Xiaojun Yao

Jingjie Zhang, Hanqun Cao, Haosen Shi et al.

Cyclic peptides are attractive therapeutic modalities because their closed-ring topology can improve stability and target specificity. However, de novo cyclic peptide design remains challenging for diffusion generators, as macrocyclization requires satisfying sparse, non-smooth, and compositional geometric constraints. Existing constraint-conditioned methods largely rely on inference-time guidance, which can steer samples toward desired closures but does not directly change the learned generative distribution. We propose GeoCycler, a reward-weighted diffusion alignment framework for training conditional latent diffusion models toward macrocyclization feasibility. GeoCycler introduces a type-gated stair reward that activates distance-based shaping only when prerequisite residue or linker types are satisfied, providing dense geometric feedback while avoiding misleading signals from chemically incompatible anchors. Together with positive-only reward weighting and replay-based stabilization, GeoCycler aligns a single generator across multiple cyclization topologies. On the LNR benchmark, GeoCycler improves pass@5 closure success over strong guidance-based baselines across stapled, head-to-tail, disulfide, and bicyclic settings. In particular, it improves head-to-tail success by 20.8 percentage points over CP-Composer while maintaining comparable amino-acid and backbone-dihedral statistics. These results suggest that training-time alignment to sparse geometric constraints is a promising alternative to relying solely on post hoc sampling-time correction for cyclic peptide generation.

Quansong He, Xiaojun Yao, Jun Wu et al.

In recent years, advanced U-like networks have demonstrated remarkable performance in medical image segmentation tasks. However, their drawbacks, including excessive parameters, high computational complexity, and slow inference speed, pose challenges for practical implementation in scenarios with limited computational resources. Existing lightweight U-like networks have alleviated some of these problems, but they often have pre-designed structures and consist of inseparable modules, limiting their application scenarios. In this paper, we propose three plug-and-play decoders by employing different discretization methods of the neural memory Ordinary Differential Equations (nmODEs). These decoders integrate features at various levels of abstraction by processing information from skip connections and performing numerical operations on upward path. Through experiments on the PH2, ISIC2017, and ISIC2018 datasets, we embed these decoders into different U-like networks, demonstrating their effectiveness in significantly reducing the number of parameters and FLOPs while maintaining performance. In summary, the proposed discretized nmODEs decoders are capable of reducing the number of parameters by about 20% ~ 50% and FLOPs by up to 74%, while possessing the potential to adapt to all U-like networks. Our code is available at https://github.com/nayutayuki/Lightweight-nmODE-Decoders-For-U-like-networks.

Pengyong Li, Jun Wang, Yixuan Qiao et al.

How to produce expressive molecular representations is a fundamental challenge in AI-driven drug discovery. Graph neural network (GNN) has emerged as a powerful technique for modeling molecular data. However, previous supervised approaches usually suffer from the scarcity of labeled data and have poor generalization capability. Here, we proposed a novel Molecular Pre-training Graph-based deep learning framework, named MPG, that leans molecular representations from large-scale unlabeled molecules. In MPG, we proposed a powerful MolGNet model and an effective self-supervised strategy for pre-training the model at both the node and graph-level. After pre-training on 11 million unlabeled molecules, we revealed that MolGNet can capture valuable chemistry insights to produce interpretable representation. The pre-trained MolGNet can be fine-tuned with just one additional output layer to create state-of-the-art models for a wide range of drug discovery tasks, including molecular properties prediction, drug-drug interaction, and drug-target interaction, involving 13 benchmark datasets. Our work demonstrates that MPG is promising to become a novel approach in the drug discovery pipeline.