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1. GraSeq: Graph and Sequence Fusion Learning for Molecular Property Prediction

   https://doi.org/10.1145/3340531.3411981  

   Guo, Zhichun; Yu, Wenhao; Zhang, Chuxu; Jiang, Meng; Chawla, Nitesh V. (January 2020, GraSeq: Graph and Sequence Fusion Learning for Molecular Property Prediction)

   null (Ed.)

   With the recent advancement of deep learning, molecular representation learning -- automating the discovery of feature representation of molecular structure, has attracted significant attention from both chemists and machine learning researchers. Deep learning can facilitate a variety of downstream applications, including bio-property prediction, chemical reaction prediction, etc. Despite the fact that current SMILES string or molecular graph molecular representation learning algorithms (via sequence modeling and graph neural networks, respectively) have achieved promising results, there is no work to integrate the capabilities of both approaches in preserving molecular characteristics (e.g, atomic cluster, chemical bond) for further improvement. In this paper, we propose GraSeq, a joint graph and sequence representation learning model for molecular property prediction. Specifically, GraSeq makes a complementary combination of graph neural networks and recurrent neural networks for modeling two types of molecular inputs, respectively. In addition, it is trained by the multitask loss of unsupervised reconstruction and various downstream tasks, using limited size of labeled datasets. In a variety of chemical property prediction tests, we demonstrate that our GraSeq model achieves better performance than state-of-the-art approaches. 

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2. Multi-layer Bundling as a New Approach for Determining Multi-scale Correlations Within a High-Dimensional Dataset

   https://doi.org/10.1007/s11538-024-01335-8  

   Fazli, Mehran; Bertram, Richard; Striegel, Deborah_A (July 2024, Bulletin of Mathematical Biology)

   Abstract The growing complexity of biological data has spurred the development of innovative computational techniques to extract meaningful information and uncover hidden patterns within vast datasets. Biological networks, such as gene regulatory networks and protein-protein interaction networks, hold critical insights into biological features’ connections and functions. Integrating and analyzing high-dimensional data, particularly in gene expression studies, stands prominent among the challenges in deciphering these networks. Clustering methods play a crucial role in addressing these challenges, with spectral clustering emerging as a potent unsupervised technique considering intrinsic geometric structures. However, spectral clustering’s user-defined cluster number can lead to inconsistent and sometimes orthogonal clustering regimes. We propose theMulti-layer Bundling (MLB)method to address this limitation, combining multiple prominent clustering regimes to offer a comprehensive data view. We call the outcome clusters “bundles”. This approach refines clustering outcomes, unravels hierarchical organization, and identifies bridge elements mediating communication between network components. By layering clustering results, MLB provides a global-to-local view of biological feature clusters enabling insights into intricate biological systems. Furthermore, the method enhances bundle network predictions by integrating thebundle co-cluster matrixwith the affinity matrix. The versatility of MLB extends beyond biological networks, making it applicable to various domains where understanding complex relationships and patterns is needed. 

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3. On the Generalization Ability of Unsupervised Pretraining

   Deng, Yuyang; Hong, Junyuan; Zhou, Jiayu; Mahdavi, Mehrdad (March 2024, International Conference on Artificial Intelligence and Statistics)

   Recent advances in unsupervised learning have shown that unsupervised pre-training, followed by fine-tuning, can improve model generalization. However, a rigorous understanding of how the representation function learned on an unlabeled dataset affects the generalization of the fine-tuned model is lacking. Existing theoretical research does not adequately account for the heterogeneity of the distribution and tasks in pre-training and fine-tuning stage. To bridge this gap, this paper introduces a novel theoretical framework that illuminates the critical factor influencing the transferability of knowledge acquired during unsupervised pre-training to the subsequent fine-tuning phase, ultimately affecting the generalization capabilities of the fine-tuned model on downstream tasks. We apply our theoretical framework to analyze generalization bound of two distinct scenarios: Context Encoder pre-training with deep neural networks and Masked Autoencoder pre-training with deep transformers, followed by fine-tuning on a binary classification task. Finally, inspired by our findings, we propose a novel regularization method during pre-training to further enhances the generalization of fine-tuned model. Overall, our results contribute to a better understanding of unsupervised pre-training and fine-tuning paradigm, and can shed light on the design of more effective pre-training algorithms. 

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4. NetQuilt: deep multispecies network-based protein function prediction using homology-informed network similarity

   https://doi.org/10.1093/bioinformatics/btab098  

   Barot, Meet; Gligorijević, Vladimir; Cho, Kyunghyun; Bonneau, Richard (February 2021, Bioinformatics)

   Martelli, Pier Luigi (Ed.)

   Abstract Motivation Transferring knowledge between species is challenging: different species contain distinct proteomes and cellular architectures, which cause their proteins to carry out different functions via different interaction networks. Many approaches to protein functional annotation use sequence similarity to transfer knowledge between species. These approaches cannot produce accurate predictions for proteins without homologues of known function, as many functions require cellular context for meaningful prediction. To supply this context, network-based methods use protein-protein interaction (PPI) networks as a source of information for inferring protein function and have demonstrated promising results in function prediction. However, most of these methods are tied to a network for a single species, and many species lack biological networks. Results In this work, we integrate sequence and network information across multiple species by computing IsoRank similarity scores to create a meta-network profile of the proteins of multiple species. We use this integrated multispecies meta-network as input to train a maxout neural network with Gene Ontology terms as target labels. Our multispecies approach takes advantage of more training examples, and consequently leads to significant improvements in function prediction performance compared to two network-based methods, a deep learning sequence-based method and the BLAST annotation method used in the Critial Assessment of Functional Annotation. We are able to demonstrate that our approach performs well even in cases where a species has no network information available: when an organism’s PPI network is left out we can use our multi-species method to make predictions for the left-out organism with good performance. Availability and implementation The code is freely available at https://github.com/nowittynamesleft/NetQuilt. The data, including sequences, PPI networks and GO annotations are available at https://string-db.org/. Supplementary information Supplementary data are available at Bioinformatics online. 

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5. GramSeq-DTA: A Grammar-Based Drug–Target Affinity Prediction Approach Fusing Gene Expression Information

   https://doi.org/10.3390/biom15030405  

   Debnath, Kusal; Rana, Pratip; Ghosh, Preetam (March 2025, Biomolecules)

   Drug–target affinity (DTA) prediction is a critical aspect of drug discovery. The meaningful representation of drugs and targets is crucial for accurate prediction. Using 1D string-based representations for drugs and targets is a common approach that has demonstrated good results in drug–target affinity prediction. However, these approach lacks information on the relative position of the atoms and bonds. To address this limitation, graph-based representations have been used to some extent. However, solely considering the structural aspect of drugs and targets may be insufficient for accurate DTA prediction. Integrating the functional aspect of these drugs at the genetic level can enhance the prediction capability of the models. To fill this gap, we propose GramSeq-DTA, which integrates chemical perturbation information with the structural information of drugs and targets. We applied a Grammar Variational Autoencoder (GVAE) for drug feature extraction and utilized two different approaches for protein feature extraction as follows: a Convolutional Neural Network (CNN) and a Recurrent Neural Network (RNN). The chemical perturbation data are obtained from the L1000 project, which provides information on the up-regulation and down-regulation of genes caused by selected drugs. This chemical perturbation information is processed, and a compact dataset is prepared, serving as the functional feature set of the drugs. By integrating the drug, gene, and target features in the model, our approach outperforms the current state-of-the-art DTA prediction models when validated on widely used DTA datasets (BindingDB, Davis, and KIBA). This work provides a novel and practical approach to DTA prediction by merging the structural and functional aspects of biological entities, and it encourages further research in multi-modal DTA prediction. 

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