Qi Si

Qi Si, Penglei Wang, Yushuai Wu et al.

Predicting spatial gene expression from routine H\&E enables large-scale molecular profiling, yet current models treat this as isolated pointwise tasks, thereby overlooking essential biological structures like gene coordination and spatial distribution. To preserve these relationships, we introduce \textbf{FLAG}, a diffusion-based framework that redefines this task as structured distribution modeling. At the same time, we identify the critical \textbf{Gene Dimension Curse}, where joint modeling gene expression and their spatial interactions fail in high-dimensional spaces, and FLAG solves this challenge by integrating a spatial graph encoder for topological consistency and utilizing Gene Foundation Model (GFM) alignment for gene-gene fidelity in the generation process. To rigorously assess model performance, we propose a set of novel structural evaluation metrics, including Gene Structural Correlation (\textbf{GSC}) and Spatial Structural Correlation (\textbf{SSC}). Our experiments demonstrate that FLAG is highly competitive in traditional accuracy (PCC/MSE) while achieving significantly enhanced structural fidelity in capturing both gene-gene and gene-spatial relationships. The code is available at https://github.com/darkflash03/FLAG.

Qi Si, Xuyang Liu, Penglei Wang et al.

RNA inverse folding, designing sequences to form specific 3D structures, is critical for therapeutics, gene regulation, and synthetic biology. Current methods, focused on sequence recovery, struggle to address structural objectives like secondary structure consistency (SS), minimum free energy (MFE), and local distance difference test (LDDT), leading to suboptimal structural accuracy. To tackle this, we propose a reinforcement learning (RL) framework integrated with a latent diffusion model (LDM). Drawing inspiration from the success of diffusion models in RNA inverse folding, which adeptly model complex sequence-structure interactions, we develop an LDM incorporating pre-trained RNA-FM embeddings from a large-scale RNA model. These embeddings capture co-evolutionary patterns, markedly improving sequence recovery accuracy. However, existing approaches, including diffusion-based methods, cannot effectively handle non-differentiable structural objectives. By contrast, RL excels in this task by using policy-driven reward optimization to navigate complex, non-gradient-based objectives, offering a significant advantage over traditional methods. In summary, we propose the Step-wise Optimization of Latent Diffusion Model (SOLD), a novel RL framework that optimizes single-step noise without sampling the full diffusion trajectory, achieving efficient refinement of multiple structural objectives. Experimental results demonstrate SOLD surpasses its LDM baseline and state-of-the-art methods across all metrics, establishing a robust framework for RNA inverse folding with profound implications for biotechnological and therapeutic applications.

Qi Si, Bo Wang, Zhao Zhang

The diffusion model has demonstrated superior performance in synthesizing diverse and high-quality images for text-guided image translation. However, there remains room for improvement in both the formulation of text prompts and the preservation of reference image content. First, variations in target text prompts can significantly influence the quality of the generated images, and it is often challenging for users to craft an optimal prompt that fully captures the content of the input image. Second, while existing models can introduce desired modifications to specific regions of the reference image, they frequently induce unintended alterations in areas that should remain unchanged. To address these challenges, we propose pix2pix-zeroCon, a zero-shot diffusion-based method that eliminates the need for additional training by leveraging patch-wise contrastive loss. Specifically, we automatically determine the editing direction in the text embedding space based on the reference image and target prompts. Furthermore, to ensure precise content and structural preservation in the edited image, we introduce cross-attention guiding loss and patch-wise contrastive loss between the generated and original image embeddings within a pre-trained diffusion model. Notably, our approach requires no additional training and operates directly on a pre-trained text-to-image diffusion model. Extensive experiments demonstrate that our method surpasses existing models in image-to-image translation, achieving enhanced fidelity and controllability.