CD4-Ser shows poor binding in radioisotope assay. Though these mimetics have similar structures, they exhibit different biochemical and biological functions. Activation of T-cells as measured by thymidine incorporation or IL-2 production revealed that CD4-Cys and CD4-Ser mimetics behave as classical antagonists. On the other hand, the CD4-Met species inhibited T-cell proliferation with an IC(50) of 30 microM but unexpectedly increased IL-2 secretion modestly at a less than 3 microM concentration. In experimental autoimmune encephalitis (EAE), CD4-Ser and CD4-Cys mimetics reduced the severity of EAE symptoms while the CD4-Met mimetic exacerbated the conditions. We propose that CD4-Cys and CD4-Ser are classical antagonists, but CD4-Met may possess properties of an inverse agonist. The structure-activity relationship of mimetics reveals that a minor change in the net hydropathic value is enough to alter the dynamic nature of the receptor-ligand complex.

Animals↗

PubMed2004

Tricyclic alkylamides as melatonin receptor ligands with antagonist or inverse agonist activity.

This work reports the design and synthesis of novel alkylamides, characterized by a dibenzo[a,d]cycloheptene nucleus, as melatonin (MLT) receptor ligands. The tricyclic scaffold was chosen on the basis of previous quantitative structure-activity studies on MT1 and MT2 antagonists, relating selective MT2 antagonism to the presence of an aromatic substituent out of the plane of the MLT indole ring. Some dibenzo seven-membered structures were thus selected because of the noncoplanar arrangement of their benzene rings, and an alkylamide chain was introduced to fit the requirements for MLT receptor binding, namely, dibenzocycloheptenes with an acylaminoalkyl side chain at position 10 and dibenzoazepines with this side chain originating from the nitrogen atom bridging the two phenyl rings. Binding affinity at human cloned MT1 and MT2 receptors was measured by 2-[125I]iodomelatonin displacement assay and intrinsic activity by the GTPgammaS test. The majority of the compounds were characterized by higher affinity at the MT2 than at the MT1 receptor and by very low intrinsic activity values, thus confirming the importance of the noncoplanar arrangement of the two aromatic rings for selective MT2 antagonism. Dibenzocycloheptenes generally displayed higher MT1 and MT 2affinity than dibenzoazepines. N-(8-Methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylmethyl)propionamide (4c) and -butyramide (4d) were the most selective MT2 receptor antagonists of the series, with MT2 receptor affinity comparable to that of melatonin and as such among the highest reported in the literature for MLT receptor antagonists. The acetamide derivative 4b produced a noticeable reduction of GTPgammaS binding at MT2 receptor, thus being among the few inverse agonists described.

Animals↗

PubMed1998

A robust numerical solution to reconstruct a globally relative shear modulus distribution from strain measurements.

To noninvasively quantify tissue elasticity for differentiating malignancy of soft tissue, we previously proposed a two-dimensional (2-D) mechanical inverse problem in which simultaneous partial differential equations (PDE's) represented the target distribution globally of relative shear moduli with respect to reference shear moduli such that the relative values could be determined from strain distributions obtained by conventional ultrasound (US) or nuclear magnetic resonance (NMR) imaging-based analysis. Here, we further consider the analytic solution in the region of interest, subsequently demonstrating that the problem is inevitably ill-conditioned in real-world applications, i.e., noise in measurement data and improper configurations of mechanical sources/reference regions make it impossible to guarantee the existence of a stable and unique target global distribution. Next, based on clarification of the inherent problematic conditions, we describe a newly developed numerical-based implicit-integration approach that novelly incorporates a computationally efficient regularization method designed to solve this differential inverse problem using just low-pass filtered spectra derived from strain measurements. To evaluate method effectiveness, reconstructions of the global distribution are carried out using intentionally created ill-conditioned models. The resultant reconstructions indicate the robust solution is highly suitable, while also showing it has high potential to be applied in the development of an effective yet versatile diagnostic tool for quantifying the distribution of elasticity in various soft tissues.

Biomechanical Phenomena↗

PubMed1994

Intercomparison of activity size distributions of thoron progeny by alpha- and gamma-counting methods.

It is difficult to calibrate sampling devices using radon or thoron progeny or particles measuring 1-4 nm; therefore, an interlaboratory comparison is important to verify the performance of graded diffusion batteries for the activity size distributions of the "unattached" progeny. This paper describes the results of an interlaboratory comparison of 220Rn progeny size distributions using graded diffusion batteries by alpha- and gamma-counting methods with different data inversion schemes. Graded diffusion batteries designed at the Inhalation Toxicology Research Institute and at the Environmental Measurement Laboratory were used in the study. Screens and backup filters from the Environmental Measurement Laboratory-graded diffusion batteries were counted simultaneously in alpha counters for total alpha activities, and those of the Inhalation Toxicology Research Institute-graded diffusion batteries were counted in a gamma detector for gamma activities from 212Pb. Because of the different counting methods and data analysis procedures used, this interlaboratory study of 220Rn progeny allows a more rigorous way of testing instrument performance. 212Pb particles generated in well-controlled environments of oxygen, nitrogen, or oxygen with 1 ppm of nitrogen oxide were measured. In general, good agreement in activity size distributions was obtained from these two methods. Some differences observed in individual size spectra were attributable to the data inversion programs used in each laboratory. When the data were analyzed by the same computer program, most differences disappeared.

Alpha Particles↗

PubMed1997

Presurgical and postsurgical mental and psychomotor development of infants with sagittal synostosis.

OBJECTIVE: The current study compared the mental and psychomotor development of infants with nonsyndromic sagittal synostosis (SS) with a demographically matched comparison group without congenital defects. Within the SS group, we tested the hypothesis that age of cranial release would be inversely correlated with mental development. DESIGN: The design was prospective and longitudinal. Participants were assessed at 4, 12, and 24 months of age. SETTING: The study was conducted in a craniofacial clinic at an urban children's hospital. PARTICIPANTS: Participants were 19 infants with SS (consecutive craniofacial program referrals) and 19 demographically matched comparison infants recruited from the community. One infant with SS did not attend the 24-month assessment. MAIN OUTCOME MEASURES: Mental and Psychomotor Indices from the Bayley Scales of Infant Development were the primary outcome measures. Subdomains of development were created using Kohen-Raz scoring procedures. All measures were determined a priori. RESULTS: Repeated-measures MANOVAs revealed no statistically significant differences in the developmental trajectories of the two groups. None of the SS group infants received Mental Development Index (MDI) scores in the mentally retarded or borderline range of intellectual functioning (i.e., below 78). An inverse correlation (r = -.30) was found between the age at surgery and Bayley growth curve coefficients; however, this association was not statistically significant (p = .10, one-tailed). CONCLUSIONS: Results are consistent with previous studies of the mental and psychomotor development of infants with nonsyndromic craniosynostoses in relation to normative test data. The relation between surgery age and developmental outcome merits further study in a larger sample with a greater range of surgery ages.

Age Factors↗

PubMed2003

Deficits in detection of inversion and eversion movements among subjects with recurrent ankle sprains.

STUDY DESIGN: Observational cross-sectional design. OBJECTIVES: To determine whether a deficit exists in the ability to perceive inversion and eversion movements among subjects with recurrent ankle sprains. BACKGROUND: Although unproven, ankle sprains are thought to recur because proprioception is impaired subsequent to the original sprain. Proprioception has been widely studied, however, the specific property of movement perception has not been rigorously examined for both inversion and eversion movements. METHODS AND MEASURES: The ability to perceive passive inversion and eversion movements imposed at the relaxed ankle was measured in 39 subjects with recurrent ankle sprains (sprainers) and 30 subjects with no history of ankle injury (controls) by an assessor masked to subject group. The 70% detection level for movement perception was determined for 3 velocities, 0.1 degrees/s, 0.5 degrees/s, and 2.5 degrees/s, tested in random order. RESULTS: The 70% detection level for inversion and eversion movements improved with increasing velocity in both groups. At all velocities, the 70% detection level for movements imposed at the ankle of the sprainers was significantly worse than for controls. CONCLUSIONS: Perception of passive inversion and eversion movements imposed at the ankle was impaired in subjects with recurrent ankle sprains. The impairment was evident at the 3 velocities tested, 0.1 degrees/s, 0.5 degrees/s, and 2.5 degrees/s.

Adolescent↗

PubMed1999

The influence of trunk modelling in 3D biomechanical analysis of simple and complex lifting tasks.

OBJECTIVE: The purpose of this study was to evaluate different methods of estimating the body segment parameters and different methods of partitioning the trunk in order to reduce errors in the inverse dynamic analysis of lifting tasks. DESIGN: The same data set was used to evaluate moment errors associated to five linked models differing by the way the trunk was modelled. BACKGROUND: The inverse dynamic analysis of complex lifting tasks involving significant lower limb displacements requires the use of upper body linked models. However, the estimation of the body segment parameters of trunk segments and the flexible properties of the trunk can lead to errors when using this modelling approach. METHODS: Twenty-one male subjects performed four lifting tasks. Five cameras, two force platforms and a dynamometric box provided inputs to five tridimensional (3D) dynamic linked models. Three modelling parameters of the trunk were tested in these models: (1) the use of a geometric or a proportional anthropometric model to estimate the body segment parameters of the trunk, (2) the location of the antero-posterior position of the centre of mass of the trunk segments (at a percentage of the trunk depth vs on a line between hips and shoulders), and (3) the partitioning of the trunk in two or three segments. The behavior of these linked models was assessed with three different error analyses. RESULTS: The results revealed that all three modelling parameters of the trunk can reduce moment errors, especially when applied to subjects characterized by a larger abdomen. CONCLUSIONS: The inverse dynamic analysis of lifting tasks using an upper body modelling approach should take into consideration the interindividual variability inherent to the trunk morphology and non-rigidity. RELEVANCE: The trunk geometry and flexibility shows considerable variability among individuals. The use of upper body linked models requires adequate modelling of this segment to minimize errors in 3D inverse dynamic analysis of lifting tasks.

Adult↗

PubMed2005

A novel method to improve prenatal diagnosis of abnormal systemic venous connections using three- and four-dimensional ultrasonography and 'inversion mode'.

OBJECTIVE: The precise prenatal diagnosis of abnormal venous connections of the fetal heart is challenging. Anatomical accuracy may be important in determining the best route for postnatal angiography, as well as the prognosis and treatment. This study was designed to determine the value of 'inversion mode', a new three- and four-dimensional (4D) rendering algorithm, in the visualization of the spatial relationships of an interrupted inferior vena cava (IVC) with azygos or hemiazygos vein continuation associated with and without heterotaxic syndromes. METHODS: Heart volumes were acquired using 4D ultrasonography and spatiotemporal image correlation in cases of interrupted IVC with azygos/hemiazygos continuation (n = 3). Volume datasets were rendered using the 'inversion mode' algorithm and abnormal images were compared to those generated from a library of normal fetuses. RESULTS: The 'inversion mode' rendering algorithm allowed the visualization of dilated azygos or hemiazygos veins and their spatial relationships with the descending aorta, the aortic arch, the superior vena cava, and the atria in cases of interrupted IVC with and without heterotaxic syndromes. CONCLUSIONS: The 'inversion mode' algorithm improves prenatal visualization of both dilated azygos and hemiazygos veins, as well as their spatial relationships with the surrounding vascular structures. This has implications for the accurate prenatal diagnosis and management of neonates with abnormal systemic venous connections.

Azygos Vein↗

PubMed2000

De novo design of peptides targeted to the EF hands of calmodulin.

This report describes the use of the concept of inversion of hydropathy patterns to the de novo design of peptides targeted to a predetermined site on a protein. Eight- and 12-residue peptides were constructed with the EF hands or Ca(2+)-coordinating sites of calmodulin as their anticipated points of interaction. These peptides, but not unrelated peptides nor those with the same amino acid composition but a scrambled sequence, interacted with the two carboxyl-terminal Ca(2+)-binding sites of calmodulin as well as the EF hands of troponin C. The interactions resulted in a conformational change whereby the 8-mer peptide-calmodulin complex could activate phosphodiesterase in the absence of Ca(2+). In contrast, the 12-mer peptide-calmodulin complex did not activate phosphodiesterase but rather inhibited activation by Ca(2+). This inhibition could be overcome by high levels of Ca(2+). Thus, it would appear that the aforementioned concept can be used to make peptide agonists and antagonists that are targeted to predetermined sites on proteins such as calmodulin.

Amino Acid Sequence↗

PubMed2000

A method for fast multislice T1 measurement: feasibility studies on phantoms, young children, and children with Canavan's disease.

We have developed a multislice protocol for quantitative T1 measurements in which the processing time and the acquisition time are under 2 minutes each for a complete brain study of 15 slices. An echoplanar, inversion-recovery image sequence is designed to collect data suitable for analysis using a linear regression algorithm. The precision is approximately twice the noise to signal ratio of the images. The accuracy of the protocol is better than 1% for T1 in the range 0-2 seconds and deviates slightly for longer T1 values. The protocol is insensitive to B1 field values. If needed, the data can be postprocessed using a slow, nonlinear algorithm to give an accuracy of less than 1% and a precision of approximately the noise to signal ratio throughout a range of T1 values from 0 to 4 seconds.

Algorithms↗

PubMed2003

Selective arterial spin labeling (SASL): perfusion territory mapping of selected feeding arteries tagged using two-dimensional radiofrequency pulses.

To date, most perfusion magnetic resonance imaging (MRI) methods using arterial spin labeling (ASL) have employed slab-selective inversion pulses or continuous labeling within a plane in order to obtain maps derived from all major blood vessels entering the brain. However, there is great potential for gaining additional information on the territories perfused by the major vessels if individual feeding arteries could be tagged. This study demonstrates noninvasive arterial perfusion territory maps obtained using two-dimensional (2D) selective inversion pulses. This method is designated "selective ASL" (SASL). The SASL method was used to tag the major arteries below the circle of Willis. A combination of 2D selective tagging and multislice readout allows perfusion territories to be clearly visualized, with likely applications to cerebrovascular disease and stroke.

Brain↗

PubMed1998

Molecular study and partial characterization of iron-only hydrogenase in Desulfovibrio fructosovorans.

An iron-only hydrogenase was partially purified and characterized from Desulfovibrio fructosovorans wild-type strain. The enzyme exhibits a molecular mass of 56 kDa and is composed of two distinct subunits HydA and HydB (46 and 13 kDa, respectively). The N-terminal amino acid sequences of the two subunits of the enzyme were determined with the aim of designing degenerate oligonucleotides. Direct and inverse polymerase chain reaction techniques were used to clone the hydrogenase encoding genes. A 9-nucleotide region located 75 bp upstream from the translational start codon of the D. fructosovorans hydA gene was found to be highly conserved. The analysis of the deduced amino acid sequence of these genes showed the presence of a signal sequence located in the small subunit, exhibiting the consensus sequence which is likely to be involved in the specific export mechanism of hydrogenases. Two ferredoxin-like motives involved in the coordination of [4Fe-4S] clusters were identified in the N-terminal domain of the large subunit. The amino acid sequence of the [Fe] hydrogenase from D. fructosovorans was compared with the amino acid sequences from eight other hydrogenases (cytoplasmic and periplasmic). These enzymes share an overall 18% identity and 28% similarity. The identity reached 73% and 69% when the D. fructosovorans hydrogenase sequence was compared with the hydrogenase sequences from Desulfovibrio vulgaris Hildenborough and Desulfovibrio vulgaris oxamicus Monticello, respectively.

Journal Article↗