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At least 19 recordsLinked to original sources
PubMedDate not supplied

Enrichment of ligands for the serotonin receptor using the Shape Signatures approach.

Shape Signatures, a new 3-dimensional molecular comparison method, has been adapted to rank ligands of the serotonin receptors. A set of 825 agonists and 400 antagonists together with approximately 10,000 randomly chosen compounds from the NCI database were used in this study. Both 1D and 2D Shape Signature databases were created, and enrichment studies were carried out. Results from these studies reveal that the 1D Shape Signature approach is highly efficient in separating agonists from a mixture of molecules which includes compounds randomly selected from the NCI database taken as inactives. It is also equally effective at separating agonists and antagonists from a pool of active ligands for the serotonin receptor. Parallel enrichment studies using 2D shape signatures showed high selectivity with more restricted coverage due to the high specificity of 2D signatures. The influence of conformational variation of the shape signature on enrichment was explored by docking a subset of ligands into the crystal structure of serotonin N-acetyltransferase. Enrichment studies on the resulting "docked" conformations produced only slightly improved results compared with the CORINA-generated conformations.

Computer Simulation↗
PubMedDate not supplied

Pose-oblivious shape signature.

A 3D shape signature is a compact representation for some essence of a shape. Shape signatures are commonly utilized as a fast indexing mechanism for shape retrieval. Effective shape signatures capture some global geometric properties which are scale, translation, and rotation invariant. In this paper, we introduce an effective shape signature which is also pose-oblivious. This means that the signature is also insensitive to transformations which change the pose of a 3D shape such as skeletal articulations. Although some topology-based matching methods can be considered pose-oblivious as well, our new signature retains the simplicity and speed of signature indexing. Moreover, contrary to topology-based methods, the new signature is also insensitive to the topology change of the shape, allowing us to match similar shapes with different genus. Our shape signature is a 2D histogram which is a combination of the distribution of two scalar functions defined on the boundary surface of the 3D shape. The first is a definition of a novel function called the local-diameter function. This function measures the diameter of the 3D shape in the neighborhood of each vertex. The histogram of this function is an informative measure of the shape which is insensitive to pose changes. The second is the centricity function that measures the average geodesic distance from one vertex to all other vertices on the mesh. We evaluate and compare a number of methods for measuring the similarity between two signatures, and demonstrate the effectiveness of our pose-oblivious shape signature within a 3D search engine application for different databases containing hundreds of models.

Algorithms↗
PubMed2003

Shape signatures: a new approach to computer-aided ligand- and receptor-based drug design.

A unifying principle of rational drug design is the use of either shape similarity or complementarity to identify compounds expected to be active against a given target. Shape similarity is the underlying foundation of ligand-based methods, which seek compounds with structure similar to known actives, while shape complementarity is the basis of most receptor-based design, where the goal is to identify compounds complementary in shape to a given receptor. These approaches can be extended to include molecular descriptors in addition to shape, such as lipophilicity or electrostatic potential. Here we introduce a new technique, which we call shape signatures, for describing the shape of ligand molecules and of receptor sites. The method uses a technique akin to ray-tracing to explore the volume enclosed by a ligand molecule, or the volume exterior to the active site of a protein. Probability distributions are derived from the ray-trace, and can be based solely on the geometry of the reflecting ray, or may include joint dependence on properties, such as the molecular electrostatic potential, computed over the surface. Our shape signatures are just these probability distributions, stored as histograms. They converge rapidly with the length of the ray-trace, are independent of molecular orientation, and can be compared quickly using simple metrics. Shape signatures can be used to test for both shape similarity between compounds and for shape complementarity between compounds and receptors and thus can be applied to problems in both ligand- and receptor-based molecular design. We present results for comparisons between small molecules of biological interest and the NCI Database using shape signatures under two different metrics. Our results show that the method can reliably extract compounds of shape (and polarity) similar to the query molecules. We also present initial results for a receptor-based strategy using shape signatures, with application to the design of new inhibitors predicted to be active against HIV protease.

Binding Sites↗
PubMed2004

Protein structure alignment and fast similarity search using local shape signatures.

We present a new method for conducting protein structure similarity searches, which improves on the efficiency of some existing techniques. Our method is grounded in the theory of differential geometry on 3D space curve matching. We generate shape signatures for proteins that are invariant, localized, robust, compact, and biologically meaningful. The invariancy of the shape signatures allows us to improve similarity searching efficiency by adopting a hierarchical coarse-to-fine strategy. We index the shape signatures using an efficient hashing-based technique. With the help of this technique we screen out unlikely candidates and perform detailed pairwise alignments only for a small number of candidates that survive the screening process. Contrary to other hashing based techniques, our technique employs domain specific information (not just geometric information) in constructing the hash key, and hence, is more tuned to the domain of biology. Furthermore, the invariancy, localization, and compactness of the shape signatures allow us to utilize a well-known local sequence alignment algorithm for aligning two protein structures. One measure of the efficacy of the proposed technique is that we were able to perform structure alignment queries 36 times faster (on the average) than a well-known method while keeping the quality of the query results at an approximately similar level.

Algorithms↗
PubMed2006

Shape Signatures: speeding up computer aided drug discovery.

Identifying potential lead molecules is becoming a more automated process. We review Shape Signatures, a tool that is effective and easy to use compared with most computer aided drug design techniques. Laboratory researchers can apply this in silico technique cost-effectively without the need for specialized computer backgrounds. Identifying a potential lead molecule requires database screening, and this becomes rate-limiting once the database becomes too large. The use of Shape Signatures eliminates this concern and offers molecule screening rates that are in advance of any currently available method. Shape Signatures provides a conduit for researchers to conduct rapid identification of potential active molecules, and studies with this tool can be initiated with only one bioactive lead or receptor site.

Computer-Aided Design↗
PubMed2006

Signature whistle shape conveys identity information to bottlenose dolphins.

Bottlenose dolphins (Tursiops truncatus) develop individually distinctive signature whistles that they use to maintain group cohesion. Unlike the development of identification signals in most other species, signature whistle development is strongly influenced by vocal learning. This learning ability is maintained throughout life, and dolphins frequently copy each other's whistles in the wild. It has been hypothesized that signature whistles can be used as referential signals among conspecifics, because captive bottlenose dolphins can be trained to use novel, learned signals to label objects. For this labeling to occur, signature whistles would have to convey identity information independent of the caller's voice features. However, experimental proof for this hypothesis has been lacking. This study demonstrates that bottlenose dolphins extract identity information from signature whistles even after all voice features have been removed from the signal. Thus, dolphins are the only animals other than humans that have been shown to transmit identity information independent of the caller's voice or location.

Animal Communication↗
PubMed2005

Virtual endoscopic visualization of the colon by shape-scale signatures.

We developed a new visualization method for virtual endoscopic examination of computed tomographic (CT) colonographic data by use of shape-scale analysis. The method provides each colonic structure of interest with a unique color, thereby facilitating rapid diagnosis of the colon. Two shape features, called the local shape index and curvedness, are used for defining the shape-scale spectrum. When we map the shape index and curvedness values within CT colonographic data to the shape-scale spectrum, specific types of colonic structures are represented by unique characteristic signatures in the spectrum. The characteristic signatures of specific types of lesions can be determined by use of computer-simulated lesions or by use of clinical data sets subjected to a computerized detection scheme. The signatures are used for defining a two-dimensional color map by assignment of a unique color to each signature region. The method was evaluated visually by use of computer-simulated lesions and clinical CT colonographic data sets, as well as by an evaluation of the human observer performance in the detection of polyps without and with the use of the color maps. The results indicate that the coloring of the colon yielded by the shape-scale color maps can be used for differentiating among the chosen colonic structures. Moreover, the results indicate that the use of the shape-scale color maps can improve the performance of radiologists in the detection of polyps in CT colonography.

Algorithms↗
PubMed2006

Shapeme histogram projection and matching for partial object recognition.

Histograms of shape signature or prototypical shapes, called shapemes, have been used effectively in previous work for 2D/3D shape matching and recognition. We extend the idea of shapeme histogram to recognize partially observed query objects from a database of complete model objects. We propose representing each model object as a collection of shapeme histograms and match the query histogram to this representation in two steps: 1) compute a constrained projection of the query histogram onto the subspace spanned by all the shapeme histograms of the model and 2) compute a match measure between the query histogram and the projection. The first step is formulated as a constrained optimization problem that is solved by a sampling algorithm. The second step is formulated under a Bayesian framework, where an implicit feature selection process is conducted to improve the discrimination capability of shapeme histograms. Results of matching partially viewed range objects with a 243 model database demonstrate better performance than the original shapeme histogram matching algorithm and other approaches.

Algorithms↗
PubMed2003

CTSS: a robust and efficient method for protein structure alignment based on local geometrical and biological features.

We present a new method for conducting protein structure similarity searches, which improves on the accuracy, robustness, and efficiency of some existing techniques. Our method is grounded in the theory of differential geometry on 3D space curve matching. We generate shape signatures for proteins that are invariant, localized, robust, compact, and biologically meaningful. To improve matching accuracy, we smooth the noisy raw atomic coordinate data with spline fitting. To improve matching efficiency, we adopt a hierarchical coarse-to-fine strategy. We use an efficient hashing-based technique to screen out unlikely candidates and perform detailed pairwise alignments only for a small number of candidates that survive the screening process. Contrary to other hashing based techniques, our technique employs domain specific information (not just geometric information) in constructing the hash key, and hence, is more tuned to the domain of biology. Furthermore, the invariancy, localization, and compactness of the shape signatures allow us to utilize a well-known local sequence alignment algorithm for aligning two protein structures. One measure of the efficacy of the proposed technique is that we were able to discover new, meaningful motifs that were not reported by other structure alignment methods.

Algorithms↗
PubMed2024

Use of 3D chaos game representation to quantify DNA sequence similarity with applications for hierarchical clustering.

A 3D chaos game is shown to be a useful way for encoding DNA sequences. Since matching subsequences in DNA converge in space in 3D chaos game encoding, a DNA sequence's 3D chaos game representation can be used to compare DNA sequences without prior alignment and without truncating or padding any of the sequences. Two proposed methods inspired by shape-similarity comparison techniques show that this form of encoding can perform as well as alignment-based techniques for building phylogenetic trees. The first method uses the volume overlap of intersecting spheres and the second uses shape signatures by summarizing the coordinates, oriented angles, and oriented distances of the 3D chaos game trajectory. The methods are tested using: (1) the first exon of the beta-globin gene for 11 species, (2) mitochondrial DNA from four groups of primates, and (3) a set of synthetic DNA sequences. Simulations show that the proposed methods produce distances that reflect the number of mutation events; additionally, on average, distances resulting from deletion mutations are comparable to those produced by substitution mutations.

Animals↗
PubMed2000

Signature-based analysis of MET proto-oncogene mutations using DHPLC.

Research tools which improve mutation detection, SNP discovery, and allele characterization will facilitate studies of cancer, inherited disease, and genomic evolution. Denaturing High-Performance Liquid Chromatography (DHPLC) is a recently developed methodology for detection of heteroduplexes formed in DNA samples containing mismatches between wild type and mutant strands. In an effort to develop a rapid, sensitive mutation detection method for studies of families with inherited kidney cancer, we evaluated DHPLC for detection and analysis of MET proto-oncogene mutations in papillary renal carcinomas (PRC). We found DHPLC to be 100% accurate in detecting 15 known disease-associated MET mutations. Significantly, each MET mutation and two novel SNPs generated a characteristic chromatographic profile or signature with reproducible distinguishing features. Standardization of DHPLC reagents and improved methods design were critical to the reliability and accuracy of mutation prediction. Improvements included addition of a 75% acetonitrile wash followed by a rejuvenating gradient, and detailed analysis of signature shape, retention time (RT), RT differences (DeltaRT), and temperature-dependent (melt) profiling. We used signatures to predict mutations in new PRC samples, mutation carriers in asymptomatic hereditary PRC family members, and in a blind study of previously characterized DNAs. Application to SNP discovery is discussed. Wiley-Liss, Inc.

Carcinoma, Renal Cell↗
PubMed2006

Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach.

The physiological roles of estrogen in sexual differentiation and development, female and male reproductive processes, and bone health are complex and diverse. Numerous natural and synthetic chemical compounds, commonly known as endocrine disrupting chemicals (EDCs), have been shown to alter the physiological effects of estrogen in humans and wildlife. As such, these EDCs may cause unanticipated and even undesirable effects. Large-scale in vitro and in vivo screening of chemicals to assess their estrogenic activity would demand a prodigious investment of time, labor, and money and would require animal testing on an unprecedented scale. Approaches in silico are increasingly recognized as playing a vital role in screening and prioritizing chemicals to extend limited resources available for experimental testing. Here, we evaluated a multistep procedure that is suitable for in silico (virtual) screening of large chemical databases to identify compounds exhibiting estrogenic activity. This procedure incorporates Shape Signatures, a novel computational tool that rapidly compares molecules on the basis of similarity in shape, polarity, and other bio-relevant properties. Using 4-hydroxy tamoxifen (4-OH TAM) and diethylstilbestrol (DES) as input queries, we employed this scheme to search a sample database of approximately 200,000 commercially available organic chemicals for matches (hits). Of the eight compounds identified computationally as potentially (anti)estrogenic, biological evaluation confirmed two as heretofore unknown estrogen antagonists. Subsequent radioligand binding assays confirmed that two of these three compounds exhibit antiestrogenic activities comparable to 4-OH TAM. Molecular modeling studies of these ligands docked inside the binding pocket of estrogen receptor alpha (ERalpha) elucidated key ligand-receptor interactions that corroborate these experimental findings. The present study demonstrates the utility of our computational scheme for this and related applications in drug discovery, predictive toxicology, and virtual screening.

Binding, Competitive↗
PubMed2026

Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.

Cellular senescence is a state of irreversible cell cycle arrest triggered by telomere erosion, persistent DNA damage or chronic stress. The accumulation of senescent cells disrupts tissue function and contributes to aging and disease. Here, we employ mass spectrometry-based proteomics to systematically interrogate dynamic proteome changes at multiple levels during the progression of replicative cellular senescence. We demonstrate that proteome changes during senescence occur in a coordinated manner, characterized by widespread protein depletion on chromatin. Moreover, components of the cytoplasmic translation machinery are depleted, while mitochondrial proteins display increased insolubility. Autophagic and proteasome activity is compromised in senescent cells along with remodeling of ubiquitin linkages and depletion of ubiquitin E3 ligases. Comparison of the senescent proteome with different pathophysiological cellular states reveals a distinctive senescent signature shaped by changes in the proteostasis network. Collectively, we provide a resource for the exploration of temporally resolved changes in the senescent proteome.

Cellular Senescence↗
PubMed2006

Xe nuclear magnetic resonance line shapes in channels decorated with paramagnetic centers.

To make predictions of the Xe NMR line shapes for Xe in channels decorated with paramagnetic centers, we consider a model system using the O(2) molecule as the paramagnetic center. The previously calculated quantum mechanical Xe@O(2) hyperfine tensor for various configurations of Xe in the presence of O(2) provides a model for the hyperfine response of Xe atom to the presence of a paramagnetic center. The averaging is carried out using the same grand canonical Monte Carlo methodology as for calculating NMR line shapes for Xe in diamagnetic channels, modified to include the effects of the hyperfine tensor response. We explore the temperature dependence of the Xe line shapes, the dependence on the concentration, and the symmetry of distribution of embedded paramagnetic centers, on the orientation of the paramagnetic center axis with respect to the channel axis, and on the radial distance of the paramagnetic center from the axis of the channel. We predict Xe line shape signatures of the presence and orientation of paramagnetic centers and deduce which tensor elements provide measures of concentration and radial distance of paramagnetic centers from the channel axis.

Journal Article↗
PubMed2006

Symbolic signatures for deformable shapes.

Recognizing classes of objects from their shape is an unsolved problem in machine vision that entails the ability of a computer system to represent and generalize complex geometrical information on the basis of a finite amount of prior data. A practical approach to this problem is particularly difficult to implement, not only because the shape variability of relevant object classes is generally large, but also because standard sensing devices used to capture the real world only provide a partial view of a scene, so there is partial information pertaining to the objects of interest. In this work, we develop an algorithmic framework for recognizing classes of deformable shapes from range data. The basic idea of our component-based approach is to generalize existing surface representations that have proven effective in recognizing specific 3D objects to the problem of object classes using our newly introduced symbolic-signature representation that is robust to deformations, as opposed to a numeric representation that is often tied to a specific shape. Based on this approach, we present a system that is capable of recognizing and classifying a variety of object shape classes from range data. We demonstrate our system in a series of large-scale experiments that were motivated by specific applications in scene analysis and medical diagnosis.

Algorithms↗
PubMed2001

A statistical 3-D pattern processing method for computer-aided detection of polyps in CT colonography.

Adenomatous polyps in the colon are believed to be the precursor to colorectal carcinoma, the second leading cause of cancer deaths in United States. In this paper, we propose a new method for computer-aided detection of polyps in computed tomography (CT) colonography (virtual colonoscopy), a technique in which polyps are imaged along the wall of the air-inflated, cleansed colon with X-ray CT. Initial work with computer aided detection has shown high sensitivity, but at a cost of too many false positives. We present a statistical approach that uses support vector machines to distinguish the differentiating characteristics of polyps and healthy tissue, and uses this information for the classification of the new cases. One of the main contributions of the paper is the new three-dimensional pattern processing approach, called random orthogonal shape sections method, which combines the information from many random images to generate reliable signatures of shape. The input to the proposed system is a collection of volume data from candidate polyps obtained by a high-sensitivity, low-specificity system that we developed previously. The results of our ten-fold cross-validation experiments show that, on the average, the system increases the specificity from 0.19 (0.35) to 0.69 (0.74) at a sensitivity level of 1.0 (0.95).

Adult↗
PubMed2003

Expression and the course of life: studies of emotion, personality, and psychopathology from a social-functional perspective.

In this paper I discuss how expressive behavior relates to personality and psychopathology, integrating recent findings from my laboratory and the insights of Charles Darwin on this topic. In the first part of the paper I challenge the view, in part espoused by Darwin, that humans are equipped to convey only a limited number of emotions with nonverbal behavior. Our lab has documented displays for several emotions, including embarrassment, love, desire, compassion, gratitude, and awe, to name just a few states that previously were thought not to possess a distinct display. I then present an argument for how individual differences in emotion, although fleeting, shape the social environment. This argument focuses on the functions of nonverbal display: to provide information to others, to evoke responses, and to serve as incentives of preceding or ensuing social behavior. This reasoning sets the stage for the study of the relationships between personality, psychopathology, and expressive behavior, to which I turn in the final part of the paper. Here I show that basic personality traits (e.g., extraversion, agreeableness) and psychological disorders (e.g., externalizing disorder in children, autism) have expressive signatures that shape social interactions and environments in profound ways that might perpetuate and transmit the trait or disorder.

Affect↗