Yiyang Gu, Junwei Yang, Junyu Luo, Ye Yuan, Bin Feng, Yingce Xia, Shufang Xie, Kaili Liu, Bohan Wu, Qi Shi, Haoran Li, Beier Xiao, Zhiping Xiao, Xiao Luo, Weizhi Zhang, Philip S. Yu, Zequn Liu, Ming Zhang. Proceedings of the 64th Annual Meeting of the Association for Computational Linguistics (Volume 1: Long Papers). 2026.

AI development is often framed as the outcome of isolated research and engineering efforts, yet evidence from deployed systems suggests that language models interact through a shared data ecosystem.While the optimization of individual models is extensively studied, the emergent properties of this interconnected population remain largely unexplored, limiting our ability to predict long-term ecosystem trajectories.We term this process data pollination, the unintentional circulation of synthetic model outputs through shared online platforms and web-scale training corpora, and formalize it as a population-based evolutionary framework to investigate stability dynamics under synthetic data training.Our theoretical analysis and controlled experiments involving 320 language models demonstrate that population dynamics can mitigate the model collapse observed in single-lineage recursive training, yielding stable or improving performance across diverse benchmarks.Crucially, we find that ecological diversity functions as a fundamental resilience mechanism that safeguards the ecosystem against collapse, highlighting the critical importance of maintaining model diversity for sustainable AI development.

Traditional drug discovery processes are both time-consuming and require extensive professional expertise. With the accumulation of drug-target interaction (DTI) data from experimental studies, leveraging modern machine-learning techniques to discern patterns between drugs and target proteins has become increasingly feasible. In this paper, we introduce the Multi-channel Interaction Network (MIN), a novel framework designed to predict DTIs through two primary components: a representation learning module and a multi-channel interaction module. The representation learning module features a C-Score Predictor-assisted screening mechanism, which selects critical residues to enhance prediction accuracy and reduce noise. The multi-channel interaction module incorporates a structure-agnostic channel, a structure-aware channel, and an extended-mixture channel, facilitating the identification of interaction patterns at various levels for optimal complementarity. Additionally, contrastive learning is utilized to harmonize the representations of diverse data types. Our experimental evaluations on public datasets demonstrate that MIN surpasses other strong DTI prediction methods. Furthermore, the case study reveals a high overlap between the residues selected by the C-Score Predictor and those in actual binding pockets, underscoring MIN's explainability capability. These findings affirm that MIN is not only a potent tool for DTI prediction but also offers fresh insights into the prediction of protein binding sites.

Drug-Target binding Affinity (DTA) prediction is essential for drug discovery. Despite the application of deep learning methods to DTA prediction, the achieved accuracy remain suboptimal. In this work, inspired by the recent success of retrieval methods, we propose kNN-DTA, a non-parametric embedding-based retrieval method adopted on a pre-trained DTA prediction model, which can extend the power of the DTA model with no or negligible cost. Different from existing methods, we introduce two neighbor aggregation ways from both embedding space and label space that are integrated into a unified framework. Specifically, we propose a label aggregation with pair-wise retrieval and a representation aggregation with point-wise retrieval of the nearest neighbors. This method executes in the inference phase and can efficiently boost the DTA prediction performance with no training cost. In addition, we propose an extension, Ada-kNN-DTA, an instance-wise and adaptive aggregation with lightweight learning. Results on four benchmark datasets show that kNN-DTA brings significant improvements, outperforming previous state-of-the-art (SOTA) results, e.g, on BindingDB IC50 and Ki testbeds, kNN-DTA obtains new records of RMSE 0.684 and 0.750 . The extended Ada-kNN-DTA further improves the performance to be 0.675 and 0.735 RMSE. These results strongly prove the effectiveness of our method. Results in other settings and comprehensive studies/analyses also show the great potential of our kNN-DTA approach.

Recent research observed a noteworthy phenomenon in large language models (LLMs), referred to as the "reversal curse."The reversal curse is that when dealing with two entities, denoted as a and b, connected by their relation R and its inverse R -1 , LLMs excel in handling sequences in the form of "aRb," but encounter challenges when processing "bR -1 a," whether in generation or comprehension.For instance, GPT-4 can accurately respond to the query "Tom Cruise's mother is?" with "Mary Lee Pfeiffer," but it struggles to provide a satisfactory answer when asked "Mary Lee Pfeiffer's son is?"In this paper, we undertake the first-ever study of how the reversal curse happens in LLMs.Our investigations reveal that the reversal curse can stem from the specific training objectives, which become particularly evident in the widespread use of next-token prediction within most causal language models.We hope this initial investigation can draw more attention to the reversal curse, as well as other underlying limitations in current LLMs. 1

Retrosynthesis, which predicts the reactants of a given target molecule, is an essential task for drug discovery. In recent years, the machine learing based retrosynthesis methods have achieved promising results. In this work, we introduce RetroKNN, a local reaction template retrieval method to further boost the performance of template-based systems with non-parametric retrieval. We first build an atom-template store and a bond-template store that contains the local templates in the training data, then retrieve from these templates with a k-nearest-neighbor (KNN) search during inference. The retrieved templates are combined with neural network predictions as the final output. Furthermore, we propose a lightweight adapter to adjust the weights when combing neural network and KNN predictions conditioned on the hidden representation and the retrieved templates. We conduct comprehensive experiments on two widely used benchmarks, the USPTO-50K and USPTO-MIT. Especially for the top-1 accuracy, we improved 7.1% on the USPTO-50K dataset and 12.0% on the USPTO-MIT dataset.These results demonstrate the effectiveness of our method.

one setup is more effective than another. In this work, we uncover the underlying characteristics of effective sets. For each training instance, we form a large, diverse pool of candidates and systematically vary the subsets used for calibration fine-tuning. Each selection strategy targets distinct aspects of the sets, such as lexical diversity or the size of the gap between positive and negatives. On three diverse scientific long-form summarization datasets (spanning biomedical, clinical, and chemical domains), we find, among others, that faithfulness calibration is optimal when the negative sets are extractive and more likely to be generated, whereas for relevance calibration, the metric margin between candidates should be maximized and surprise-the disagreement between model and metric defined candidate rankings-minimized. Code to create, select, and optimize calibration sets is available at https://github.com/griff4692/calibrating-summaries.

In this paper, we define a widely neglected property in dialogue text, duality, which is a hierarchical property that is reflected in human behaviours in daily conversations: Based on the logic in a conversation (or a sentence), people can infer follow-up utterances (or tokens) based on the previous text, and vice versa.We propose a hierarchical duality learning for dialogue (HDLD) to simulate this human cognitive ability, for generating high quality responses that connect both previous and follow-up dialogues.HDLD utilizes hierarchical dualities at token hierarchy and utterance hierarchy.HDLD maximizes the mutual information between past and future utterances.Thus, even if the future text is invisible during inference, HDLD is capable of estimating future information implicitly based on dialogue history and generates both coherent and informative responses.In contrast to previous approaches that solely utilize future text as auxiliary information to encode during training, HDLD leverages duality to enable interaction between dialogue history and the future.This enhances the utilization of dialogue data, leading to the improvement in both automatic and human evaluation.

Retrosynthesis, which aims to find a route to synthesize a target molecule from commercially available starting materials, is a critical task in drug discovery and materials design. Recently, the combination of ML-based single-step reaction predictors with multi-step planners has led to promising results. However, the single-step predictors are mostly trained offline to optimize the single-step accuracy, without considering complete routes. Here, we leverage reinforcement learning (RL) to improve the single-step predictor, by using a tree-shaped MDP to optimize complete routes. Specifically, we propose a novel online training algorithm, called Planning with Dual Value Networks (PDVN), which alternates between the planning phase and updating phase. In PDVN, we construct two separate value networks to predict the synthesizability and cost of molecules, respectively. To maintain the single-step accuracy, we design a two-branch network structure for the single-step predictor. On the widely-used USPTO dataset, our PDVN algorithm improves the search success rate of existing multi-step planners (e.g., increasing the success rate from 85.79% to 98.95% for Retro$^{\ast}$, and reducing the number of model calls by half while solving 99.47% molecules for RetroGraph). Additionally, PDVN helps find shorter synthesis routes (e.g., reducing the average route length from 5.76 to 4.83 for Retro$^{\ast}$, and from 5.63 to 4.78 for RetroGraph).

Antibodies are proteins that effectively protect the human body by binding to pathogens. Recently, deep learning-based computational antibody design has attracted popular attention since it automatically mines the antibody patterns from data that could be complementary to human experiences. However, the computational methods heavily rely on high-quality antibody structure data, which is quite limited. Besides, the complementarity-determining region (CDR), which is the key component of an antibody that determines the specificity and binding affinity, is highly variable and hard to predict. Therefore, the limited availability of high-quality antibody structure data exacerbates the difficulty of CDR generation. Fortunately, there is a large amount of sequence data for antibodies that can help model the CDR and reduce reliance on structure data. By witnessing the success of pre-training models for protein modeling, in this paper, we develop the antibody pre-training language model and incorporate it into the antigen-specific antibody design model in a systemic way. Specifically, we first pre-train a novel antibody language model based on the sequence data, then propose a one-shot way for sequence and structure generation of CDR to mitigate the high cost and error propagation associated with autoregressive methods, and finally leverage the pre-trained antibody model for the antigen-specific antibody generation model with some carefully designed modules. Our experiments demonstrate the superiority of our method over previous baselines in tasks such as sequence and structure generation, CDR-H3 design for antigen binding, and antibody optimization1. The code is available at https://github.com/KyGao/ABGNN.

Molecular pre-training, which is about to learn an effective representation for molecules on large amount of data, has attracted substantial attention in cheminformatics and bioinformatics. A molecule can be viewed as either a graph (where atoms are connected by bonds) or a SMILES sequence (where depth-first-search is applied to the molecular graph with specific rules). The Transformer and graph neural networks (GNN) are two representative methods to deal with the sequential data and the graphic data, which can globally and locally model the molecules respectively and are supposed to be complementary. In this work, we propose to leverage both representations and design a new pre-training algorithm, dual-view molecule pre-training (briefly, DVMP), that can effectively combine the strengths of both types of molecule representations. DVMP has a Transformer branch and a GNN branch, and the two branches are pre-trained to maintain the semantic consistency of molecules. After pre-training, we can use either the Transformer branch (this one is recommended according to empirical results), the GNN branch, or both for downstream tasks. DVMP is tested on 11 molecular property prediction tasks and outperforms strong baselines. Furthermore, we test DVMP on three retrosynthesis tasks and it achieves state-of-the-art results. Our code is released at https://github.com/microsoft/DVMP.

Modeling the interaction between proteins and ligands and accurately predicting their binding structures is a critical yet challenging task in drug discovery. Recent advancements in deep learning have shown promise in addressing this challenge, with sampling-based and regression-based methods emerging as two prominent approaches. However, these methods have notable limitations. Sampling-based methods often suffer from low efficiency due to the need for generating multiple candidate structures for selection. On the other hand, regression-based methods offer fast predictions but may experience decreased accuracy. Additionally, the variation in protein sizes often requires external modules for selecting suitable binding pockets, further impacting efficiency. In this work, we propose FABind, an end-to-end model that combines pocket prediction and docking to achieve accurate and fast protein-ligand binding. FABind incorporates a unique ligand-informed pocket prediction module, which is also leveraged for docking pose estimation. The model further enhances the docking process by incrementally integrating the predicted pocket to optimize protein-ligand binding, reducing discrepancies between training and inference. Through extensive experiments on benchmark datasets, our proposed FABind demonstrates strong advantages in terms of effectiveness and efficiency compared to existing methods. Our code is available at https://github.com/QizhiPei/FABind.

Precisely predicting the drug-drug interaction (DDI) is an important application and host research topic in drug discovery, especially for avoiding the adverse effect when using drug combination treatment for patients. Nowadays, machine learning and deep learning methods have achieved great success in DDI prediction. However, we notice that most of the works ignore the importance of the relation type when building the DDI prediction models. In this work, we propose a novel R$^2$-DDI framework, which introduces a relation-aware feature refinement module for drug representation learning. The relation feature is integrated into drug representation and refined in the framework. With the refinement features, we also incorporate the consistency training method to regularize the multi-branch predictions for better generalization. Through extensive experiments and studies, we demonstrate our R$^2$-DDI approach can significantly improve the DDI prediction performance over multiple real-world datasets and settings, and our method shows better generalization ability with the help of the feature refinement design.

Accurate prediction of drug-target affinity (DTA) is of vital importance in early-stage drug discovery, facilitating the identification of drugs that can effectively interact with specific targets and regulate their activities. While wet experiments remain the most reliable method, they are time-consuming and resource-intensive, resulting in limited data availability that poses challenges for deep learning approaches. Existing methods have primarily focused on developing techniques based on the available DTA data, without adequately addressing the data scarcity issue. To overcome this challenge, we present the Semi-Supervised Multi-task training (SSM) framework for DTA prediction, which incorporates three simple yet highly effective strategies: (1) A multi-task training approach that combines DTA prediction with masked language modeling using paired drug-target data. (2) A semi-supervised training method that leverages large-scale unpaired molecules and proteins to enhance drug and target representations. This approach differs from previous methods that only employed molecules or proteins in pre-training. (3) The integration of a lightweight cross-attention module to improve the interaction between drugs and targets, further enhancing prediction accuracy. Through extensive experiments on benchmark datasets such as BindingDB, DAVIS and KIBA, we demonstrate the superior performance of our framework. Additionally, we conduct case studies on specific drug-target binding activities, virtual screening experiments, drug feature visualizations and real-world applications, all of which showcase the significant potential of our work. In conclusion, our proposed SSM-DTA framework addresses the data limitation challenge in DTA prediction and yields promising results, paving the way for more efficient and accurate drug discovery processes.

Retrosynthetic planning, which aims to find a reaction pathway to synthesize a target molecule, plays an important role in chemistry and drug discovery. This task is usually modeled as a search problem. Recently, data-driven methods have attracted many research interests and shown promising results for retrosynthetic planning. We observe that the same intermediate molecules are visited many times in the searching process, and they are usually independently treated in previous tree-based methods (e.g., AND-OR tree search, Monte Carlo tree search). Such redundancies make the search process inefficient. We propose a graph-based search policy that eliminates the redundant explorations of any intermediate molecules. As searching over a graph is more complicated than over a tree, we further adopt a graph neural network to guide the search over graphs. Meanwhile, our method can search a batch of targets together in the graph and remove the inter-target duplication in the tree-based search methods. Experimental results on two datasets demonstrate the effectiveness of our method. Especially on the widely used USPTO benchmark, we improve the search success rate to 99.47%, advancing previous state-of-the-art performance for 2.6 points.

Molecular representation learning has attracted much attention recently. A molecule can be viewed as a 2D graph with nodes/atoms connected by edges/bonds, and can also be represented by a 3D conformation with 3-dimensional coordinates of all atoms. We note that most previous work handles 2D and 3D information separately, while jointly leveraging these two sources may foster a more informative representation. In this work, we explore this appealing idea and propose a new representation learning method based on a unified 2D and 3D pre-training. Atom coordinates and interatomic distances are encoded and then fused with atomic representations through graph neural networks. The model is pre-trained on three tasks: reconstruction of masked atoms and coordinates, 3D conformation generation conditioned on 2D graph, and 2D graph generation conditioned on 3D conformation. We evaluate our method on 11 downstream molecular property prediction tasks: 7 with 2D information only and 4 with both 2D and 3D information. Our method achieves state-of-the-art results on 10 tasks, and the average improvement on 2D-only tasks is 8.3%. Our method also achieves significant improvement on two 3D conformation generation tasks.

Multilingual Neural Machine Translation (MNMT) enables one system to translate sentences from multiple source languages to multiple target languages, greatly reducing deployment costs compared with conventional bilingual systems.The MNMT training benefit, however, is often limited to many-to-one directions.The model suffers from poor performance in one-to-many and many-to-many with zero-shot setup.To address this issue, this paper discusses how to practically build MNMT systems that serve arbitrary X-Y translation directions while leveraging multilinguality with a two-stage training strategy of pretraining and finetuning.Experimenting with the WMT'21 multilingual translation task, we demonstrate that our systems outperform the conventional baselines of direct bilingual models and pivot translation models for most directions, averagely giving +6.0 and +4.1 BLEU, without the need for architecture change or extra data collection.Moreover, we also examine our proposed approach in an extremely large-scale data setting to accommodate practical deployment scenarios.

AI-empowered drug recommendation has become an important task in healthcare research areas, which offers an additional perspective to assist human doctors with more accurate and more efficient drug prescriptions. Generally, drug recommendation is based on patients' diagnosis results in the electronic health records. We assume that there are three key factors to be addressed in drug recommendation: 1) elimination of recommendation bias due to limitations of observable information, 2) better utilization of historical health condition and 3) coordination of multiple drugs to control safety. To this end, we propose DrugRec, a causal inference based drug recommendation model. The causal graphical model can identify and deconfound the recommendation bias with front-door adjustment. Meanwhile, we model the multi-visit in the causal graph to characterize a patient's historical health conditions. Finally, we model the drug-drug interactions (DDIs) as the propositional satisfiability (SAT) problem, and solving the SAT problem can help better coordinate the recommendation. Comprehensive experiment results show that our proposed model achieves state-of-the-art performance on the widely used datasets MIMIC-III and MIMIC-IV, demonstrating the effectiveness and safety of our method.

Well understanding protein function and structure in computational biology helps in the understanding of human beings. To face the limited proteins that are annotated structurally and functionally, the scientific community embraces the self-supervised pre-training methods from large amounts of unlabeled protein sequences for protein embedding learning. However, the protein is usually represented by individual amino acids with limited vocabulary size (e.g. 20 type proteins), without considering the strong local semantics existing in protein sequences. In this work, we propose a novel pre-training modeling approach SPRoBERTa. We first present an unsupervised protein tokenizer to learn protein representations with local fragment pattern. Then, a novel framework for deep pre-training model is introduced to learn protein embeddings. After pre-training, our method can be easily fine-tuned for different protein tasks, including amino acid-level prediction task (e.g. secondary structure prediction), amino acid pair-level prediction task (e.g. contact prediction) and also protein-level prediction task (remote homology prediction, protein function prediction). Experiments show that our approach achieves significant improvements in all tasks and outperforms the previous methods. We also provide detailed ablation studies and analysis for our protein tokenizer and training framework.

MOTIVATION: Molecule generation, which is to generate new molecules, is an important problem in bioinformatics. Typical tasks include generating molecules with given properties, molecular property improvement (i.e. improving specific properties of an input molecule), retrosynthesis (i.e. predicting the molecules that can be used to synthesize a target molecule), etc. Recently, deep-learning-based methods received more attention for molecule generation. The labeled data of bioinformatics is usually costly to obtain, but there are millions of unlabeled molecules. Inspired by the success of sequence generation in natural language processing with unlabeled data, we would like to explore an effective way of using unlabeled molecules for molecule generation. RESULTS: We propose a new method, back translation for molecule generation, which is a simple yet effective semisupervised method. Let X be the source domain, which is the collection of properties, the molecules to be optimized, etc. Let Y be the target domain which is the collection of molecules. In particular, given a main task which is about to learn a mapping from the source domain X to the target domain Y, we first train a reversed model g for the Y to X mapping. After that, we use g to back translate the unlabeled data in Y to X and obtain more synthetic data. Finally, we combine the synthetic data with the labeled data and train a model for the main task. We conduct experiments on molecular property improvement and retrosynthesis, and we achieve state-of-the-art results on four molecule generation tasks and one retrosynthesis benchmark, USPTO-50k. AVAILABILITY AND IMPLEMENTATION: Our code and data are available at https://github.com/fyabc/BT4MolGen. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: The interaction between drugs and targets (DTI) in human body plays a crucial role in biomedical science and applications. As millions of papers come out every year in the biomedical domain, automatically discovering DTI knowledge from biomedical literature, which are usually triplets about drugs, targets and their interaction, becomes an urgent demand in the industry. Existing methods of discovering biological knowledge are mainly extractive approaches that often require detailed annotations (e.g. all mentions of biological entities, relations between every two entity mentions, etc.). However, it is difficult and costly to obtain sufficient annotations due to the requirement of expert knowledge from biomedical domains. RESULTS: To overcome these difficulties, we explore an end-to-end solution for this task by using generative approaches. We regard the DTI triplets as a sequence and use a Transformer-based model to directly generate them without using the detailed annotations of entities and relations. Further, we propose a semi-supervised method, which leverages the aforementioned end-to-end model to filter unlabeled literature and label them. Experimental results show that our method significantly outperforms extractive baselines on DTI discovery. We also create a dataset, KD-DTI, to advance this task and release it to the community. AVAILABILITY AND IMPLEMENTATION: Our code and data are available at https://github.com/bert-nmt/BERT-DTI. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Recently the concept of teaching has been introduced into machine learning, in which a teacher model is used to guide the training of a student model (which will be used in real tasks) through data selection, loss function design, etc. Learning to reweight, which is a specific kind of teaching that reweights training data using a teacher model, receives much attention due to its simplicity and effectiveness. In existing learning to reweight works, the teacher model only utilizes shallow/surface information such as training iteration number and loss/accuracy of the student model from training/validation sets, but ignores the internal states of the student model, which limits the potential of learning to reweight. In this work, we propose an improved data reweighting algorithm, in which the student model provides its internal states to the teacher model, and the teacher model returns adaptive weights of training samples to enhance the training of the student model. The teacher model is jointly trained with the student model using meta gradients propagated from a validation set. Experiments on image classification with clean/noisy labels and neural machine translation empirically demonstrate that our algorithm makes significant improvement over previous methods.

Sequence learning has attracted much research attention from the machine learning community in recent years. In many applications, a sequence learning task is usually associated with multiple temporally correlated auxiliary tasks, which are different in terms of how much input information to use or which future step to predict. For example, (i) in simultaneous machine translation, one can conduct translation under different latency (i.e., how many input words to read/wait before translation); (ii) in stock trend forecasting, one can predict the price of a stock in different future days (e.g., tomorrow, the day after tomorrow). While it is clear that those temporally correlated tasks can help each other, there is a very limited exploration on how to better leverage multiple auxiliary tasks to boost the performance of the main task. In this work, we introduce a learnable scheduler to sequence learning, which can adaptively select auxiliary tasks for training depending on the model status and the current training data. The scheduler and the model for the main task are jointly trained through bi-level optimization. Experiments show that our method significantly improves the performance of simultaneous machine translation and stock trend forecasting.

Zhen Wu, Lijun Wu, Qi Meng, Yingce Xia, Shufang Xie, Tao Qin, Xinyu Dai, Tie-Yan Liu. Proceedings of the 2021 Conference of the North American Chapter of the Association for Computational Linguistics: Human Language Technologies. 2021.

Tokenization is the first step of many natural language processing (NLP) tasks and plays an important role for neural NLP models. Tokenizaton method such as byte-pair encoding (BPE), which can greatly reduce the large vocabulary and deal with out-of-vocabulary words, has shown to be effective and is widely adopted for sequence generation tasks. While various tokenization methods exist, there is no common acknowledgement which is the best. In this work, we propose to leverage the mixed representations from different tokenization methods for sequence generation tasks, in order to boost the model performance with unique characteristics and advantages of individual tokenization methods. Specifically, we introduce a new model architecture to incorporate mixed representations and a co-teaching algorithm to better utilize the diversity of different tokenization methods. Our approach achieves significant improvements on neural machine translation (NMT) tasks with six language pairs (e.g., English$\leftrightarrow$German, English$\leftrightarrow$Romanian), as well as an abstractive summarization task.