Antibodies defend our health by binding to antigens with high specificity and potentiality, primarily relying on the Complementarity-Determining Region (CDR). Yet, current experimental methods of discovering new antibody CDRs are heavily time-consuming. Computational design could alleviate this burden; especially, protein language models have proven quite beneficial in many recent studies. However, most existing models solely focus on antibody potentiality and struggle to encapsulate the diverse range of plausible CDR candidates, limiting their effectiveness in real-world scenarios as binding is only one factor in the multitude of drug-forming criteria. In this paper, we introduce PG-AbD, a framework uniting Generative Flow Networks (GFlowNets) and pretrained Protein Language Models (PLMs) to successfully generate highly potent, diverse and novel antibody candidates. We innovatively construct a Products of Experts (PoE) composed by the global-distribution-modeling PLM and the local-distribution-modeling Potts Model to serve as the reward function of GFlowNet. The joint training paradigm is introduced, where PoE is trained by contrastive divergence with the negative samples generated by GFlowNet, and then guides GFlowNet to sample diverse antibody candidates. We evaluate PG-AbD on extensive antibody design benchmarks. It significantly outperforms existing methods in diversity (13.5% on RabDab, 31.1% on SabDab) while maintaining optimal potential and novelty. Generated antibodies are also found to form stable, regular 3D structures with their corresponding antigens, demonstrating the great potential of PG-AbD to accelerate real-world antibody discovery.

Proteins, as essential biomolecules, play a central role in biological processes, including metabolic reactions and DNA replication. Accurate prediction of their properties and functions is crucial in biological applications. Recent development of protein language models (pLMs) with supervised fine tuning provides a promising solution to this problem. However, the fine-tuned model is tailored for particular downstream prediction task, and achieving general-purpose protein understanding remains a challenge. In this paper, we introduce Structure-Enhanced Protein Instruction Tuning (SEPIT) framework to bridge this gap. Our approach incorporates a novel structure-aware module into pLMs to enrich their structural knowledge, and subsequently integrates these enhanced pLMs with large language models (LLMs) to advance protein understanding. In this framework, we propose a novel instruction tuning pipeline. First, we warm up the enhanced pLMs using contrastive learning and structure denoising. Then, caption-based instructions are used to establish a basic understanding of proteins. Finally, we refine this understanding by employing a mixture of experts (MoEs) to capture more complex properties and functional information with the same number of activated parameters. Moreover, we construct the largest and most comprehensive protein instruction dataset to date, which allows us to train and evaluate the general-purpose protein understanding model. Extensive experiments on both open-ended generation and closed-set answer tasks demonstrate the superior performance of SEPIT over both closed-source general LLMs and open-source LLMs trained with protein knowledge.

The transferability of deep neural networks (DNNs) has made significant progress in image and language processing. However, due to the heterogeneity among tables, such DNN bonus is still far from being well exploited on tabular data prediction (e.g., regression or classification tasks). Condensing knowledge from diverse domains, language models (LMs) possess the capability to comprehend feature names from various tables, potentially serving as versatile learners in transferring knowledge across distinct tables and diverse prediction tasks, but their discrete text representation space is inherently incompatible with numerical feature values in tables. In this paper, we present TP-BERTa, a specifically pre-trained LM for tabular data prediction. Concretely, a novel relative magnitude tokenization converts scalar numerical feature values to finely discrete, high-dimensional tokens, and an intra-feature attention approach integrates feature values with the corresponding feature names. Comprehensive experiments demonstrate that our pre-trained TP-BERTa leads the performance among tabular DNNs and is competitive with Gradient Boosted Decision Tree models in typical tabular data regime.

Molecular de novo design is a critical yet challenging task in scientific fields, aiming to design novel molecular structures with desired property profiles. Significant progress has been made by resorting to generative models for graphs. However, limited attention is paid to hierarchical generative models, which can exploit the inherent hierarchical structure (with rich semantic information) of the molecular graphs and generate complex molecules of larger size that we shall demonstrate to be difficult for most existing models. The primary challenge to hierarchical generation is the non-differentiable issue caused by the generation of intermediate discrete coarsened graph structures. To sidestep this issue, we cast the tricky hierarchical generation problem over discrete spaces as the reverse process of hierarchical representation learning and propose MolHF, a new hierarchical flow-based model that generates molecular graphs in a coarse-to-fine manner. Specifically, MolHF first generates bonds through a multi-scale architecture, then generates atoms based on the coarsened graph structure at each scale. We demonstrate that MolHF achieves state-of-the-art performance in random generation and property optimization, implying its high capacity to model data distribution. Furthermore, MolHF is the first flow-based model that can be applied to model larger molecules (polymer) with more than 100 heavy atoms. The code and models are available at https://github.com/violet-sto/MolHF.

Since annotating medical images for segmentation tasks commonly incurs expensive costs, it is highly desirable to design an annotation-efficient method to alleviate the annotation burden. Recently, contrastive learning has exhibited a great potential in learning robust representations to boost downstream tasks with limited labels. In medical imaging scenarios, ready-made meta labels (i.e., specific attribute information of medical images) inherently reveal semantic relationships among images, which have been used to define positive pairs in previous work. However, the multi-perspective semantics revealed by various meta labels are usually incompatible and can incur intractable "semantic contradiction" when combining different meta labels. In this paper, we tackle the issue of "semantic contradiction" in a gradient-guided manner using our proposed Gradient Mitigator method, which systematically unifies multi-perspective meta labels to enable a pre-trained model to attain a better high-level semantic recognition ability. Moreover, we emphasize that the fine-grained discrimination ability is vital for segmentation-oriented pre-training, and develop a novel method called Gradient Filter to dynamically screen pixel pairs with the most discriminating power based on the magnitude of gradients. Comprehensive experiments on four medical image segmentation datasets verify that our new method GCL: (1) learns informative image representations and considerably boosts segmentation performance with limited labels, and (2) shows promising generalizability on out-of-distribution datasets.

Many crucial scientific problems involve designing novel molecules with desired properties, which can be formulated as a black-box optimization problem over the *discrete* chemical space. In practice, multiple conflicting objectives and costly evaluations (e.g., wet-lab experiments) make the *diversity* of candidates paramount. Computational methods have achieved initial success but still struggle with considering diversity in both objective and search space. To fill this gap, we propose a multi-objective Bayesian optimization (MOBO) algorithm leveraging the hypernetwork-based GFlowNets (HN-GFN) as an acquisition function optimizer, with the purpose of sampling a diverse batch of candidate molecular graphs from an approximate Pareto front. Using a single preference-conditioned hypernetwork, HN-GFN learns to explore various trade-offs between objectives. We further propose a hindsight-like off-policy strategy to share high-performing molecules among different preferences in order to speed up learning for HN-GFN. We empirically illustrate that HN-GFN has adequate capacity to generalize over preferences. Moreover, experiments in various real-world MOBO settings demonstrate that our framework predominantly outperforms existing methods in terms of candidate quality and sample efficiency. The code is available at https://github.com/violet-sto/HN-GFN.

MOTIVATION: Drug response prediction (DRP) plays an important role in precision medicine (e.g. for cancer analysis and treatment). Recent advances in deep learning algorithms make it possible to predict drug responses accurately based on genetic profiles. However, existing methods ignore the potential relationships among genes. In addition, similarity among cell lines/drugs was rarely considered explicitly. RESULTS: We propose a novel DRP framework, called TGSA, to make better use of prior domain knowledge. TGSA consists of Twin Graph neural networks for Drug Response Prediction (TGDRP) and a Similarity Augmentation (SA) module to fuse fine-grained and coarse-grained information. Specifically, TGDRP abstracts cell lines as graphs based on STRING protein-protein association networks and uses Graph Neural Networks (GNNs) for representation learning. SA views DRP as an edge regression problem on a heterogeneous graph and utilizes GNNs to smooth the representations of similar cell lines/drugs. Besides, we introduce an auxiliary pre-training strategy to remedy the identified limitations of scarce data and poor out-of-distribution generalization. Extensive experiments on the GDSC2 dataset demonstrate that our TGSA consistently outperforms all the state-of-the-art baselines under various experimental settings. We further evaluate the effectiveness and contributions of each component of TGSA via ablation experiments. The promising performance of TGSA shows enormous potential for clinical applications in precision medicine. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/violet-sto/TGSA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.