Accurate drug-target affinity (DTA) prediction holds significant potential in the field of artificial intelligence (AI)-based drug discovery. However, existing methods primarily operate at a single scale, specifically at the macro (residue) scale for target proteins and the micro (atom) scale for drugs, which limits their ability to provide information at micro (atom) scale for targets and macro (functional group, FG) scale for drugs. This limitation hinders a comprehensive understanding of the binding patterns and properties of drug-target pairs. In this paper, we propose a progressive Macro-to-Micro 3D Modeling Network (M²N) that enables macro (residue/FG) to micro (atom) scale unified modeling, termed cross-scale, to predict DTA. Specifically, M²N operates drugs by learning their chemical properties and structural characteristics from a 3D FG graph to a 3D atom graph. Correspondingly, M²N encodes proteins from a 3D residue graph to a 3D atom graph to exploit their sequence, evolutionary, and geometric representations. Such cross-scale 3D modeling scheme allows for coarse-to-fine embedding optimization, followed by an adaptive fusion module to dynamically integrate the refined features by end-to-end learning. Extensive experiments on two datasets indicate that M²N not only outperforms state-of-the-art methods under various conditions, but also provides a new paradigm for target and drug unified modeling.

While metabolic imaging can facilitate early diagnosis by revealing physiological changes of lesions, it is limited by high cost, high radiation risk, and potential renal impairment. Thus, developing an effective approach for Anatomical-to-Metabolic Image Synthesis (A2MIS) is highly required. However, existing methods are heavily hindered by the gap between distinct domains, and fail to provide a confidence score for the synthesized images, severely restricting their clinical applications. Here, we propose a novel Residual-guided Latent Brownian-bridge Co-Diffusion (RLBCD) model for A2MIS. Specifically, RLBCD starts with a co-diffusion process that leverages a residual diffusion branch to capture inter-domain differences, which are injected into an enhanced diffusion branch to maximally reconstruct modality-specific details. Furthermore, to explore desired residual guidance, we investigate the encoder and decoder features in diffusion models, and accordingly design a Hybrid-Granularity Fusion to integrate consistent semantics and complementary information for fine-grained reconstruction. Additionally, a latent consistency score is developed to enhance the restoration of modality-specific information, which also serves as an indicator of the inherent confidence of the synthesized images. Extensive experiments conducted on five public and in-house datasets demonstrate that RLBCD not only outperforms state-of-the-art methods for A2MIS, but also is valuable for downstream clinic applications.