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PubMed2004

Metabolic profiling: a new tool in the study of wood formation.

In the realm of plant genomics, metabolic profiling has become a valuable tool with which to assess the effect of genetic and/or environmental factors on plant development. This paper reports the first application of metabolic profiling on differentiating xylem tissue of loblolly pine. A protocol is presented for the analysis of loblolly pine xylem tissue. The effects of sample preparation, extraction, and derivatization on the corresponding metabolite profiles and yields have been investigated and are reported. Gas chromatography-mass spectroscopy has been used to quantify >60 polar and lipophilic metabolites from wood-forming tissue. It was possible to assign chemical structures to approximately half of these compounds. Comparison of six loblolly pine genotypes, three high cellulose (50-52%) and three medium (45-48%) cellulose, showed distinct metabolic profiles. Principal component analysis enabled the assignment of metabolic phenotypes using these large data sets. Metabolic phenotype clustering occurred in which the three high-cellulose genotypes were segregated from the medium-cellulose genotypes. These results demonstrate the use of metabolic profiling for the study of wood-forming tissue and as a tool in functional genomics.

Cellulose↗
PubMed2005

Use of fatty acid profiles to identify food-borne bacterial pathogens and aerobic endospore-forming bacilli.

Capillary gas chromatography (GC) with flame ionization detection was used to determine the cellular fatty acid profiles of various food-borne microbial pathogens and to compare the fatty acid profiles of spores and vegetative cells of the same endospore-forming bacilli. Fifteen bacteria, representing eight genera (Staphylococcus, Listeria, Bacillus, Yersinia, Salmonella, Shigella, Escherichia, and Vibrio) and 11 species were used to compare the extracted fatty acid methyl esters (FAMEs). Endospore-forming bacilli were processed to obtain pure spores and whole cell FAMEs for GC analysis. A data set for each bacterial agent was prepared using fatty acid profiles from five replicates prepared on different days. The results showed that these fatty acid intensity profiles were unique for each of the 11 species and that they could be used as a fingerprint for the organisms. The cellular fatty acid profiles for Bacillus anthracis and Bacillus cereus show that there are two branched chain fatty acids, iso 17:1 omega10c and 17:1 anteiso, which are unique in these species. Iso 17:1 omega10c is present in B. cereus vegetative cells and spores but is not observed in B. anthracis. The 17:1 anteiso fatty acid is present in B. anthracis cells but not in B. cereus cells. Fatty acids 16:0 2OH and 17:0 iso 3OH are present in B. anthracis and B. cereus spores but not in the vegetative cells. In summary, analysis of FAMEs from bacteria and spores can provide a sensitive procedure for the identification of food-borne pathogens.

Bacillus anthracis↗
PubMed2005

Interaction profiles of protein kinase-inhibitor complexes and their application to virtual screening.

A major challenge facing structure-based drug discovery efforts is how to leverage the massive amount of experimental (X-ray and NMR) and virtual structural information generated from drug discovery projects. Many important drug targets have large numbers of protein-inhibitor complexes, necessitating tools to compare and contrast their similarities and differences. This information would be valuable for understanding potency and selectivity of inhibitors and could be used to define target constraints to assist virtual screening. We describe a profile-based approach that enables us to capture the conservation of interactions between a set of protein-ligand receptor complexes. The use of profiles provides a sensitive means to compare multiple inhibitors binding to a drug target. We demonstrate the utility of profile-based analysis of small molecule complexes from the protein-kinase family to identify similarities and differences in binding of ATP, p38, and CDK2 compounds to kinases and how these profiles can be applied to differentiate the selectivity of these inhibitors. Importantly, our virtual screening results demonstrate superior enrichment of kinase inhibitors using profile-based methods relative to traditional scoring functions. Interaction-based analysis should provide a valuable tool for understanding inhibitor binding to other important drug targets.

Adenosine Triphosphate↗
PubMed2005

Fast small molecule similarity searching with multiple alignment profiles of molecules represented in one-dimension.

Multiple sequence alignment has proven to be a powerful method for creating protein and DNA sequence alignment profiles. These profiles of protein families are useful tools for identifying conserved motifs, such as the catalytic triad of the serine protease family or the seven transmembrane helices of the G-protein coupled receptor family. Ultimately, the understanding of the critical motifs within a family is useful for identifying new members of the family. Due to the complexity of protein-ligand recognition, no universally accepted method exists for clustering small molecules into families with the same or similar biological activity. A combination of the concept of multiple sequence alignment and the 1-dimensional molecular representation described earlier offers a new method for profiling sets of small molecules with the same biological activity. These small molecule profiles can isolate key commonalities within the set of bioactive compounds much like a multiple sequence alignment can isolate critical motifs within a protein family. The small molecule profiles then make useful tools for searching small molecule databases for new compounds with the same biological activity. The technique is demonstrated here using the human ether-a-go-go potassium channel and the kinase SRC.

Algorithms↗
PubMed1998

Second generation "peptoid" CCK-B receptor antagonists: identification and development of N-(adamantyloxycarbonyl)-alpha-methyl-(R)-tryptophan derivative (CI-1015) with an improved pharmacokinetic profile.

We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was determined that CI-988 had low bioavailability in both rodent and nonrodent species. In the clinic, it was further established that CI-988 had poor bioavailability. Thus, there was a need to identify an analogue with an improved pharmacokinetic (PK) profile. The poor bioavailability was attributed to poor absorption and efficient hepatic extraction. We envisaged that reducing the molecular weight of the parent compound (5, MW = 614) would lead to better absorption. Thus, we synthesized a series of analogues in which the key alpha-methyltryptophan and adamantyloxycarbonyl moieties, required for receptor binding, were kept intact and the C-terminus was extensively modified. This SAR study led to the identification of tricyclo[3.3.1.1(3,7)]dec-2-yl [1S-[1 alpha(S*)2 beta]-[2-[(2-hydroxycyclohexyl)amino]-1-(1H-indol-3- ylmethyl)-1-methyl-2-oxoethyl]carbamate (CI-1015, 31) with binding affinities of 3.0 and 2900 nM for the CCK-B and CCK-A receptors, respectively. The compound showed CCK-B antagonist profile in the rat ventromedial hypothalamus assay with a Ke of 34 nM. It also showed an anxiolytic like profile orally in a standard anxiety paradigm (X-maze) with a minimum effective dose (MED) of 0.1 microgram/kg. Although the compound is less water soluble than CI-988, oral bioavailability in rat was improved nearly 10 times relative to CI-988 when dosed in HP beta CD. The blood-brain permeability of CI-1015 (31) was also enhanced relative to CI-988 (5). On the basis of the overall improved pharmacokinetic profile as well as enhanced brain penetration, CI-1015 (31) was chosen as a development candidate.

Adamantane↗
PubMedDate not supplied

Molecular profiling of experimental Parkinson's disease: direct analysis of peptides and proteins on brain tissue sections by MALDI mass spectrometry.

Direct molecular profiling of biological samples using matrix-assisted laser desorption ionization mass spectrometry is a powerful tool for identifying phenotypic markers. In this report, protein profiling was used for the first time to generate peptide and protein profiles of brain tissue sections obtained from experimental Parkinson's disease (unilaterally 6-hydroxydopamine treated rats). The mass spectrometer was used to map the peptide and protein expression directly on 12 microm tissue sections in mass-to-charge (m/z) values, providing the capability of mapping specific molecules of the original sample, that is, localization, intensity and m/z ratio. Several protein expression profile differences were found in the dopamine depleted side of the brain when compared to the corresponding intact side, for example, calmodulin, cytochrome c, and cytochrome c oxidase. An increased ratio of post-translational modifications such as acetylations were found in the striatum of proteins in the dopamine depleted side of the brain. These modifications were decreased after subchronic administration of L-Dopa. The present study shows that unique protein profiles can be obtained in specific brain regions (and subregions) directly on brain tissue sections and allows for the study of complex biochemical processes such as those occurring in experimental Parkinson's disease.

Adrenergic Agents↗
PubMed1997

Improved assessment of intravascular Doppler coronary flow velocity profile.

Easy and safe in-vivo flow velocity studies in small coronary arteries have become feasible using a 0.014 'or 0.018' guidewire with an integrated Doppler probe in its tip (FloWire, Cardiometrics). Assessment of the flow velocity profile by the ratio of diastolic to systolic flow velocity (DSVR) is used as a diagnostic parameter. However, DSVR is a coarse quantifier of the flow velocity profile, and is subject to large physiologic variance and depends crucially on the quality of the Doppler signal. The aim of our study was to test parameters derived from statistical time series analysis for monitoring the quality of the instantaneous peak velocity (IPV) signal. Improvement of quantification of changes in quality and shape of flow velocity profiles by these parameters as compared to DSVR was a second goal. We investigated analog-digital converted IPV-signals and video registrations of corresponding greyscale spectra of intracoronary Doppler flow velocity signals. The signals were analyzed by using the autocorrelation function (ACF) in the time domain and a fast Fourier transform (FFT) in the frequency domain (standard time series statistics). The first minimum of autocorrelation function turned out to be very sensitive to signal quality, and Fisher's g of the periodogram was the parameter of choice for shape analysis. In 11 patients with coronary artery disease, pre and post PTCA, the sensitivity of DSVR and signal to noise ratio to changes in shape and quality of the flow velocity signals was compared to that of the new parameters. Nineteen Doppler flow velocity samples of good quality from measurements in nonstenotic vessels and 7 flow velocity tracings with visible artefacts were used to assess the value of these parameters in monitoring signal quality. By comparison with corresponding parameters in use (SNR and DSVR) a significantly improved performance of the new statistical parameters was observed with respect to sensitivity to changes in signal quality and flow profile. In view of these results and because of the short calculation time of these variables they should be used for on-line quality control and analysis of flow velocity profiles.

Adult↗
PubMed2000

Variation in flexural properties of photo-pultruded composite archwires: analyses of round and rectangular profiles.

Prototype continuous, unidirectional, fiber-reinforced composite archwires were manufactured into round and rectangular profiles utilizing a photo-pultrusion process. Both 0.022 inch (0.56 mm) diameter and 0.021 x 0.028 inch (0.53 x 0.71 mm) rectangular composites were formed utilizing commercially available S2-glass reinforcement within a polymeric matrix. Reinforcement was varied according to the number, denier and twists per inch (TPI) of four S2-glass yarns to volume levels of 32-74% for round and 41-61% for rectangular profiles. Cross-sectional geometry was evaluated via light microscopy to determine loading characteristics; whereas two flexural properties (the elastic moduli and flexural strengths) were determined by 3-point bending tests. Morphological evaluation of samples revealed that as the TPI increased from 1 to 8, the yarns were more separated from one another and distributed more peripherally within a profile. For round and rectangular profiles utilizing 1 TPI fibers, moduli increased with fiber content approaching theoretical values. For round profiles utilizing 1 TPI and 4 TPI fibers, flexural strengths increased until the loading geometry was optimized. In contrast, the flexural strengths of composites that were pultruded with 8 TPI fibers were not improved at any loading level. Doubling the denier of the yarn, without altering the loading, increased both the moduli and flexural strengths in rectangular samples; whereas, the increases observed in round samples were not statistically significant. At optimal loading the maximum mean moduli and strengths equaled 53.6 +/- 2.0 and 1.36 +/- 0.17 GPa for round wire and equaled 45.7 +/- 0.8 and 1.40 +/- 0.05 GPa for rectangular wires, respectively. These moduli were midway between that of martensitic NiTi (33.4 GPa) and beta-titanium (72.4 GPa), and produced about one-quarter the force of a stainless steel wire per unit of activation. Values of strengths placed this composite material in the range of published values for beta-titanium wires (1.3-1.5 GPa).

Journal Article↗
PubMed1996

In-vitro dissolution profile comparison: statistics and analysis, model dependent approach.

PURPOSE: To develop and propose a "model dependent' approach for the in-vitro dissolution profiles comparison. METHODS: Diltiazem hydrochloride tablet dissolution profiles were compared using a statistical approach based on a mathematical model. A similarity region (SR) was defined based on the intra- and inter-lot parameter variances of the final production size standard lots. Statistical distances between the test and reference lot parameter means were computed and normalized. A 90% confidence region (CR) was developed around the statistical distance. The confidence region was compared with the similarity region to assess the similarity or dis-similarity of the test and reference (REF) lot dissolution profiles. Two test lots, one with a "minor' modification (mm) the other with a "major' modification (MM), were evaluated. RESULTS: "Weibull' was selected as the "model' function. A comparison of the confidence regions around the statistical distance of "mm-REF' and "MM-REF' with the similarity region, suggested that the dissolution profiles of the "minor' modification lot were similar and that of "major' modification lot were dis-similar to the reference lot. CONCLUSIONS: A "model dependent' approach was shown to be useful for the inter-lot in-vitro dissolution profiles comparison.

Cardiovascular Agents↗
PubMed2001

Relationship between plasma leptin levels and lipid profiles among school children in Taiwan--the Taipei Children Heart Study.

Leptin, an adipose tissue-derived of gene product, is important in energy metabolism. However, the role of leptin in the metabolism of lipids is still not clear in humans. The purpose of this study was to evaluate the association of plasma leptin concentrations and lipid profiles among school children in Taiwan. After multistage sampling of 85 junior high schools in Taipei, we randomly selected 1264 children (617 boys and 647 girls) aged 12-16 years for this study. We measured the anthropometric variables, lifestyle factors and biochemical parameters among these children. Anthropometric measurements included body height (BH) and weight (BW) and we calculated body mass index (BMI) as the ratio of the BW to the square of the BH, expressed in kg/m2. Plasma leptin levels were measured by radioimmunoassay. We also measured lipid profiles including serum total cholesterol (CHOL), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), apolipoprotein-A1 (Apo-A1), apolipoprotein-B (Apo-B), and lipoprotein(a) (Lp(a)) levels, and calculated low density lipoprotein-cholesterol (LDL-C) levels and CHOL to HDL-C ratio (TCHR). Girls had higher leptin, CHOL, TG, HDL-C, (LDL-C), Apo-A1, Apo-B, and Lp(a) levels and lower BMI than boys did. Plasma leptin concentrations were significantly positively correlated with TG, LDL-C, and Apo-B, but negatively with HDL-C and Apo-A1 in both the genders. Children with higher plasma leptin levels (>75th percentiles) have significantly higher TG, HDL-C, LDL-C, TCHR, and Apo-B than those with relatively lower leptin levels. In multivariate regression analyses, the association between plasma leptin level and lipid profiles (such as CHOL, TG, and Apo-B) were still significant (p < 0.05) even after adjusting for BMI among boys. However, this association became attenuated and insignificant among girls. Finally, in the model that included the standard covariates, plasma leptin was the most predictive of CHOL, TG and Apo-B levels among those school children in Taiwan. Our results suggest that plasma leptin and BMI were independently associated with the lipids and lipoprotein profiles among Taiwanese Children. In both genders, children in the top 25% of the leptin distribution have more adverse lipid and lipoprotein profiles.

Adolescent↗
PubMed1995

Controlled release of substituted benzoic and naphthoic acids using Carbopol gels: measurement of drug concentration profiles and correlation to release rate kinetics.

PURPOSE: The objective of this study is to correlate drug release mechanism with measured drug concentration profiles in gel layers of Carbopol matrices containing mesalamine or benzoic acid. METHODS: Release rate experiments with Carbopol matrices were performed using a rotating disk apparatus. Matrices were frozen and the gel layer in the matrices was sliced using a microtome in a cryostat. Drug concentration profiles were determined by direct measurement of the concentration of the drug in the gel slices. The pH of the slices was measured using microelectrodes, and water content was measured by Karl Fisher titration. RESULTS: The concentration gradient in mesalamine matrices decreased over time and correlated with square root of time release rate kinetics. The concentration profiles of benzoic acid were unchanged over time and correlated with zero order release rate kinetics. Carbopol gel layers were highly hydrated (93-95% water). Gel layers in matrices with mesalamine had a more alkaline microenvironmental pH. This higher pH resulted in increased growth of the thickness of the gel layer and a reduction drug diffusivity in comparison to benzoic acid matrices. CONCLUSIONS: The release rate kinetics of mesalamine and benzoic acid correlated to the measured concentration profiles. The shape of the concentration profiles is determined by the rate of growth of the Carbopol gel layer and drug diffusivity.

Acrylic Resins↗
PubMed1999

Profiles of self-esteem in early adolescence: identification and investigation of adaptive correlates.

Investigated profiles of self-esteem during early adolescence and their adaptive correlates in two separate longitudinal studies. Using multidimensional ratings of self-esteem within a developmental-ecological framework, cluster analysis revealed five distinct profiles for each sample. The profiles found were characterized by differing patterns of self-evaluation across major contexts of development, including consistently positive or negative ratings for all domains as well as more variable patterns in which ratings for one or more domains (e.g., school) were elevated or diminished relative to those for other areas. Profiles, in turn, were found to be related to measures of youth adjustment both concurrently and longitudinally, independent of their associations with ratings of global self-esteem. Prospective analyses in each study further revealed that profile type predicted differential change in measures of youth adjustment over time, whereas this type of relationship was not found for global ratings of self-esteem. Implications for esteem-enhancement interventions with youth are discussed.

Adaptation, Psychological↗
PubMed2004

Test-retest reliability of static EMG scan configural profiling.

Measurement techniques or instruments are typically evaluated along the dimensions of reliability and validity. The focus of this investigation was to assess the test-retest reliability of a static EMG scan profile (sESP) method using 64 chronic pain participants. The test-retest interval was 30-33 days. Reliability coefficients were expressed using the Profile Similarity Coefficient (rp) in place of the more traditional Pearson Product Moment Correlation. sESP reliabilities were calculated for posture laterality for the head and neck, back, and overall profiles (head, neck, and back combined). The reliability coefficients ranged from .57 to .80. The back profile was the least reliable with a range of .55-.59 whereas the overall profiles were the most reliable, .78-.80. The analysis method was judged to be very conservative with its use of rp, a protracted intertest interval period, and weighting the data by their variances. These results can be viewed as setting the lower reliability limit for sESP.

Adult↗
PubMed2004

Use of glancing angle X-ray powder diffractometry to depth-profile phase transformations during dissolution of indomethacin and theophylline tablets.

PURPOSE: The purpose of this study was (i) to develop glancing angle x-ray powder diffractometry (XRD) as a method for profiling phase transformations as a function of tablet depth; and (ii) to apply this technique to (a) study indomethacin crystallization during dissolution of partially amorphous indomethacin tablets and to (b) profile anhydrate --> hydrate transformations during dissolution of theophylline tablets. METHODS: The intrinsic dissolution rates of indomethacin and theophylline were determined after different pharmaceutical processing steps. Phase transformations during dissolution were evaluated by various techniques. Transformation in the bulk and on the tablet surface was characterized by conventional XRD and scanning electron microscopy, respectively. Glancing angle XRD enabled us to profile these transformations as a function of depth from the tablet surface. RESULTS: Pharmaceutical processing resulted in a decrease in crystallinity of both indomethacin and theophylline. When placed in contact with the dissolution medium, while indomethacin recrystallized, theophylline anhydrate rapidly converted to theophylline monohydrate. Due to intimate contact with the dissolution medium, drug transformation occurred to a greater extent at or near the tablet surface. Glancing angle XRD enabled us to depth profile the extent of phase transformations as a function of the distance from the tablet surface. The processed sample (both indomethacin and theophylline) transformed more rapidly than did the corresponding unprocessed drug. Several challenges associated with the glancing angle technique, that is, the effects of sorbed water, phase transformations during the experimental timescale, and the influence of phase transformation on penetration depth, were addressed. CONCLUSIONS: Increased solubility, and consequently dissolution rate, is one of the potential advantages of metastable phases. This advantage is negated if, during dissolution, the metastable to stable transformation rate >> dissolution rate. Glancing angle XRD enabled us to quantify and thereby profile phase transformations as a function of compact depth. The technique has potential utility in monitoring surface reactions, both chemical decomposition and physical transformations, in pharmaceutical systems.

Drug Stability↗
PubMed2002

Cyclosporine microemulsion (Neoral) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation.

UNLABELLED: Recent data suggest that optimal cyclosporine (CsA) exposure early post-transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration-controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral. An international, prospective, multicenter study examined the feasibility, accuracy, precision and clinical utility of cyclosporine microemulsion (Neoral) absorption profiling in de novo renal transplant recipients receiving basiliximab immunoprophylaxis and cyclosporine microemulsion maintenance immunosuppression. The nested pharmacokinetic study reported here was conducted in 4 study centers in which full (11-point) pharmacokinetic profiles were performed on days 3, 7, 14 and 84 post-transplant to examine absorption profile and absorption efficiency, and to determine optimal sparse-sampling pharmacokinetic methods to predict Neoral exposure. Twenty-four patients had complete 12-h pharmacokinetic (PK) data on all 4 sampling days. Area under the time-concentration curve (AUC) over the first 4 h of the 12-h dosage interval (AUC[0-4]) and AUC over the entire 12-h dosage interval (AUC[0-12]) reached 3803 +/- 1033 and 7462 +/- 2120 microg.h/L respectively, by day 3, remained stable throughout the first 2 weeks, and declined to 2310 +/- 698 and 4062 +/- 1158 microg.h/L by day 84 (p < 0.001). AUC[0-4], capturing the drug absorption phase, represented 52% of the AUC[0-12] values across the four PK study days (mean R2 > 0.90). Between-patient variability was highest for C0 and C1 (mean coefficient of variation [c.v.] 36-47%), and lower for C2 (mean c.v. 28%) and subsequent time-points during the dosing interval. Mean relative CsA absorption, measured by dose- and weight-adjusted AUC[0-4] and AUC[0-12], increased significantly over time. The dose- and weight-corrected AUC[0-4h] (DWC.AUC[0-4]) rose by over 100% (p < 0.001) from 753 +/- 202 at day 3 to 905 +/- 232 at day 7, 1080 +/- 330 at day 14 and 1521 +/- 316 by day 84, while the dose-and weight-corrected AUC[0-12h] (DWC.AUC[0-12]) rose by over 80% (p < 0.001) from 1477 +/- 390 microg.h/L/ mg/kg on day 3, to 1721 +/- 426 on day 7, 2086 +/- 478 on day 14 and 2690 +/- 602 on day 84 (p < 0.001). Relative CsA absorption varied over 5-fold between patients at day 3, but patients tended to remain within the same quartiles over time. Sparse-sample modeling identified optimum 3-point, 2-point and 1-point predictors for AUC[0-4] and AUC[0-12]. C2 was the most accurate and robust .1-point predictor for AUC[0-4] (mean R2: 0.80), while C3 was superior for AUC[0-12] (mean R2: 0.75). C0 was not a good predictor of either AUC[0-4] or AUC[0-12] (mean R2: 0.13 and 0.24, respectively). CONCLUSION: Absorption profiling defines the heterogeneity in CsA exposure and relative absorption post-transplant. A 2-h post-dose blood sample is the most consistent, accurate and robust single-point predictor of the absorption phase measured by AUC[0-4] and should replace trough level monitoring for accurate concentration-control of Neoral therapy in the clinical setting. The use of additional samples at 1 and 3h is more complex and costly, but increases prediction accuracy and may be valuable in selected patients with erratic absorption.

Area Under Curve↗
PubMed1992

Assessment of protein models with three-dimensional profiles.

As methods for determining protein three-dimensional (3D) structure develop, a continuing problem is how to verify that the final protein model is correct. The revision of several protein models to correct errors has prompted the development of new criteria for judging the validity of X-ray and NMR structures, as well as the formation of energetic and empirical methods to evaluate the correctness of protein models. The challenge is to distinguish between a mistraced or wrongly folded model, and one that is basically correct, but not adequately refined. We show that an effective test of the accuracy of a 3D protein model is a comparison of the model to its own amino-acid sequence, using a 3D profile, computed from the atomic coordinates of the structure 3D profiles of correct protein structures match their own sequences with high scores. In contrast, 3D profiles for protein models known to be wrong score poorly. An incorrectly modelled segment in an otherwise correct structure can be identified by examining the profile score in a moving-window scan. The accuracy of a protein model can be assessed by its 3D profile, regardless of whether the model has been derived by X-ray, NMR or computational procedures.

Amino Acid Sequence↗
PubMed2000

Widespread aneuploidy revealed by DNA microarray expression profiling.

Expression profiling using DNA microarrays holds great promise for a variety of research applications, including the systematic characterization of genes discovered by sequencing projects. To demonstrate the general usefulness of this approach, we recently obtained expression profiles for nearly 300 Saccharomyces cerevisiae deletion mutants. Approximately 8% of the mutants profiled exhibited chromosome-wide expression biases, leading to spurious correlations among profiles. Competitive hybridization of genomic DNA from the mutant strains and their isogenic parental wild-type strains showed they were aneuploid for whole chromosomes or chromosomal segments. Expression profile data published by several other laboratories also suggest the use of aneuploid strains. In five separate cases, the extra chromosome harboured a close homologue of the deleted gene; in two cases, a clear growth advantage for cells acquiring the extra chromosome was demonstrated. Our results have implications for interpreting whole-genome expression data, particularly from cells known to suffer genomic instability, such as malignant or immortalized cells.

Aneuploidy↗
PubMed1998

Functional characterisation of the human cloned 5-HT7 receptor (long form); antagonist profile of SB-258719.

1. The functional profile of the long form of the human cloned 5-HT7 receptor (designated h5-HT7(a)) was investigated using a number of 5-HT receptor agonists and antagonists and compared with its binding profile. Receptor function was measured using adenylyl cyclase activity in washed membranes from HEK293 cells stably expressing the recombinant h5-HT7(a) receptor. 2. The receptor binding profile, determined by competition with [3H]-5-CT, was consistent with that previously reported for the h5-HT7(a) receptor. The selective 5-HT7 receptor antagonist SB-258719 ((R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]ben zene sulfonamide) displayed high affinity (pKi 7.5) for the receptor. 3. In the adenylyl cyclase functional assay, 5-CT and 8-OH-DPAT were both full agonists compared to 5-HT and the rank order of potency for agonists (5-CT > 5-HT > 8-OH-DPAT) was the same in functional and binding studies. 4. Risperidone, methiothepin, mesulergine, clozapine, olanzapine, ketanserin and SB-258719 antagonised surmountably 5-CT-stimulated adenylyl cyclase activity. Schild analysis of the antagonism by SB-258719 gave a pA2 of 7.2+/-0.2 and slope not significantly different from 1, consistent with competitive antagonism. 5. The same antagonists also inhibited basal adenylyl cyclase activity with a rank order of potency in agreement with those for antagonist potency and binding affinity. Both SB-258719 and mesulergine displayed apparent partial inverse agonist profiles compared to the other antagonists tested. These inhibitory effects of antagonists appear to be 5-HT7 receptor-mediated and to reflect inverse agonism. 6. It is concluded that in this expression system, the h5-HT7(a) receptor shows the expected binding and functional profile and displays constitutive activity, revealing inverse agonist activity for a range of antagonists.

Adenylyl Cyclases↗