Chaohao Yuan

Han Zhang, Guo-Hua Yuan, Chaohao Yuan et al.

Modeling cellular states and predicting their responses to perturbations are central challenges in computational biology and the development of virtual cells. Existing foundation models for single-cell transcriptomics provide powerful static representations, but they do not explicitly model the distribution of cellular states for generative simulation. Here, we introduce Lingshu-Cell, a masked discrete diffusion model that learns transcriptomic state distributions and supports conditional simulation under perturbation. By operating directly in a discrete token space that is compatible with the sparse, non-sequential nature of single-cell transcriptomic data, Lingshu-Cell captures complex transcriptome-wide expression dependencies across approximately 18,000 genes without relying on prior gene selection, such as filtering by high variability or ranking by expression level. Across diverse tissues and species, Lingshu-Cell accurately reproduces transcriptomic distributions, marker-gene expression patterns and cell-subtype proportions, demonstrating its ability to capture complex cellular heterogeneity. Moreover, by jointly embedding cell type or donor identity with perturbation, Lingshu-Cell can predict whole-transcriptome expression changes for novel combinations of identity and perturbation. It achieves leading performance on the Virtual Cell Challenge H1 genetic perturbation benchmark and in predicting cytokine-induced responses in human PBMCs. Together, these results establish Lingshu-Cell as a flexible cellular world model for in silico simulation of cell states and perturbation responses, laying the foundation for a new paradigm in biological discovery and perturbation screening.

Tian Bian, Yifan Niu, Chaohao Yuan et al.

Circuit discovery has recently attracted attention as a potential research direction to explain the non-trivial behaviors of language models. It aims to find the computational subgraphs, also known as circuits, within the model that are responsible for solving specific tasks. However, most existing studies overlook the holistic nature of these circuits and require designing specific corrupted activations for different tasks, which is inaccurate and inefficient. In this work, we propose an end-to-end approach based on the principle of Information Bottleneck, called IBCircuit, to identify informative circuits holistically. IBCircuit is an optimization framework for holistic circuit discovery and can be applied to any given task without tediously corrupted activation design. In both the Indirect Object Identification (IOI) and Greater-Than tasks, IBCircuit identifies more faithful and minimal circuits in terms of critical node components and edge components compared to recent related work.

Chaohao Yuan, Chenghao Xiao, Yu Rong et al.

SFT and RLVR represent two fundamental yet distinct paradigms for LLM post-training, each excelling in distinct dimensions. SFT expands knowledge breadth while RLVR enhances reasoning depth. Yet integrating these complementary strengths remains a formidable challenge. Sequential training can cause catastrophic forgetting, and joint optimization often suffers from severe gradient conflicts. We analyze SFT and RLVR through the lens of task vectors and reveal three structural properties behind these failures: a 30* magnitude disparity, 45* sign interference, and heterogeneous module-wise update distributions. These findings show SFT and RLVR are difficult to integrate directly, but they also suggest that the two paradigms modify partly complementary components of the model. Motivated by these observations, we propose Decoupled Test-time Synthesis (DoTS), a post-hoc framework allows SFT and RLVR checkpoints to be trained independently and synthesizes their capabilities only at inference time via task vector arithmetic, without updating model parameters. To reduce interference, DOTS applies selective sparsification with norm-preserving rescaling. It then uses Bayesian optimization on a small set of unlabeled queries to search for combination coefficients on the Pareto frontier of consistency and perplexity. Empirically, \ours matches or exceeds the performance of training-based SFT--RLVR integration methods across multiple mathematical reasoning benchmarks, incurring only $\sim$3\% of the computational cost. When applied to stronger post-trained checkpoints, DOTS surpasses SOTA models and generalizes to out-of-domain benchmarks without re-tuning. Code is available at https://github.com/chaohaoyuan/DoTS.

Yikun Zhang, Geyan Ye, Chaohao Yuan et al.

Molecule-and-text cross-modal representation learning has emerged as a promising direction for enhancing the quality of molecular representation, thereby improving performance in various scientific fields. However, most approaches employ a global alignment approach to learn the knowledge from different modalities that may fail to capture fine-grained information, such as molecule-and-text fragments and stereoisomeric nuances, which is crucial for downstream tasks. Furthermore, it is incapable of modeling such information using a similar global alignment strategy due to the lack of annotations about the fine-grained fragments in the existing dataset. In this paper, we propose Atomas, a hierarchical molecular representation learning framework that jointly learns representations from SMILES strings and text. We design a Hierarchical Adaptive Alignment model to automatically learn the fine-grained fragment correspondence between two modalities and align these representations at three semantic levels. Atomas's end-to-end training framework supports understanding and generating molecules, enabling a wider range of downstream tasks. Atomas achieves superior performance across 12 tasks on 11 datasets, outperforming 11 baseline models thus highlighting the effectiveness and versatility of our method. Scaling experiments further demonstrate Atomas's robustness and scalability. Moreover, visualization and qualitative analysis, validated by human experts, confirm the chemical relevance of our approach. Codes are released on https://github.com/yikunpku/Atomas.

Chaohao Yuan, Songyou Li, Geyan Ye et al.

The core challenge of de novo protein design lies in creating proteins with specific functions or properties, guided by certain conditions. Current models explore to generate protein using structural and evolutionary guidance, which only provide indirect conditions concerning functions and properties. However, textual annotations of proteins, especially the annotations for protein domains, which directly describe the protein's high-level functionalities, properties, and their correlation with target amino acid sequences, remain unexplored in the context of protein design tasks. In this paper, we propose Protein-Annotation Alignment Generation, PAAG, a multi-modality protein design framework that integrates the textual annotations extracted from protein database for controllable generation in sequence space. Specifically, within a multi-level alignment module, PAAG can explicitly generate proteins containing specific domains conditioned on the corresponding domain annotations, and can even design novel proteins with flexible combinations of different kinds of annotations. Our experimental results underscore the superiority of the aligned protein representations from PAAG over 7 prediction tasks. Furthermore, PAAG demonstrates a significant increase in generation success rate (24.7% vs 4.7% in zinc finger, and 54.3% vs 22.0% in the immunoglobulin domain) in comparison to the existing model. We anticipate that PAAG will broaden the horizons of protein design by leveraging the knowledge from between textual annotation and proteins.