To efficiently save cost and reduce risk in drug research and development, there is a pressing demand to develop in silico methods to predict drug sensitivity to cancer cells. With the exponentially increasing number of multi-omics data derived from high-throughput techniques, machine learning-based methods have been applied to the prediction of drug sensitivities. However, these methods have drawbacks either in the interpretability of the mechanism of drug action or limited performance in modeling drug sensitivity. In this paper, we presented a pathway-guided deep neural network (DNN) model to predict the drug sensitivity in cancer cells. Biological pathways describe a group of molecules in a cell that collaborates to control various biological functions like cell proliferation and death, thereby abnormal function of pathways can result in disease. To take advantage of the excellent predictive ability of DNN and the biological knowledge of pathways, we reshaped the canonical DNN structure by incorporating a layer of pathway nodes and their connections to input gene nodes, which makes the DNN model more interpretable and predictive compared to canonical DNN. We have conducted extensive performance evaluations on multiple independent drug sensitivity data sets and demonstrated that our model significantly outperformed the canonical DNN model and eight other classical regression models. Most importantly, we observed a remarkable activity decrease in disease-related pathway nodes during forward propagation upon inputs of drug targets, which implicitly corresponds to the inhibition effect of disease-related pathways induced by drug treatment on cancer cells. Our empirical experiments showed that our method achieves pharmacological interpretability and predictive ability in modeling drug sensitivity in cancer cells. The web server, the processed data sets, and source codes for reproducing our work are available at .

BackgroundIdentifying specific residues for protein-DNA interactions are of considerable importance to better recognize the binding mechanism of protein-DNA complexes. Despite the fact that many computational DNA-binding residue prediction approaches have been developed, there is still significant room for improvement concerning overall performance and availability.ResultsHere, we present an efficient approach termed PDRLGB that uses a light gradient boosting machine (LightGBM) to predict binding residues in protein-DNA complexes. Initially, we extract a wide variety of 913 sequence and structure features with a sliding window of 11. Then, we apply the random forest algorithm to sort the features in descending order of importance and obtain the optimal subset of features using incremental feature selection. Based on the selected feature set, we use a light gradient boosting machine to build the prediction model for DNA-binding residues. Our PDRLGB method shows better overall predictive accuracy and relatively less training time than other widely used machine learning (ML) methods such as random forest (RF), Adaboost and support vector machine (SVM). We further compare PDRLGB with various existing approaches on the independent test datasets and show improvement in results over the existing state-of-the-art approaches.ConclusionsPDRLGB is an efficient approach to predict specific residues for protein-DNA interactions.

Protein-RNA interactions play essential roles in many biological aspects. Quantifying the binding affinity of protein-RNA complexes is helpful to the understanding of protein-RNA recognition mechanisms and identification of strong binding partners. Due to experimentally measured protein-RNA binding affinity data available is still limited to date, there is a pressing demand for accurate and reliable computational approaches. In this paper, we propose a computational approach, PredPRBA, which can effectively predict protein-RNA binding affinity using gradient boosted regression trees. We build a dataset of protein-RNA binding affinity that includes 103 protein-RNA complex structures manually collected from related literature. Then, we generate 37 kinds of sequence and structural features and explore the relationship between the features and protein-RNA binding affinity. We find that the binding affinity mainly depends on the structure of RNA molecules. According to the type of RNA associated with proteins composed of the protein-RNA complex, we split the 103 protein-RNA complexes into six categories. For each category, we build a gradient boosted regression tree (GBRT) model based on the generated features. We perform a comprehensive evaluation for the proposed method on the binding affinity dataset using leave-one-out cross-validation. We show that PredPRBA achieves correlations ranging from 0.723 to 0.897 among six categories, which is significantly better than other typical regression methods and the pioneer protein-RNA binding affinity predictor SPOT-Seq-RNA. In addition, a user-friendly web server has been developed to predict the binding affinity of protein-RNA complexes. The PredPRBA webserver is freely available at .

Interactions between proteins and DNAs play essential roles in many biological processes. DNA binding proteins can be classified into two categories. Double-stranded DNA-binding proteins (DSBs) bind to double-stranded DNA and are involved in a series of cell functions such as gene expression and regulation. Single-stranded DNA-binding proteins (SSBs) are necessary for DNA replication, recombination, and repair and are responsible for binding to the single-stranded DNA. Therefore, the effective classification of DNA-binding proteins is helpful for functional annotations of proteins. In this work, we propose PredPSD, a computational method based on sequence information that accurately predicts SSBs and DSBs. It introduces three novel feature extraction algorithms. In particular, we use the autocross-covariance (ACC) transformation to transform feature matrices into fixed-length vectors. Then, we put the optimal feature subset obtained by the minimal-redundancy-maximal-relevance criterion (mRMR) feature selection algorithm into the gradient tree boosting (GTB). In 10-fold cross-validation based on a benchmark dataset, PredPSD achieves promising performances with an AUC score of 0.956 and an accuracy of 0.912, which are better than those of existing methods. Moreover, our method has significantly improved the prediction accuracy in independent testing. The experimental results show that PredPSD can significantly recognize the binding specificity and differentiate DSBs and SSBs.

ABSTRACT In this article, we investigate the horizontal trajectory tracking problem for an underactuated stratospheric airship subject to nonvanishing external disturbances and model uncertainties. By transforming the tracking errors into new virtual error variables, we can specify the transient and steady-state tracking performance of the resulting nonlinear system quantitatively, which means that under the proposed control scheme, the tracking errors will converge to prescribed residual sets around the origin before a preselected finite time with decay rates no less than a preassignable value. To address unknown items, minimal learning parameter (MLP) techniques for neural networks (NNs) approximation are employed, which efficaciously relax the computational burden, enhance the robustness against dynamics uncertainties and provide an improved property for disturbances rejection. A finite-time convergent observer (FTCO) is incorporated into the control framework to realise output-feedback control, ensuring that estimation errors are bounded during operation and approach zero within a finite time. Stability analysis proves that all the closed-loop signals are uniformly bounded. The effectiveness and advantages of the proposed control strategy are verified by simulation results.

The interaction between protein and DNA plays an essential function in various critical natural processes, like DNA replication, transcription, splicing, and repair. Studying the binding affinity of proteins to DNA helps to understand the recognition mechanism of protein-DNA complexes. Since there are still many limitations on the protein-DNA binding affinity data measured by experiments, accurate and reliable calculation methods are necessarily required. So we put forward a computational approach in this paper, called PreDBA, that can forecast protein-DNA binding affinity effectively by using heterogeneous ensemble models. One hundred protein-DNA complexes are manually collected from the related literature as a data set for protein-DNA binding affinity. Then, 52 sequence and structural features are obtained. Based on this, the correlation between these 52 characteristics and protein-DNA binding affinity is calculated. Furthermore, we found that the protein-DNA binding affinity is affected by the DNA molecule structure of the compound. We classify all protein-DNA compounds into five classifications based on the DNA structure related to the proteins that make up the protein-DNA complexes. In each group, a stacked heterogeneous ensemble model is constructed based on the obtained features. In the end, based on the binding affinity data set, we used the leave-one-out cross-validation to evaluate the proposed method comprehensively. In the five categories, the Pearson correlation coefficient values of our recommended method range from 0.735 to 0.926. We have demonstrated the advantages of the proposed method compared to other machine learning methods and currently existing protein-DNA binding affinity prediction approach.

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Motivation: To efficiently save cost and reduce risk in drug research and development, there is a pressing demand to develop in-silico methods to predict drug sensitivity to cancer cells. With the exponentially increasing number of multi-omics data derived from high-throughput techniques, machine learning-based methods have been applied to the prediction of drug sensitivities. However, these methods have drawbacks either in the interpretability of mechanism of drug action or limited performance in modeling drug sensitivity. Results: In this paper, we presented a pathway-guided deep neural network model, referred to as pathDNN, to predict the drug sensitivity to cancer cells. Biological pathways describe a group of molecules in a cell that collaborates to control various biological functions like cell proliferation and death, thereby abnormal function of pathways can result in disease. To make advantage of both the excellent predictive ability of deep neural network and the biological knowledge of pathways, we reshape the canonical DNN structure by incorporating a layer of pathway nodes and their connections to input gene nodes, which makes the DNN model more interpretable and predictive compared to canonical DNN. We have conducted extensive performance evaluations on multiple independent drug sensitivity data sets, and demonstrate that pathDNN significantly outperformed canonical DNN model and seven other classical regression models. Most importantly, we observed remarkable activity decreases of disease-related pathway nodes during forward propagation upon inputs of drug targets, which implicitly corresponds to the inhibition effect of disease-related pathways induced by drug treatment on cancer cells. Our empirical experiments show that pathDNN achieves pharmacological interpretability and predictive ability in modeling drug sensitivity to cancer cells. Availability: The web server, as well as the processed data sets and source codes for reproducing our work, is available at