Hyperspectral videos (HSVs), with their inherent spatial-spectral-temporal structure, offer distinct advantages in challenging tracking scenarios such as cluttered backgrounds and small objects. However, existing methods primarily focus on spatial interactions between the template and search regions, often overlooking spectral interactions, leading to suboptimal performance. To address this issue, this paper investigates spectral interactions from both the architectural and training perspectives. At the architectural level, we first establish band-wise long-range spatial relationships between the template and search regions using Transformers. We then model spectral interactions using the inclusion-exclusion principle from set theory, treating them as the union of spatial interactions across all bands. This enables the effective integration of both shared and band-specific spatial cues. At the training level, we introduce a spectral loss to enforce material distribution alignment between the template and predicted regions, enhancing robustness to shape deformation and appearance variations. Extensive experiments demonstrate that our tracker achieves state-of-the-art tracking performance. The source code, trained models and results will be publicly available via https://github.com/bearshng/suit to support reproducibility.

Machine learning including modern deep learning models has been extensively used in drug design and screening. However, reliable prediction of molecular properties is still challenging when exploring out-of-domain regimes, even for deep neural networks. Therefore, it is important to understand the uncertainty of model predictions, especially when the predictions are used to guide further experiments. In this study, we explored the utility and effectiveness of evidential uncertainty in compound screening. The evidential Graphormer model was proposed for uncertainty-guided discovery of KDM1A/LSD1 inhibitors. The benchmarking results illustrated that (i) Graphormer exhibited comparative predictive power to state-of-the-art models, and (ii) evidential regression enabled well-ranked uncertainty estimates and calibrated predictions. Subsequently, we leveraged time-splitting on the curated KDM1A/LSD1 dataset to simulate out-of-distribution predictions. The retrospective virtual screening showed that the evidential uncertainties helped reduce false positives among the top-acquired compounds and thus enabled higher experimental validation rates. The trained model was then used to virtually screen an independent in-house compound set. The top 50 compounds ranked by two different ranking strategies were experimentally validated, respectively. In general, our study highlighted the importance to understand the uncertainty in prediction, which can be recognized as an interpretable dimension to model predictions.

The peripheral structures of mammalian sensory organs often serve to support their functionality, such as alignment of hair cells to the mechanical properties of the inner ear. Here, we examined the structure-function relationship for mammalian olfaction by creating an anatomically accurate computational nasal model for the domestic cat (Felis catus) based on high resolution microCT and sequential histological sections. Our results showed a distinct separation of respiratory and olfactory flow regimes, featuring a high-speed dorsal medial stream that increases odor delivery speed and efficiency to the ethmoid olfactory region without compromising the filtration and conditioning purpose of the nose. These results corroborated previous findings in other mammalian species, which implicates a common theme to deal with the physical size limitation of the head that confines the nasal airway from increasing in length infinitely as a straight tube. We thus hypothesized that these ethmoid olfactory channels function as parallel coiled chromatograph channels, and further showed that the theoretical plate number, a widely-used indicator of gas chromatograph efficiency, is more than 100 times higher in the cat nose than an "amphibian-like" straight channel fitting the similar skull space, at restful breathing state. The parallel feature also reduces airflow speed within each coil, which is critical to achieve the high plate number, while feeding collectively from the high-speed dorsal medial stream so that total odor sampling speed is not sacrificed. The occurrence of ethmoid turbinates is an important step in the evolution of mammalian species that correlates to their expansive olfactory function and brain development. Our findings reveal novel mechanisms on how such structure may facilitate better olfactory performance, furthering our understanding of the successful adaptation of mammalian species, including F. catus, a popular pet, to diverse environments.

Accurate prediction of atomic partial charges with high-level quantum mechanics (QM) methods suffers from high computational cost. Numerous feature-engineered machine learning (ML)-based predictors with favorable computability and reliability have been developed as alternatives. However, extensive expertise effort was needed for feature engineering of atom chemical environment, which may consequently introduce domain bias. In this study, SuperAtomicCharge, a data-driven deep graph learning framework, was proposed to predict three important types of partial charges (i.e. RESP, DDEC4 and DDEC78) derived from high-level QM calculations based on the structures of molecules. SuperAtomicCharge was designed to simultaneously exploit the 2D and 3D structural information of molecules, which was proved to be an effective way to improve the prediction accuracy of the model. Moreover, a simple transfer learning strategy and a multitask learning strategy based on self-supervised descriptors were also employed to further improve the prediction accuracy of the proposed model. Compared with the latest baselines, including one GNN-based predictor and two ML-based predictors, SuperAtomicCharge showed better performance on all the three external test sets and had better usability and portability. Furthermore, the QM partial charges of new molecules predicted by SuperAtomicCharge can be efficiently used in drug design applications such as structure-based virtual screening, where the predicted RESP and DDEC4 charges of new molecules showed more robust scoring and screening power than the commonly used partial charges. Finally, two tools including an online server (http://cadd.zju.edu.cn/deepchargepredictor) and the source code command lines (https://github.com/zjujdj/SuperAtomicCharge) were developed for the easy access of the SuperAtomicCharge services.

Molecular property prediction models based on machine learning algorithms have become important tools to triage unpromising lead molecules in the early stages of drug discovery. Compared with the mainstream descriptor- and graph-based methods for molecular property predictions, SMILES-based methods can directly extract molecular features from SMILES without human expert knowledge, but they require more powerful algorithms for feature extraction and a larger amount of data for training, which makes SMILES-based methods less popular. Here, we show the great potential of pre-training in promoting the predictions of important pharmaceutical properties. By utilizing three pre-training tasks based on atom feature prediction, molecular feature prediction and contrastive learning, a new pre-training method K-BERT, which can extract chemical information from SMILES like chemists, was developed. The calculation results on 15 pharmaceutical datasets show that K-BERT outperforms well-established descriptor-based (XGBoost) and graph-based (Attentive FP and HRGCN+) models. In addition, we found that the contrastive learning pre-training task enables K-BERT to 'understand' SMILES not limited to canonical SMILES. Moreover, the general fingerprints K-BERT-FP generated by K-BERT exhibit comparative predictive power to MACCS on 15 pharmaceutical datasets and can also capture molecular size and chirality information that traditional binary fingerprints cannot capture. Our results illustrate the great potential of K-BERT in the practical applications of molecular property predictions in drug discovery.

Accurate predictions of druggability and bioactivities of compounds are desirable to reduce the high cost and time of drug discovery. After more than five decades of continuing developments, quantitative structure-activity relationship (QSAR) methods have been established as indispensable tools that facilitate fast, reliable and affordable assessments of physicochemical and biological properties of compounds in drug-discovery programs. Currently, there are mainly two types of QSAR methods, descriptor-based methods and graph-based methods. The former is developed based on predefined molecular descriptors, whereas the latter is developed based on simple atomic and bond information. In this study, we presented a simple but highly efficient modeling method by combining molecular graphs and molecular descriptors as the input of a modified graph neural network, called hyperbolic relational graph convolution network plus (HRGCN+). The evaluation results show that HRGCN+ achieves state-of-the-art performance on 11 drug-discovery-related datasets. We also explored the impact of the addition of traditional molecular descriptors on the predictions of graph-based methods, and found that the addition of molecular descriptors can indeed boost the predictive power of graph-based methods. The results also highlight the strong anti-noise capability of our method. In addition, our method provides a way to interpret models at both the atom and descriptor levels, which can help medicinal chemists extract hidden information from complex datasets. We also offer an HRGCN+'s online prediction service at https://quantum.tencent.com/hrgcn/.

Although a wide variety of machine learning (ML) algorithms have been utilized to learn quantitative structure-activity relationships (QSARs), there is no agreed single best algorithm for QSAR learning. Therefore, a comprehensive understanding of the performance characteristics of popular ML algorithms used in QSAR learning is highly desirable. In this study, five linear algorithms [linear function Gaussian process regression (linear-GPR), linear function support vector machine (linear-SVM), partial least squares regression (PLSR), multiple linear regression (MLR) and principal component regression (PCR)], three analogizers [radial basis function support vector machine (rbf-SVM), K-nearest neighbor (KNN) and radial basis function Gaussian process regression (rbf-GPR)], six symbolists [extreme gradient boosting (XGBoost), Cubist, random forest (RF), multiple adaptive regression splines (MARS), gradient boosting machine (GBM), and classification and regression tree (CART)] and two connectionists [principal component analysis artificial neural network (pca-ANN) and deep neural network (DNN)] were employed to learn the regression-based QSAR models for 14 public data sets comprising nine physicochemical properties and five toxicity endpoints. The results show that rbf-SVM, rbf-GPR, XGBoost and DNN generally illustrate better performances than the other algorithms. The overall performances of different algorithms can be ranked from the best to the worst as follows: rbf-SVM > XGBoost > rbf-GPR > Cubist > GBM > DNN > RF > pca-ANN > MARS > linear-GPR ≈ KNN > linear-SVM ≈ PLSR > CART ≈ PCR ≈ MLR. In terms of prediction accuracy and computational efficiency, SVM and XGBoost are recommended to the regression learning for small data sets, and XGBoost is an excellent choice for large data sets. We then investigated the performances of the ensemble models by integrating the predictions of multiple ML algorithms. The results illustrate that the ensembles of two or three algorithms in different categories can indeed improve the predictions of the best individual ML algorithms.

SUMMARY: High-level quantum mechanics (QM) methods are no doubt the most reliable approaches for the prediction of atomic charges, but it usually needs very large computational resources, which apparently hinders the use of high-quality atomic charges in large-scale molecular modeling, such as high-throughput virtual screening. To solve this problem, several algorithms based on machine-learning (ML) have been developed to fit high-level QM atomic charges. Here, we proposed DeepChargePredictor, a web server that is able to generate the high-level QM atomic charges for small molecules based on two state-of-the-art ML algorithms developed in our group, namely AtomPathDescriptor and DeepAtomicCharge. These two algorithms were seamlessly integrated into the platform with the capability to predict three kinds of charges (i.e. RESP, AM1-BCC and DDEC) widely used in structure-based drug design. Moreover, we have comprehensively evaluated the performance of these charges generated by DeepChargePredictor for large-scale drug design applications, such as end-point binding free energy calculations and virtual screening, which all show reliable or even better performance compared with the baseline methods. AVAILABILITY AND IMPLEMENTATION: The data in the article can be obtained on the web page http://cadd.zju.edu.cn/deepchargepredictor/publication. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Most sensory systems are remarkable in their temporal precision, reflected in such phrases as "a flash of light" or "a twig snap". Yet taste is complicated by the transport processes of stimuli through the papilla matrix to reach taste receptors, processes that are poorly understood. We computationally modeled the surface of the human tongue as a microfiber porous medium and found that time-concentration profiles within the papilla zone rise with significant delay that well match experimental ratings of perceived taste intensity to a range of sweet and salty stimuli for both rapid pulses and longer sip-and-hold exposures. Diffusivity of these taste stimuli, determined mostly by molecular size, correlates greatly with time and slope to reach peak intensity: smaller molecular size may lead to quicker taste perception. Our study demonstrates the novelty of modeling the human tongue as a porous material to drastically simplify computational approaches and that peripheral transport processes may significantly affect the temporal profile of taste perception, at least to sweet and salty compounds.