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A new method to estimate ligand-receptor energetics.

In the discovery of new drugs, lead identification and optimization have assumed critical importance given the number of drug targets generated from genetic, genomics, and proteomic technologies. High-throughput experimental screening assays have been complemented recently by "virtual screening" approaches to identify and filter potential ligands when the characteristics of a target receptor structure of interest are known. Virtual screening mandates a reliable procedure for automatic ranking of structurally distinct ligands in compound library databases. Computing a rank score requires the accurate prediction of binding affinities between these ligands and the target. Many current scoring strategies require information about the target three-dimensional structure. In this study, a new method to estimate the free binding energy between a ligand and receptor is proposed. We extend a central idea previously reported (Bock, J. R., and Gough, D. A. (2001) Predicting protein-protein interactions from primary structure. Bioinformatics 17, 455-460; Bock, J. R., and Gough, D. A. (2002) Whole-proteome interaction mining. Bioinformatics, in press) that uses simple descriptors to represent biomolecules as input examples to train a support vector machine (Smola, A. J., and Schölkopf, B. (1998) A Tutorial on Support Vector Regression, Neuro-COLT Technical Report NC-TR-98-030, Royal Holloway College, University of London, UK) and the application of the trained system to previously unseen pairs, estimating their propensity for interaction. Here we seek to learn the function that maps features of a receptor-ligand pair onto their equilibrium free binding energy. These features do not comprise any direct information about the three-dimensional structures of ligand or target. In cross-validation experiments, it is demonstrated that objective measurements of prediction error rate and rank-ordering statistics are competitive with those of several other investigations, most of which depend on three-dimensional structural data. The size of the sample (n = 2,671) indicates that this approach is robust and may have widespread applicability beyond restricted families of receptor types. It is concluded that newly sequenced proteins, or those for which three-dimensional crystal structures are not easily obtained, can be rapidly analyzed for their binding potential against a library of ligands using this methodology.

Drug Design↗

Support vector machines for prediction of protein subcellular location.

Support Vector Machine (SVM), which is one kind of learning machines, was applied to predict the subcellular location of proteins from their amino acid composition. In this research, the proteins are classified into the following 12 groups: (1) chloroplast, (2) cytoplasm, (3) cytoskeleton, (4) endoplasmic reticulum, (5) extracall, (6) Golgi apparatus, (7) lysosome, (8) mitochondria, (9) nucleus, (10) peroxisome, (11) plasma membrane, and (12) vacuole, which have covered almost all the organelles and subcellular compartments in an animal or plant cell. The examination for the self-consistency and the jackknife test of the SVMs method was tested for the three sets: 2022 proteins, 2161 proteins, and 2319 proteins. As a result, the correct rate of self-consistency and jackknife test reaches 91 and 82% for 2022 proteins, 89 and 75% for 2161 proteins, and 85 and 73% for 2319 proteins, respectively. Furthermore, the predicting rate was tested by the three independent testing datasets containing 2240 proteins, 2513 proteins, and 2591 proteins. The correct prediction rates reach 82, 75, and 73% for 2240 proteins, 2513 proteins, and 2591 proteins, respectively.

Algorithms↗

Three machine learning techniques for automatic determination of rules to control locomotion.

Automatic prediction of gait events (e.g., heel contact, flat foot, initiation of the swing, etc.) and corresponding profiles of the activations of muscles is important for real-time control of locomotion. This paper presents three supervised machine learning (ML) techniques for prediction of the activation patterns of muscles and sensory data, based on the history of sensory data, for walking assisted by a functional electrical stimulation (FES). Those ML's are: 1) a multilayer perceptron with Levenberg-Marquardt modification of backpropagation learning algorithm; 2) an adaptive-network-based fuzzy inference system (ANFIS); and 3) a combination of an entropy minimization type of inductive learning (IL) technique and a radial basis function (RBF) type of artificial neural network with orthogonal least squares learning algorithm. Here we show the prediction of the activation of the knee flexor muscles and the knee joint angle for seven consecutive strides based on the history of the knee joint angle and the ground reaction forces. The data used for training and testing of ML's was obtained from a simulation of walking assisted with an FES system [39]. The ability of generating rules for an FES controller was selected as the most important criterion when comparing the ML's. Other criteria such as generalization of results, computational complexity, and learning rate were also considered. The minimal number of rules and the most explicit and comprehensible rules were obtained by ANFIS. The best generalization was obtained by the IL and RBF network.

Algorithms↗

Structural bioinformatics prediction of membrane-binding proteins.

Membrane-binding peripheral proteins play important roles in many biological processes, including cell signaling and membrane trafficking. Unlike integral membrane proteins, these proteins bind the membrane mostly in a reversible manner. Since peripheral proteins do not have canonical transmembrane segments, it is difficult to identify them from their amino acid sequences. As a first step toward genome-scale identification of membrane-binding peripheral proteins, we built a kernel-based machine learning protocol. Key features of known membrane-binding proteins, including electrostatic properties and amino acid composition, were calculated from their amino acid sequences and tertiary structures, which were then incorporated into the support vector machine to perform the classification. A data set of 40 membrane-binding proteins and 230 non-membrane-binding proteins was used to construct and validate the protocol. Cross-validation and holdout evaluation of the protocol showed that the accuracy of the prediction reached up to 93.7% and 91.6%, respectively. The protocol was applied to the prediction of membrane-binding properties of four C2 domains from novel protein kinases C. Although these C2 domains have 50% sequence identity, only one of them was predicted to bind the membrane, which was verified experimentally with surface plasmon resonance analysis. These results suggest that our protocol can be used for predicting membrane-binding properties of a wide variety of modular domains and may be further extended to genome-scale identification of membrane-binding peripheral proteins.

Amino Acid Sequence↗

Prediction of transporter family from protein sequence by support vector machine approach.

Transporters play key roles in cellular transport and metabolic processes, and in facilitating drug delivery and excretion. These proteins are classified into families based on the transporter classification (TC) system. Determination of the TC family of transporters facilitates the study of their cellular and pharmacological functions. Methods for predicting TC family without sequence alignments or clustering are particularly useful for studying novel transporters whose function cannot be determined by sequence similarity. This work explores the use of a machine learning method, support vector machines (SVMs), for predicting the family of transporters from their sequence without the use of sequence similarity. A total of 10,636 transporters in 13 TC subclasses, 1914 transporters in eight TC families, and 168,341 nontransporter proteins are used to train and test the SVM prediction system. Testing results by using a separate set of 4351 transporters and 83,151 nontransporter proteins show that the overall accuracy for predicting members of these TC subclasses and families is 83.4% and 88.0%, respectively, and that of nonmembers is 99.3% and 96.6%, respectively. The accuracies for predicting members and nonmembers of individual TC subclasses are in the range of 70.7-96.1% and 97.6-99.9%, respectively, and those of individual TC families are in the range of 60.6-97.1% and 91.5-99.4%, respectively. A further test by using 26,139 transmembrane proteins outside each of the 13 TC subclasses shows that 90.4-99.6% of these are correctly predicted. Our study suggests that the SVM is potentially useful for facilitating functional study of transporters irrespective of sequence similarity.

Amino Acid Sequence↗

A novel incremental principal component analysis and its application for face recognition.

Principal component analysis (PCA) has been proven to be an efficient method in pattern recognition and image analysis. Recently, PCA has been extensively employed for face-recognition algorithms, such as eigenface and fisherface. The encouraging results have been reported and discussed in the literature. Many PCA-based face-recognition systems have also been developed in the last decade. However, existing PCA-based face-recognition systems are hard to scale up because of the computational cost and memory-requirement burden. To overcome this limitation, an incremental approach is usually adopted. Incremental PCA (IPCA) methods have been studied for many years in the machine-learning community. The major limitation of existing IPCA methods is that there is no guarantee on the approximation error. In view of this limitation, this paper proposes a new IPCA method based on the idea of a singular value decomposition (SVD) updating algorithm, namely an SVD updating-based IPCA (SVDU-IPCA) algorithm. In the proposed SVDU-IPCA algorithm, we have mathematically proved that the approximation error is bounded. A complexity analysis on the proposed method is also presented. Another characteristic of the proposed SVDU-IPCA algorithm is that it can be easily extended to a kernel version. The proposed method has been evaluated using available public databases, namely FERET, AR, and Yale B, and applied to existing face-recognition algorithms. Experimental results show that the difference of the average recognition accuracy between the proposed incremental method and the batch-mode method is less than 1%. This implies that the proposed SVDU-IPCA method gives a close approximation to the batch-mode PCA method.

Algorithms↗

Sparse Bayesian learning for efficient visual tracking.

This paper extends the use of statistical learning algorithms for object localization. It has been shown that object recognizers using kernel-SVMs can be elegantly adapted to localization by means of spatial perturbation of the SVM. While this SVM applies to each frame of a video independently of other frames, the benefits of temporal fusion of data are well-known. This is addressed here by using a fully probabilistic Relevance Vector Machine (RVM) to generate observations with Gaussian distributions that can be fused over time. Rather than adapting a recognizer, we build a displacement expert which directly estimates displacement from the target region. An object detector is used in tandem, for object verification, providing the capability for automatic initialization and recovery. This approach is demonstrated in real-time tracking systems where the sparsity of the RVM means that only a fraction of CPU time is required to track at frame rate. An experimental evaluation compares this approach to the state of the art showing it to be a viable method for long-term region tracking.

Algorithms↗

An image-based protein-ligand binding representation learning framework via multi-level flexible dynamics trajectory pre-training.

MOTIVATION: Accurate prediction of protein-ligand binding (PLB) relationships plays a crucial role in drug discovery, which helps identify drugs that modulate the activity of specific targets. Traditional biological assays for measuring PLB relationships are time consuming and costly. In addition, models for predicting PLB relationships have been developed and widely used in drug discovery tasks. However, learning more accurate PLB representations is essential to meet the stringent standards required for drug discovery. RESULTS: We propose an image-based PLB representation learning framework, called ImagePLB, which equips ligand representation learner (LRL) and protein representation learner (PRL) to accept 3D multi-view ligand images and protein graphs as input, respectively, and learns rich interaction information between ligand and protein through a binding representation learner (BRL). Considering the scarcity of protein-ligand pairs, we further propose a multi-level next trajectory prediction (MLNTP) task to pre-train ImagePLB on the 4D flexible dynamics trajectory of 16 972 complexes, including ligand level, protein level, and complex level, to learn information related to trajectories. Besides, by introducing trajectory regularization (TR), we effectively alleviate the problem of high (even almost identical) feature similarity caused by adjacent trajectories. Compared with the current state-of-the-art methods, ImagePLB has achieved competitive improvements on PLB-related prediction tasks, including protein-ligand affinity and efficacy prediction tasks. This study opens the door to the image-based PLB learning paradigm. AVAILABILITY AND IMPLEMENTATION: All data and implementation details of code can be obtained from https://github.com/HongxinXiang/ImagePLB.

Ligands↗

Simultaneous quantification of carbamazepine crystal forms in ternary mixtures (I, III, and IV) by diffuse reflectance FTIR spectroscopy (DRIFTS) and multivariate calibration.

Diffuse reflectance FTIR spectroscopy (DRIFTS) coupled with modern multivariate calibration methods, namely artificial neural networks (ANNs) in two versions (ANN-raw and ANN-pca), support vector machines (SVMs), lazy learning (LL) and partial least squares (PLS) regression, is used in this study for the quantification of carbamazepine crystal forms in ternary powder mixtures (I, III, and IV). Two spectral regions (675-1180 and 3400-3600/cm) were selected and the data were partitioned into training and test subsets applying the Kennard-Stone design. It was found that all the selected algorithms perform better than the PLS regression (root mean squared error of prediction (RMSEP) from 3.0% to 8.2%). ANN-raw, trained on uncompressed spectral data, shows best predictive performance (RMSEP < 2.25%) but longest computation (up to 10 min). Principal component analysis (PCA) compression of the input spectral data accelerates significantly the computation (<16 s) at a relatively low cost in precision (RMSEP < 3.24%). The LL algorithm shows excellent performance in the 3400-3600/cm range (RMSEP < 1.6%), but in the 675-1180/cm range it shows strong dependence on data set structure (RMSEP between 1.6% and 8.9%). SVMs perform comparably well with ANNs (RMSEP < 3.1%), not showing the long computation time of ANNs (<1 s) and therefore may provide an attractive alternative to ANNs.

Algorithms↗

A three-metabolite microbiota-associated signature for early risk stratification of gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes and long-term metabolic and cardiovascular risk. However, oral glucose tolerance testing at 24-28 gestational weeks limits early risk stratification. Gut microbiota-associated metabolites may reflect early metabolic abnormalities, including those relevant to cardiometabolic health, but robust early-pregnancy biomarkers remain limited. METHODS: We conducted a multicenter nested case-control and prospective study involving 2,693 pregnant women. Untargeted metabolomics and metagenomics were integrated to identify GDM-associated metabolites and gut microbial alterations. Three consistently dysregulated metabolites, 3-hydroxydecanoic acid, &#x3b3;-Glu-Leu, and propionic acid, were quantified by targeted LC-MS/MS. Candidate algorithms were compared using repeated 10-fold cross-validation, and a final generalized linear model was externally and prospectively validated. RESULTS: Women who later developed GDM showed an adverse early-pregnancy metabolic profile, including higher BMI, triglycerides, and platelet count. Untargeted metabolomics identified 14 persistently altered metabolites enriched in energy, oxidative stress, and amino acid metabolism pathways. Metagenomics revealed taxonomic restructuring and coordinated microbiota-metabolite associations. The three-metabolite model achieved AUCs of 0.838 (95% CI, 0.791-0.885) in training, 0.840 (95% CI, 0.769-0.911) in internal validation, 0.955 (95% CI, 0.925-0.985) and 0.917 (95% CI, 0.875-0.958) in two external cohorts, and 0.969 (95% CI, 0.937-1.000) in the prospective cohort. CONCLUSION: Early microbiota-associated metabolic dysregulation is detectable before routine GDM diagnosis. This compact three-metabolite panel may support early GDM risk stratification and provides metabolic evidence relevant to broader cardiometabolic risk assessment in pregnancy.

Humans↗

Classification of a diverse set of Tetrahymena pyriformis toxicity chemical compounds from molecular descriptors by statistical learning methods.

Toxicity of various compounds has been measured in many studies by their toxic effects against Tetrahymena pyriformis. Efforts have also been made to use computational quantitative structure-activity relationship (QSAR) and statistical learning methods (SLMs) for predicting Tetrahymena pyriformis toxicity (TPT) at impressive accuracies. Because of the diversity of compounds and toxicity mechanisms, it is desirable to explore additional methods and to examine if these methods are applicable to more diverse sets of compounds. We tested several SLMs (logistic regression, C4.5 decision tree, k-nearest neighbor, probabilistic neural network, support vector machines) for their capability in predicting TPT by using 1129 compounds (841 TPT and 288 non-TPT agents) which are more diverse than those in other studies. A feature selection method was used for improving prediction performance and selecting molecular descriptors responsible for distinguishing TPT and non-TPT agents. The prediction accuracies are 86.9% approximately 94.2% for TPT and 71.2% approximately 87.5% for non-TPT agents based on 5-fold cross-validation studies, which are comparable to some of earlier studies despite the use of more diverse sets of compounds. The selected molecular descriptors are consistent with those used in other studies and experimental findings. These suggest that SLMs are useful for predicting TPT potential of diverse sets of compounds and for characterizing the molecular descriptors associated with TPT.

Animals↗

Classification of incidental carcinoma of the prostate using learning vector quantization and support vector machines.

The subclassification of incidental prostatic carcinoma into the categories T1a and T1b is of major prognostic and therapeutic relevance. In this paper an attempt was made to find out which properties mainly predispose to these two tumor categories, and whether it is possible to predict the category from a battery of clinical and histopathological variables using newer methods of multivariate data analysis. The incidental prostatic carcinomas of the decade 1990-99 diagnosed at our department were reexamined. Besides acquisition of routine clinical and pathological data, the tumours were scored by immunohistochemistry for proliferative activity and p53-overexpression. Tumour vascularization (angiogenesis) and epithelial texture were investigated by quantitative stereology. Learning vector quantization (LVQ) and support vector machines (SVM) were used for the purpose of prediction of tumour category from a set of 10 input variables (age, Gleason score, preoperative PSA value, immunohistochemical scores for proliferation and p53-overexpression, 3 stereological parameters of angiogenesis, 2 stereological parameters of epithelial texture). In a stepwise logistic regression analysis with the tumour categories T1a and T1b as dependent variables, only the Gleason score and the volume fraction of epithelial cells proved to be significant as independent predictor variables of the tumour category. Using LVQ and SVM with the information from all 10 input variables, more than 80 of the cases could be correctly predicted as T1a or T1b category with specificity, sensitivity, negative and positive predictive value from 74-92%. Using only the two significant input variables Gleason score and epithelial volume fraction, the accuracy of prediction was not worse. Thus, descriptive and quantitative texture parameters of tumour cells are of major importance for the extent of propagation in the prostate gland in incidental prostatic adenocarcinomas. Classical statistical tools and neuronal approaches led to consistent conclusions.

Adenocarcinoma↗

Prediction of functional class of the SARS coronavirus proteins by a statistical learning method.

The complete genome of severe acute respiratory syndrome coronavirus (SARS-CoV) reveals the existence of putative proteins unique to SARS-CoV. Identification of their function facilitates a mechanistic understanding of SARS infection and drug development for its treatment. The sequence of the majority of these putative proteins has no significant similarity to those of known proteins, which complicates the task of using sequence analysis tools to probe their function. Support vector machines (SVM), useful for predicting the functional class of distantly related proteins, is employed to ascribe a possible functional class to SARS-CoV proteins. Testing results indicate that SVM is able to predict the functional class of 73% of the known SARS-CoV proteins with available sequences and 67% of 18 other novel viral proteins. A combination of the sequence comparison method BLAST and SVMProt can further improve the prediction accuracy of SMVProt such that the functional class of two additional SARS-CoV proteins is correctly predicted. Our study suggests that the SARS-CoV genome possibly contains a putative voltage-gated ion channel, structural proteins, a carbon-oxygen lyase, oxidoreductases acting on the CH-OH group of donors, and an ATP-binding cassette transporter. A web version of our software, SVMProt, is accessible at http://jing.cz3.nus.edu.sg/cgi-bin/svmprot.cgi .

Adenosine Triphosphate↗

Rule generation for protein secondary structure prediction with support vector machines and decision tree.

Support vector machines (SVMs) have shown strong generalization ability in a number of application areas, including protein structure prediction. However, the poor comprehensibility hinders the success of the SVM for protein structure prediction. The explanation of how a decision made is important for accepting the machine learning technology, especially for applications such as bioinformatics. The reasonable interpretation is not only useful to guide the "wet experiments," but also the extracted rules are helpful to integrate computational intelligence with symbolic AI systems for advanced deduction. On the other hand, a decision tree has good comprehensibility. In this paper, a novel approach to rule generation for protein secondary structure prediction by integrating merits of both the SVM and decision tree is presented. This approach combines the SVM with decision tree into a new algorithm called SVM_ DT, which proceeds in three steps. This algorithm first trains an SVM. Then, a new training set is generated through careful selection from the output of the SVM. Finally, the obtained training set is used to train a decision tree learning system and to extract the corresponding rule sets. The results of the experiments of protein secondary structure prediction on RS126 data set show that the comprehensibility of SVM_DT is much better than that of the SVM. Moreover, the generalization ability of SVM_DT is better than that of C4.5 decision trees and is similar to that of the SVM. Hence, SVM_DT can be used not only for prediction, but also for guiding biological experiments.

Algorithms↗

Response rates to six recruitment mailing formats and two messages about a nutrition program for women 50-79 years old.

Recruiting participants for large prevention trials is time consuming and costly. In order to test various recruitment techniques, we conducted two studies of response rates to recruitment mailings for the Women's Health Trial. The potential participants, 50- to 79-year-old women, were requested to return an enclosed postcard to learn more about the trial. In the first study, we sent at random either a short or a long message to a group of University of Miami personnel (N = 862) and a Dade County cohort (N = 2964). More university women responded to the short message than to the long message (22.4% vs 16.4%, p = 0.024). Similarly, more of the Dade County cohort replied to the short message than to the long one (12.1% vs 9.6%, p = 0.027). The long message listed details of the intervention (e.g., modifying recipes) that some women may have used to decide they were not interested in participating. In the second study, we examined response rates to two different ways of addressing the mailing, i.e., handwritten envelopes and machine-printed labels; we also evaluated three methods for delivering the short message: (1) formal invitation, (2) business letter with an inside name and address of the recipient, and (3) business letter without the recipient's name and address. Response rates were similar between the methods of addressing envelopes and among the three vehicles for the message, suggesting that the least costly method of mailing should be used.

Aged↗

Hierarchical modeling of tumor subtypes in cell lines using large-scale genomic datasets.

Cancer cell lines (CLs) are widely used to study tumor biology and drug response, yet their translational relevance is often limited by inaccurate subtype annotations. Existing CL-tumor matching approaches are frequently constrained by flat classification schemes, weak subtype definitions, and the exclusion of normal tissue references, leading to potential confounding of tumor-specific and tissue-of-origin signals. To address these limitations, a hierarchical classification (HC) framework is presented in which CLs are aligned with patient tumors across biological resolutions, from organ to molecular subtype. Gene expression profiles from 802 CLs, 5,612 tumors from The Cancer Genome Atlas (TCGA) , and 8,939 non-cancerous tissues were integrated to separate oncogenic signals from tissue-specific signals. Node-specific features were selected using maximum relevance minimum redundancy, and balanced accuracies of 89% in cross-validation and 75%, and 80% on external datasets were achieved. Through the framework, 43 CLs were reassigned, and clinically relevant underrepresented subtypes were identified.

cancer cell lines↗

The future of pediatric vesicoureteral reflux management.

BACKGROUND AND OBJECTIVE: Vesicoureteral reflux (VUR) is a common condition in pediatric urology, yet important uncertainties persist regarding risk stratification, imaging strategies, and prevention of long-term renal damage. Emerging technologies may help address these challenges. This review provides a forward-looking overview of recent advances in artificial intelligence (AI) and immunomodulation that may influence future management of pediatric VUR. METHODS: A forward-looking literature review was performed using the PubMed database (January 2000-March 2025), focusing on studies addressing AI, immunomodulation, or vaccination in the context of VUR and urinary tract infections. Criteria of inclusion were the relevance to pediatric VUR, the novelty of the proposed concept, the potential clinical implications and, for the AI literature, the existence of a clinical evaluation of the algorithm on a dataset from patients. KEY FINDINGS AND LIMITATIONS: AI-based models show promising performance in supporting clinical decision-making, including prediction of the need for voiding cystourethrography, automated grading of VUR, estimation of recurrent urinary tract infection risk and prediction of chemoprophylaxis. These tools may facilitate more individualized diagnostic and therapeutic strategies, although current evidence is largely retrospective and requires prospective validation. Immunization and immunomodulatory approaches aim to reduce infection burden and modulate inflammatory pathways associated with renal scarring. While early experimental and adult clinical data are encouraging, pediatric-specific evidence remains limited, and clinical applicability in children with VUR is not yet established. CONCLUSION: Artificial intelligence and immunologically targeted strategies represent complementary, emerging approaches that may contribute to more personalized management of pediatric VUR. At present, both should be regarded as exploratory tools whose clinical impact will depend on further validation and appropriately designed pediatric studies.

Humans↗

Speeding disease gene discovery by sequence based candidate prioritization.

BACKGROUND: Regions of interest identified through genetic linkage studies regularly exceed 30 centimorgans in size and can contain hundreds of genes. Traditionally this number is reduced by matching functional annotation to knowledge of the disease or phenotype in question. However, here we show that disease genes share patterns of sequence-based features that can provide a good basis for automatic prioritization of candidates by machine learning. RESULTS: We examined a variety of sequence-based features and found that for many of them there are significant differences between the sets of genes known to be involved in human hereditary disease and those not known to be involved in disease. We have created an automatic classifier called PROSPECTR based on those features using the alternating decision tree algorithm which ranks genes in the order of likelihood of involvement in disease. On average, PROSPECTR enriches lists for disease genes two-fold 77% of the time, five-fold 37% of the time and twenty-fold 11% of the time. CONCLUSION: PROSPECTR is a simple and effective way to identify genes involved in Mendelian and oligogenic disorders. It performs markedly better than the single existing sequence-based classifier on novel data. PROSPECTR could save investigators looking at large regions of interest time and effort by prioritizing positional candidate genes for mutation detection and case-control association studies.

Algorithms↗