Jianqiang Li

Junkai Ji, Zhangfan Yang, Dong Xu et al.

Drug discovery is a time-consuming and expensive process, with traditional high-throughput and docking-based virtual screening hampered by low success rates and limited scalability. Recent advances in generative modelling, including autoregressive, diffusion, and flow-based approaches, have enabled de novo ligand design beyond the limits of enumerative screening. Yet these models often suffer from inadequate generalization, limited interpretability, and an overemphasis on binding affinity at the expense of key pharmacological properties, thereby restricting their translational utility. Here we present Trio, a molecular generation framework integrating fragment-based molecular language modeling, reinforcement learning, and Monte Carlo tree search, for effective and interpretable closed-loop targeted molecular design. Through the three key components, Trio enables context-aware fragment assembly, enforces physicochemical and synthetic feasibility, and guides a balanced search between the exploration of novel chemotypes and the exploitation of promising intermediates within protein binding pockets. Experimental results show that Trio reliably achieves chemically valid and pharmacologically enhanced ligands, outperforming state-of-the-art approaches with improved binding affinity (+7.85%), drug-likeness (+11.10%) and synthetic accessibility (+12.05%), while expanding molecular diversity more than fourfold.

Chenxi Zhao, Jianqiang Li, Qing Zhao et al.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by amyloid-beta plaques and tau neurofibrillary tangles, which serve as key histopathological features. The identification and segmentation of these lesions are crucial for understanding AD progression but remain challenging due to the lack of large-scale annotated datasets and the impact of staining variations on automated image analysis. Deep learning has emerged as a powerful tool for pathology image segmentation; however, model performance is significantly influenced by variations in staining characteristics, necessitating effective stain normalization and enhancement techniques. In this study, we address these challenges by introducing an open-source dataset (ADNP-15) of neuritic plaques (i.e., amyloid deposits combined with a crown of dystrophic tau-positive neurites) in human brain whole slide images. We establish a comprehensive benchmark by evaluating five widely adopted deep learning models across four stain normalization techniques, providing deeper insights into their influence on neuritic plaque segmentation. Additionally, we propose a novel image enhancement method that improves segmentation accuracy, particularly in complex tissue structures, by enhancing structural details and mitigating staining inconsistencies. Our experimental results demonstrate that this enhancement strategy significantly boosts model generalization and segmentation accuracy. All datasets and code are open-source, ensuring transparency and reproducibility while enabling further advancements in the field.