Showing 1–50 of 244 results for author: Li, S Z

BioM-JEPA: joint-embedding prediction of graph-connected gene blocks in single cells

Authors: Yuhao Wang, Zelin Zang, Yuxuan Liu, Zhen Lei, Stan Z. Li

Abstract: Single-cell transcriptomes are sparse observations of coordinated biological programmes, yet most self-supervised models learn by reconstructing individual genes. Here we present BioM-JEPA, a joint-embedding predictive architecture that instead predicts aggregate representations of graph-connected gene blocks defined by protein-association and corpus-derived coexpression evidence. A student networ… ▽ More Single-cell transcriptomes are sparse observations of coordinated biological programmes, yet most self-supervised models learn by reconstructing individual genes. Here we present BioM-JEPA, a joint-embedding predictive architecture that instead predicts aggregate representations of graph-connected gene blocks defined by protein-association and corpus-derived coexpression evidence. A student network infers each target-block representation from the remaining genes in a cell, while a slowly updated teacher supplies the corresponding target from the full observed gene set. Under the reported extraction procedure, block-level prediction produced embeddings with higher effective rank and weaker association with detected-gene depth in the tested diagnostics than token-prediction, random-block and reconstruction controls. Across CellBench tasks, frozen BioM-JEPA embeddings retained expression, pathway and neighbourhood information and achieved the lowest aggregate perturbation-response error among the evaluated models. Representation diagnostics were also consistent with canonical pancreatic programmes and compositional relationships between genetic perturbations. Linear attention avoids constructing a quadratic gene-by-gene attention matrix; in a matched one-epoch hPancreas experiment at batch size 8, BioM-JEPA provided 5.75-fold higher fine-tuning throughput and 3.76-fold higher held-out embedding throughput than scFoundation. Together, these results support graph-connected gene blocks as useful prediction units for JEPA-style representation learning in single-cell biology. △ Less

Submitted 6 August, 2026; originally announced August 2026.

Comments: 34 pages, 6 figures, and 13 supplementary tables (Tables S1-S13); includes Supplementary Information with detailed training and evaluation protocols. Numerical source data for all figures are provided as ancillary files; training code and the BioM-JEPA checkpoint will be released via GitHub

scTranslation: A Comprehensive Benchmark for Single-Cell Multi-Omics Modality Translation

Authors: Jiabei Cheng, Jingbo Zhou, Jun Xia, Changkai Li, Zhen Lei, Chang Yu, Stan Z. Li

Abstract: Simultaneous measurement of multiple omics modalities in single cells enables researchers to gain a more comprehensive understanding of cellular states and regulatory mechanisms. However, due to high experimental costs, significant noise, and incomplete modality coverage, a variety of computational methods for modality translation have emerged in recent years. Despite the development of translatio… ▽ More Simultaneous measurement of multiple omics modalities in single cells enables researchers to gain a more comprehensive understanding of cellular states and regulatory mechanisms. However, due to high experimental costs, significant noise, and incomplete modality coverage, a variety of computational methods for modality translation have emerged in recent years. Despite the development of translation models, there is still a lack of systematic benchmark evaluation in terms of datasets, evaluation metrics, and influencing factors. To address this, we present scTranslation, a comprehensive benchmark for single-cell multi-omics modality translation tasks. It includes diverse translation datasets, integrates state-of-the-art models, and provides a comprehensive evaluation metrics. In addition, we assess model performance under different scenarios, such as feature selection, feature quality, and few-shot settings. These factors significantly affect model performance but have rarely been systematically studied before. Leveraging this benchmark, we conduct a large-scale study of current methods, report many insightful findings that open up new possibilities for future development. The benchmark is open-sourced to facilitate future research. The code is anonymously released at https://github.com/Bunnybeibei/scTranslation. △ Less

Submitted 2 June, 2026; originally announced June 2026.

ViroBench: Benchmarking Nucleotide Foundation Models on Viral Genomics Tasks

Authors: Dongxin Ye, Fang Hu, Han Hu, Shu Hu, Yang Tan, Wanli Ouyang, Stan Z. Li, Jie Cui, Nanqing Dong

Abstract: Nucleotide sequences constitute the fundamental genetic basis of biological systems, rendering viral genomic analysis critical for biomedical advancement. Despite progress in biological foundation models, specifically nucleotide foundation models (NFMs), the field lacks a unified standard for viral genomics to facilitate community development and enforce biosecurity constraints. To address this, w… ▽ More Nucleotide sequences constitute the fundamental genetic basis of biological systems, rendering viral genomic analysis critical for biomedical advancement. Despite progress in biological foundation models, specifically nucleotide foundation models (NFMs), the field lacks a unified standard for viral genomics to facilitate community development and enforce biosecurity constraints. To address this, we introduce ViroBench, the first comprehensive and large-scale benchmark specifically designed for NFMs in viral settings. ViroBench evaluates models across two critical dimensions: biological understanding and latent biosecurity risk, covering 18 diverse scenarios within 4 task types. Extensive evaluation of 66 NFMs across diverse architectures yields three critical conclusions. Firstly, NFMs exhibit a performance degradation in biological understanding under phylogenetic and temporal shifts, indicating weak extrapolation capabilities. Secondly, generation tasks reveal a decoupling between statistical likelihood and biological functional validity, posing latent biosecurity risks. Thirdly, controlled ablation studies reveal that taxonomic diversity in pretraining data outweighs parameter scale. Specifically, a lightweight baseline trained on diverse data achieves a 67.5% performance gain over its original model. Overall, ViroBench provides interpretable, diagnostic evaluations and a reproducible measurement framework for future research on viral nucleotide foundation models. The datasets and code are publicly available at https://github.com/QIANJINYDX/ViroBench. △ Less

Submitted 24 May, 2026; originally announced May 2026.

Comments: 42 pages,15 figures

scHelix: Asymmetric Dual-Stream Integration via Explicit Gene-Level Disentanglement

Authors: Xichen Yan, Zelin Zang, Changxi Chi, Jingbo Zhou, Chang Yu, Jinlin Wu, Shenghui Cheng, Fuji Yang, Jiebo Luo, Zhen Lei, Stan Z. Li

Abstract: A critical challenge in single-cell RNA sequencing (scRNA-seq) integration is resolving the tension between eliminating batch effects and maintaining biological fidelity. While recent evidence indicates that batch effects manifest heterogeneously across genes, most existing methods process the transcriptome uniformly, frequently resulting in over-correction and loss of subtle biological signals. T… ▽ More A critical challenge in single-cell RNA sequencing (scRNA-seq) integration is resolving the tension between eliminating batch effects and maintaining biological fidelity. While recent evidence indicates that batch effects manifest heterogeneously across genes, most existing methods process the transcriptome uniformly, frequently resulting in over-correction and loss of subtle biological signals. To address this, we present scHelix, a dataset-adaptive framework that fundamentally changes how features are processed by explicitly partitioning genes into domain-invariant Anchors and domain-sensitive Variants at the input level. scHelix utilizes a dual-stream sparse diffusion encoder equipped with stop-gradient graph caching to efficiently learn multi-scale structural representations. The core of our approach is a novel asymmetric Align-Refine-Fuse protocol: the unstable Variant stream is first aligned to the robust topology of the Anchor stream, followed by a conservative refinement phase where the Anchor stream absorbs denoised details via bounded residual gating. This divide-and-conquer architecture prevents shortcut learning and ensures robust batch removal without compromising the integrity of biological clusters. Extensive benchmarking demonstrates that scHelix outperforms state-of-the-art methods. △ Less

Submitted 18 May, 2026; originally announced May 2026.

Comments: 17 pages, 8 figures, accepted by KDD 26

MetaGEM: Bottom-Up Reconstruction of Genome-Scale Metabolic Networks via Deep Enzyme-Metabolite Anchoring

Authors: Weiyu Xiao, Jiangbin Zheng, Stan Z. Li

Abstract: Genome-scale metabolic models (GEMs) are essential tools for systems biology and rational chassis design, but conventional top-down reconstruction depends heavily on sequence homology and often leaves unknown enzymes and metabolic dark matter unresolved. Direct reconstruction from metabolomics is also difficult because mapping observed metabolites to reactions is an ill-posed inverse problem with… ▽ More Genome-scale metabolic models (GEMs) are essential tools for systems biology and rational chassis design, but conventional top-down reconstruction depends heavily on sequence homology and often leaves unknown enzymes and metabolic dark matter unresolved. Direct reconstruction from metabolomics is also difficult because mapping observed metabolites to reactions is an ill-posed inverse problem with combinatorial ambiguity and possible spurious networks. Here we present MetaGEM, a bottom-up framework that uses enzymes as physical anchors to convert system-level network inference into enzyme-metabolite interaction prediction. MetaGEM uses a multimodal dual-tower architecture that combines protein evolutionary semantics from a protein language model with three-dimensional metabolite representations. It further introduces contrastive learning with hard negative mining to separate structurally similar metabolites and reduce false positive interactions. On a de-homologized benchmark, MetaGEM achieves state-of-the-art enzyme-metabolite prediction performance, with AUROC of 0.9701 and MCC of 0.8033, and remains robust under low sequence identity splits. In downstream reconstruction, MetaGEM generates functional genome-scale metabolic models for Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa. The reconstructed models improve network connectivity, capture promiscuous enzymes, and show strong agreement with experimental phenotype microarray and gene essentiality data. These results indicate that MetaGEM provides a practical route from metabolomic evidence to computable metabolic networks and offers a foundation for automated AI-driven virtual cell reconstruction. △ Less

Submitted 14 May, 2026; originally announced May 2026.

Comments: 21 pages, 5 figures, 3 tables

MSC Class: 92C42; 92C40; 68T05; 90C11 ACM Class: I.2.6; I.5.1; J.3

TCRTransBench: A Comprehensive Benchmark for Bidirectional TCR-Peptide Sequence Generation

Authors: Yiming Wang, Weiyu Xiao, Jiangbin Zheng, Stan Z. Li

Abstract: T-cell receptor (TCR) interactions with antigenic peptides underpin adaptive immunity and are pivotal for personalized immunotherapy and vaccine development. Despite recent progress, computational modeling of TCR-peptide specificity remains challenging due to data scarcity, complex sequence dependencies, and the absence of standardized evaluation frameworks. To systematically address these issues,… ▽ More T-cell receptor (TCR) interactions with antigenic peptides underpin adaptive immunity and are pivotal for personalized immunotherapy and vaccine development. Despite recent progress, computational modeling of TCR-peptide specificity remains challenging due to data scarcity, complex sequence dependencies, and the absence of standardized evaluation frameworks. To systematically address these issues, we introduce TCRTransBench, a comprehensive benchmark for bidirectional TCR-peptide sequence generation tasks. Specifically, we define two sequence-to-sequence (seq2seq) tasks: generating antigenic peptides from TCR sequences (TCR2PEP) and generating TCR sequences from antigenic peptides (PEP2TCR). Our framework provides a rigorously curated, MHC-free dataset comprising tens of thousands of validated TCR-peptide pairs, along with diverse evaluation metrics that integrate computational efficiency, sequence accuracy, and biological plausibility. Extensive benchmarking across representative neural architectures, including recurrent, convolutional, and transformer-based models, reveals key trade-offs among performance metrics, highlighting the effectiveness of transformers in capturing intricate biological interactions and the necessity of biologically informed evaluation criteria. TCRTransBench establishes standardized tasks, datasets, and evaluation protocols, laying a robust foundation for future computational advances in immunological sequence modeling and therapeutic protein design. △ Less

Submitted 6 May, 2026; originally announced May 2026.

Comments: 13 pages, 5 figures, 2 tables

ACM Class: I.2.6; I.5.1; J.3

MAT-Cell: A Multi-Agent Tree-Structured Reasoning Framework for Batch-Level Single-Cell Annotation

Authors: Yehui Yang, Zelin Zang, Xienan Zheng, Yuzhe Jia, Changxi Chi, Jingbo Zhou, Chang Yu, Jinlin Wu, Fuji Yang, Jiebo Luo, Zhen Lei, Stan Z. Li

Abstract: Automated single-cell annotation is difficult when the most abundant genes are not the most discriminative ones, or when a target state is poorly covered by a fixed reference atlas. GPTCelltype-style one-shot prompting allows large language models (LLMs) to produce plausible labels from generic expression signals, while reference-based annotators can force unfamiliar states into the nearest known… ▽ More Automated single-cell annotation is difficult when the most abundant genes are not the most discriminative ones, or when a target state is poorly covered by a fixed reference atlas. GPTCelltype-style one-shot prompting allows large language models (LLMs) to produce plausible labels from generic expression signals, while reference-based annotators can force unfamiliar states into the nearest known category. We propose MAT-Cell, a prompt-driven framework for batch-level single-cell annotation that separates evidence grounding from label decision. MAT-Cell first uses Reverse Verification Query (RVQ) to combine tissue context, observed differentially expressed genes, and LLM-elicited biological priors into structured candidate-specific premises. Verifier agents then convert these premises into explicit premise-to-claim reasoning trees, and bounded multi-round debate compares,challenges, and revises the resulting claims before consensus or final adjudication.The returned Syllogistic Derivation Tree (SDT) provides an auditable debate trace rather than a formal proof of the annotation. In open-candidate benchmarks across five datasets, a locally deployed Qwen3-30B model with MAT-Cell achieves 75.5% average accuracy, compared with 64.2% for the strongest evaluated CoT baseline and 51.9% for the strongest evaluated scPilot variant. In oracle-candidate bench-marks across three species,MAT-Cell remains competitive across backbones, and local inference substantially reduces monetary cost for batch annotation. Code is available at: https://anonymous.4open.science/r/MATCell-4067 △ Less

Submitted 7 May, 2026; v1 submitted 7 April, 2026; originally announced April 2026.

Beyond the Academic Monoculture: A Unified Framework and Industrial Perspective for Attributed Graph Clustering

Authors: Yunhui Liu, Yue Liu, Yongchao Liu, Tao Zheng, Stan Z. Li, Xinwang Liu, Tieke He

Abstract: Attributed Graph Clustering (AGC) is a fundamental unsupervised task that partitions nodes into cohesive groups by jointly modeling structural topology and node attributes. While the advent of graph neural networks and self-supervised learning has catalyzed a proliferation of AGC methodologies, a widening chasm persists between academic benchmark performance and the stringent demands of real-world… ▽ More Attributed Graph Clustering (AGC) is a fundamental unsupervised task that partitions nodes into cohesive groups by jointly modeling structural topology and node attributes. While the advent of graph neural networks and self-supervised learning has catalyzed a proliferation of AGC methodologies, a widening chasm persists between academic benchmark performance and the stringent demands of real-world industrial deployment. To bridge this gap, this survey provides a comprehensive, industrially grounded review of AGC from three complementary perspectives. First, we introduce the Encode-Cluster-Optimize taxonomic framework, which decomposes the diverse algorithmic landscape into three orthogonal, composable modules: representation encoding, cluster projection, and optimization strategy. This unified paradigm enables principled architectural comparisons and inspires novel methodological combinations. Second, we critically examine prevailing evaluation protocols to expose the field's academic monoculture: a pervasive over-reliance on small, homophilous citation networks, the inadequacy of supervised-only metrics for an inherently unsupervised task, and the chronic neglect of computational scalability. In response, we advocate for a holistic evaluation standard that integrates supervised semantic alignment, unsupervised structural integrity, and rigorous efficiency profiling. Third, we explicitly confront the practical realities of industrial deployment. By analyzing operational constraints such as massive scale, severe heterophily, and tabular feature noise alongside extensive empirical evidence from our companion benchmark, we outline actionable engineering strategies. Furthermore, we chart a clear roadmap for future research, prioritizing heterophily-robust encoders, scalable joint optimization, and unsupervised model selection criteria to meet production-grade requirements. △ Less

Submitted 21 March, 2026; originally announced March 2026.

The Trinity of Consistency as a Defining Principle for General World Models

Authors: Jingxuan Wei, Siyuan Li, Yuhang Xu, Zheng Sun, Junjie Jiang, Hexuan Jin, Caijun Jia, Honghao He, Xinglong Xu, Xi bai, Chang Yu, Yumou Liu, Junnan Zhu, Xuanhe Zhou, Jintao Chen, Xiaobin Hu, Shancheng Pang, Bihui Yu, Ran He, Zhen Lei, Stan Z. Li, Conghui He, Shuicheng Yan, Cheng Tan

Abstract: The construction of World Models capable of learning, simulating, and reasoning about objective physical laws constitutes a foundational challenge in the pursuit of Artificial General Intelligence. Recent advancements represented by video generation models like Sora have demonstrated the potential of data-driven scaling laws to approximate physical dynamics, while the emerging Unified Multimodal M… ▽ More The construction of World Models capable of learning, simulating, and reasoning about objective physical laws constitutes a foundational challenge in the pursuit of Artificial General Intelligence. Recent advancements represented by video generation models like Sora have demonstrated the potential of data-driven scaling laws to approximate physical dynamics, while the emerging Unified Multimodal Model (UMM) offers a promising architectural paradigm for integrating perception, language, and reasoning. Despite these advances, the field still lacks a principled theoretical framework that defines the essential properties requisite for a General World Model. In this paper, we propose that a World Model must be grounded in the Trinity of Consistency: Modal Consistency as the semantic interface, Spatial Consistency as the geometric basis, and Temporal Consistency as the causal engine. Through this tripartite lens, we systematically review the evolution of multimodal learning, revealing a trajectory from loosely coupled specialized modules toward unified architectures that enable the synergistic emergence of internal world simulators. To complement this conceptual framework, we introduce CoW-Bench, a benchmark centered on multi-frame reasoning and generation scenarios. CoW-Bench evaluates both video generation models and UMMs under a unified evaluation protocol. Our work establishes a principled pathway toward general world models, clarifying both the limitations of current systems and the architectural requirements for future progress. △ Less

Submitted 26 February, 2026; originally announced February 2026.

Comments: 119 pages, 50 figures

VecFormer: Towards Efficient and Generalizable Graph Transformer with Graph Token Attention

Authors: Jingbo Zhou, Jun Xia, Siyuan Li, Yunfan Liu, Wenjun Wang, Yufei Huang, Changxi Chi, Mutian Hong, Zhuoli Ouyang, Shu Wang, Zhongqi Wang, Xingyu Wu, Chang Yu, Stan Z. Li

Abstract: Graph Transformer has demonstrated impressive capabilities in the field of graph representation learning. However, existing approaches face two critical challenges: (1) most models suffer from exponentially increasing computational complexity, making it difficult to scale to large graphs; (2) attention mechanisms based on node-level operations limit the flexibility of the model and result in poor… ▽ More Graph Transformer has demonstrated impressive capabilities in the field of graph representation learning. However, existing approaches face two critical challenges: (1) most models suffer from exponentially increasing computational complexity, making it difficult to scale to large graphs; (2) attention mechanisms based on node-level operations limit the flexibility of the model and result in poor generalization performance in out-of-distribution (OOD) scenarios. To address these issues, we propose \textbf{VecFormer} (the \textbf{Vec}tor Quantized Graph Trans\textbf{former}), an efficient and highly generalizable model for node classification, particularly under OOD settings. VecFormer adopts a two-stage training paradigm. In the first stage, two codebooks are used to reconstruct the node features and the graph structure, aiming to learn the rich semantic \texttt{Graph Codes}. In the second stage, attention mechanisms are performed at the \texttt{Graph Token} level based on the transformed cross codebook, reducing computational complexity while enhancing the model's generalization capability. Extensive experiments on datasets of various sizes demonstrate that VecFormer outperforms the existing Graph Transformer in both performance and speed. △ Less

Submitted 23 February, 2026; originally announced February 2026.

Dynamics-inspired Structure Hallucination for Protein-protein Interaction Modeling

Authors: Fang Wu, Stan Z. Li

Abstract: Protein-protein interaction (PPI) represents a central challenge within the biology field, and accurately predicting the consequences of mutations in this context is crucial for drug design and protein engineering. Deep learning (DL) has shown promise in forecasting the effects of such mutations, but is hindered by two primary constraints. First, the structures of mutant proteins are often elusive… ▽ More Protein-protein interaction (PPI) represents a central challenge within the biology field, and accurately predicting the consequences of mutations in this context is crucial for drug design and protein engineering. Deep learning (DL) has shown promise in forecasting the effects of such mutations, but is hindered by two primary constraints. First, the structures of mutant proteins are often elusive to acquire. Secondly, PPI takes place dynamically, which is rarely integrated into the DL architecture design. To address these obstacles, we present a novel framework named Refine-PPI with two key enhancements. First, we introduce a structure refinement module trained by a mask mutation modeling (MMM) task on available wild-type structures, which is then transferred to produce the inaccessible mutant structures. Second, we employ a new kind of geometric network, called the probability density cloud network (PDC-Net), to capture 3D dynamic variations and encode the atomic uncertainty associated with PPI. Comprehensive experiments on SKEMPI.v2 substantiate the superiority of Refine-PPI over all existing tools for predicting free energy change. These findings underscore the effectiveness of our hallucination strategy and the PDC module in addressing the absence of mutant protein structure and modeling geometric uncertainty. △ Less

Submitted 8 January, 2026; originally announced January 2026.

Journal ref: Transactions on Machine Learning Research 2025

On the Design of One-step Diffusion via Shortcutting Flow Paths

Authors: Haitao Lin, Peiyan Hu, Minsi Ren, Zhifeng Gao, Zhi-Ming Ma, Guolin ke, Tailin Wu, Stan Z. Li

Abstract: Recent advances in few-step diffusion models have demonstrated their efficiency and effectiveness by shortcutting the probabilistic paths of diffusion models, especially in training one-step diffusion models from scratch (\emph{a.k.a.} shortcut models). However, their theoretical derivation and practical implementation are often closely coupled, which obscures the design space. To address this, we… ▽ More Recent advances in few-step diffusion models have demonstrated their efficiency and effectiveness by shortcutting the probabilistic paths of diffusion models, especially in training one-step diffusion models from scratch (\emph{a.k.a.} shortcut models). However, their theoretical derivation and practical implementation are often closely coupled, which obscures the design space. To address this, we propose a common design framework for representative shortcut models. This framework provides theoretical justification for their validity and disentangles concrete component-level choices, thereby enabling systematic identification of improvements. With our proposed improvements, the resulting one-step model achieves a new state-of-the-art FID50k of 2.85 on ImageNet-256x256 under the classifier-free guidance setting with one step generation, and further reaches FID50k of 2.53 with 2x training steps. Remarkably, the model requires no pre-training, distillation, or curriculum learning. We believe our work lowers the barrier to component-level innovation in shortcut models and facilitates principled exploration of their design space. △ Less

Submitted 1 February, 2026; v1 submitted 3 December, 2025; originally announced December 2025.

Comments: 10 pages of main body, conference paper

Learning Cell-Aware Hierarchical Multi-Modal Representations for Robust Molecular Modeling

Authors: Mengran Li, Zelin Zang, Wenbin Xing, Junzhou Chen, Ronghui Zhang, Jiebo Luo, Stan Z. Li

Abstract: Understanding how chemical perturbations propagate through biological systems is essential for robust molecular property prediction. While most existing methods focus on chemical structures alone, recent advances highlight the crucial role of cellular responses such as morphology and gene expression in shaping drug effects. However, current cell-aware approaches face two key limitations: (1) modal… ▽ More Understanding how chemical perturbations propagate through biological systems is essential for robust molecular property prediction. While most existing methods focus on chemical structures alone, recent advances highlight the crucial role of cellular responses such as morphology and gene expression in shaping drug effects. However, current cell-aware approaches face two key limitations: (1) modality incompleteness in external biological data, and (2) insufficient modeling of hierarchical dependencies across molecular, cellular, and genomic levels. We propose CHMR (Cell-aware Hierarchical Multi-modal Representations), a robust framework that jointly models local-global dependencies between molecules and cellular responses and captures latent biological hierarchies via a novel tree-structured vector quantization module. Evaluated on nine public benchmarks spanning 728 tasks, CHMR outperforms state-of-the-art baselines, yielding average improvements of 3.6% on classification and 17.2% on regression tasks. These results demonstrate the advantage of hierarchy-aware, multimodal learning for reliable and biologically grounded molecular representations, offering a generalizable framework for integrative biomedical modeling. The code is in https://github.com/limengran98/CHMR. △ Less

Submitted 26 November, 2025; originally announced November 2025.

Comments: Accepted to AAAI 2026 (Oral)

MergeDNA: Context-aware Genome Modeling with Dynamic Tokenization through Token Merging

Authors: Siyuan Li, Kai Yu, Anna Wang, Zicheng Liu, Chang Yu, Jingbo Zhou, Qirong Yang, Yucheng Guo, Xiaoming Zhang, Stan Z. Li

Abstract: Modeling genomic sequences faces two unsolved challenges: the information density varies widely across different regions, while there is no clearly defined minimum vocabulary unit. Relying on either four primitive bases or independently designed DNA tokenizers, existing approaches with naive masked language modeling pre-training often fail to adapt to the varying complexities of genomic sequences.… ▽ More Modeling genomic sequences faces two unsolved challenges: the information density varies widely across different regions, while there is no clearly defined minimum vocabulary unit. Relying on either four primitive bases or independently designed DNA tokenizers, existing approaches with naive masked language modeling pre-training often fail to adapt to the varying complexities of genomic sequences. Leveraging Token Merging techniques, this paper introduces a hierarchical architecture that jointly optimizes a dynamic genomic tokenizer and latent Transformers with context-aware pre-training tasks. As for network structures, the tokenization module automatically chunks adjacent bases into words by stacking multiple layers of the differentiable token merging blocks with local-window constraints, then a Latent Encoder captures the global context of these merged words by full-attention blocks. Symmetrically employing a Latent Decoder and a Local Decoder, MergeDNA learns with two pre-training tasks: Merged Token Reconstruction simultaneously trains the dynamic tokenization module and adaptively filters important tokens, while Adaptive Masked Token Modeling learns to predict these filtered tokens to capture informative contents. Extensive experiments show that MergeDNA achieves superior performance on three popular DNA benchmarks and several multi-omics tasks with fine-tuning or zero-shot evaluation, outperforming typical tokenization methods and large-scale DNA foundation models. △ Less

Submitted 17 November, 2025; originally announced November 2025.

Comments: AAAI 2026 (Oral Presentation) Preprint

Departures: Distributional Transport for Single-Cell Perturbation Prediction with Neural Schrödinger Bridges

Authors: Changxi Chi, Yufei Huang, Jun Xia, Jiangbin Zheng, Yunfan Liu, Zelin Zang, Stan Z. Li

Abstract: Predicting single-cell perturbation outcomes directly advances gene function analysis and facilitates drug candidate selection, making it a key driver of both basic and translational biomedical research. However, a major bottleneck in this task is the unpaired nature of single-cell data, as the same cell cannot be observed both before and after perturbation due to the destructive nature of sequenc… ▽ More Predicting single-cell perturbation outcomes directly advances gene function analysis and facilitates drug candidate selection, making it a key driver of both basic and translational biomedical research. However, a major bottleneck in this task is the unpaired nature of single-cell data, as the same cell cannot be observed both before and after perturbation due to the destructive nature of sequencing. Although some neural generative transport models attempt to tackle unpaired single-cell perturbation data, they either lack explicit conditioning or depend on prior spaces for indirect distribution alignment, limiting precise perturbation modeling. In this work, we approximate Schrödinger Bridge (SB), which defines stochastic dynamic mappings recovering the entropy-regularized optimal transport (OT), to directly align the distributions of control and perturbed single-cell populations across different perturbation conditions. Unlike prior SB approximations that rely on bidirectional modeling to infer optimal source-target sample coupling, we leverage Minibatch-OT based pairing to avoid such bidirectional inference and the associated ill-posedness of defining the reverse process. This pairing directly guides bridge learning, yielding a scalable approximation to the SB. We approximate two SB models, one modeling discrete gene activation states and the other continuous expression distributions. Joint training enables accurate perturbation modeling and captures single-cell heterogeneity. Experiments on public genetic and drug perturbation datasets show that our model effectively captures heterogeneous single-cell responses and achieves state-of-the-art performance. △ Less

Submitted 17 November, 2025; originally announced November 2025.

Multimodal Regression for Enzyme Turnover Rates Prediction

Authors: Bozhen Hu, Cheng Tan, Siyuan Li, Jiangbin Zheng, Sizhe Qiu, Jun Xia, Stan Z. Li

Abstract: The enzyme turnover rate is a fundamental parameter in enzyme kinetics, reflecting the catalytic efficiency of enzymes. However, enzyme turnover rates remain scarce across most organisms due to the high cost and complexity of experimental measurements. To address this gap, we propose a multimodal framework for predicting the enzyme turnover rate by integrating enzyme sequences, substrate structure… ▽ More The enzyme turnover rate is a fundamental parameter in enzyme kinetics, reflecting the catalytic efficiency of enzymes. However, enzyme turnover rates remain scarce across most organisms due to the high cost and complexity of experimental measurements. To address this gap, we propose a multimodal framework for predicting the enzyme turnover rate by integrating enzyme sequences, substrate structures, and environmental factors. Our model combines a pre-trained language model and a convolutional neural network to extract features from protein sequences, while a graph neural network captures informative representations from substrate molecules. An attention mechanism is incorporated to enhance interactions between enzyme and substrate representations. Furthermore, we leverage symbolic regression via Kolmogorov-Arnold Networks to explicitly learn mathematical formulas that govern the enzyme turnover rate, enabling interpretable and accurate predictions. Extensive experiments demonstrate that our framework outperforms both traditional and state-of-the-art deep learning approaches. This work provides a robust tool for studying enzyme kinetics and holds promise for applications in enzyme engineering, biotechnology, and industrial biocatalysis. △ Less

Submitted 15 September, 2025; originally announced September 2025.

Comments: 9 pages, 5 figures. This paper was withdrawn from the IJCAI 2025 proceedings due to the lack of participation in the conference and presentation

SketchAgent: Generating Structured Diagrams from Hand-Drawn Sketches

Authors: Cheng Tan, Qi Chen, Jingxuan Wei, Gaowei Wu, Zhangyang Gao, Siyuan Li, Bihui Yu, Ruifeng Guo, Stan Z. Li

Abstract: Hand-drawn sketches are a natural and efficient medium for capturing and conveying ideas. Despite significant advancements in controllable natural image generation, translating freehand sketches into structured, machine-readable diagrams remains a labor-intensive and predominantly manual task. The primary challenge stems from the inherent ambiguity of sketches, which lack the structural constraint… ▽ More Hand-drawn sketches are a natural and efficient medium for capturing and conveying ideas. Despite significant advancements in controllable natural image generation, translating freehand sketches into structured, machine-readable diagrams remains a labor-intensive and predominantly manual task. The primary challenge stems from the inherent ambiguity of sketches, which lack the structural constraints and semantic precision required for automated diagram generation. To address this challenge, we introduce SketchAgent, a multi-agent system designed to automate the transformation of hand-drawn sketches into structured diagrams. SketchAgent integrates sketch recognition, symbolic reasoning, and iterative validation to produce semantically coherent and structurally accurate diagrams, significantly reducing the need for manual effort. To evaluate the effectiveness of our approach, we propose the Sketch2Diagram Benchmark, a comprehensive dataset and evaluation framework encompassing eight diverse diagram categories, such as flowcharts, directed graphs, and model architectures. The dataset comprises over 6,000 high-quality examples with token-level annotations, standardized preprocessing, and rigorous quality control. By streamlining the diagram generation process, SketchAgent holds great promise for applications in design, education, and engineering, while offering a significant step toward bridging the gap between intuitive sketching and machine-readable diagram generation. The benchmark is released at https://huggingface.co/datasets/DiagramAgent/Sketch2Diagram-Benchmark. △ Less

Submitted 2 August, 2025; originally announced August 2025.

Comments: Accepted by IJCAI 2025

TrinityDNA: A Bio-Inspired Foundational Model for Efficient Long-Sequence DNA Modeling

Authors: Qirong Yang, Yucheng Guo, Zicheng Liu, Yujie Yang, Qijin Yin, Siyuan Li, Shaomin Ji, Linlin Chao, Xiaoming Zhang, Stan Z. Li

Abstract: The modeling of genomic sequences presents unique challenges due to their length and structural complexity. Traditional sequence models struggle to capture long-range dependencies and biological features inherent in DNA. In this work, we propose TrinityDNA, a novel DNA foundational model designed to address these challenges. The model integrates biologically informed components, including Groove F… ▽ More The modeling of genomic sequences presents unique challenges due to their length and structural complexity. Traditional sequence models struggle to capture long-range dependencies and biological features inherent in DNA. In this work, we propose TrinityDNA, a novel DNA foundational model designed to address these challenges. The model integrates biologically informed components, including Groove Fusion for capturing DNA's structural features and Gated Reverse Complement (GRC) to handle the inherent symmetry of DNA sequences. Additionally, we introduce a multi-scale attention mechanism that allows the model to attend to varying levels of sequence dependencies, and an evolutionary training strategy that progressively adapts the model to both prokaryotic and eukaryotic genomes. TrinityDNA provides a more accurate and efficient approach to genomic sequence modeling, offering significant improvements in gene function prediction, regulatory mechanism discovery, and other genomics applications. Our model bridges the gap between machine learning techniques and biological insights, paving the way for more effective analysis of genomic data. Additionally, we introduced a new DNA long-sequence CDS annotation benchmark to make evaluations more comprehensive and oriented toward practical applications. △ Less

Submitted 6 March, 2026; v1 submitted 25 July, 2025; originally announced July 2025.

Comments: AAAI 2026

PRING: Rethinking Protein-Protein Interaction Prediction from Pairs to Graphs

Authors: Xinzhe Zheng, Hao Du, Fanding Xu, Jinzhe Li, Zhiyuan Liu, Wenkang Wang, Tao Chen, Wanli Ouyang, Stan Z. Li, Yan Lu, Nanqing Dong, Yang Zhang

Abstract: Deep learning-based computational methods have achieved promising results in predicting protein-protein interactions (PPIs). However, existing benchmarks predominantly focus on isolated pairwise evaluations, overlooking a model's capability to reconstruct biologically meaningful PPI networks, which is crucial for biology research. To address this gap, we introduce PRING, the first comprehensive be… ▽ More Deep learning-based computational methods have achieved promising results in predicting protein-protein interactions (PPIs). However, existing benchmarks predominantly focus on isolated pairwise evaluations, overlooking a model's capability to reconstruct biologically meaningful PPI networks, which is crucial for biology research. To address this gap, we introduce PRING, the first comprehensive benchmark that evaluates protein-protein interaction prediction from a graph-level perspective. PRING curates a high-quality, multi-species PPI network dataset comprising 21,484 proteins and 186,818 interactions, with well-designed strategies to address both data redundancy and leakage. Building on this golden-standard dataset, we establish two complementary evaluation paradigms: (1) topology-oriented tasks, which assess intra and cross-species PPI network construction, and (2) function-oriented tasks, including protein complex pathway prediction, GO module analysis, and essential protein justification. These evaluations not only reflect the model's capability to understand the network topology but also facilitate protein function annotation, biological module detection, and even disease mechanism analysis. Extensive experiments on four representative model categories, consisting of sequence similarity-based, naive sequence-based, protein language model-based, and structure-based approaches, demonstrate that current PPI models have potential limitations in recovering both structural and functional properties of PPI networks, highlighting the gap in supporting real-world biological applications. We believe PRING provides a reliable platform to guide the development of more effective PPI prediction models for the community. The dataset and source code of PRING are available at https://github.com/SophieSarceau/PRING. △ Less

Submitted 22 October, 2025; v1 submitted 7 July, 2025; originally announced July 2025.

HDTree: Generative Modeling of Cellular Hierarchies for Robust Lineage Inference

Authors: Zelin Zang, WenZhe Li, Yongjie Xu, Chang Yu, Changxi Chi, Jingbo Zhou, Zhen Lei, Stan Z. Li

Abstract: In single-cell research, tracing and analyzing high-throughput single-cell differentiation trajectories is crucial for understanding biological processes. Key to this is the robust modeling of hierarchical structures that govern cellular development. Traditional methods face limitations in computational cost, performance, and stability. VAE-based approaches have made strides but still require bran… ▽ More In single-cell research, tracing and analyzing high-throughput single-cell differentiation trajectories is crucial for understanding biological processes. Key to this is the robust modeling of hierarchical structures that govern cellular development. Traditional methods face limitations in computational cost, performance, and stability. VAE-based approaches have made strides but still require branch-specific network modules, limiting their scalability and stability, while often suffering from posterior collapse. To overcome these challenges, we introduce HDTree, a generative modeling framework designed for robust lineage inference. HDTree captures tree relationships within a hierarchical latent space using a unified hierarchical codebook and employs a quantized diffusion process to model continuous cell state transitions. By aligning the generative process with the Waddington landscape, this method not only improves stability and scalability but also enhances the biological plausibility of inferred lineages. HDTree's effectiveness is demonstrated through comparisons on both general-purpose and single-cell datasets, where it outperforms existing methods in lineage inference accuracy, reconstruction quality, and hierarchical consistency. These contributions enable accurate and efficient modeling of cellular differentiation paths, offering reliable insights for biological discovery.\footnote{Code is available at https://github.com/zangzelin/code\_HDTree\_icml. △ Less

Submitted 18 May, 2026; v1 submitted 29 June, 2025; originally announced June 2025.

Comments: accepted by ICML26

Doloris: Dual Conditional Diffusion Implicit Bridges with Sparsity Masking Strategy for Unpaired Single-Cell Perturbation Estimation

Authors: Changxi Chi, Jun Xia, Yufei Huang, Zhuoli Ouyang, Cheng Tan, Yunfan Liu, Jingbo Zhou, Chang Yu, Liangyu Yuan, Siyuan Li, Zelin Zang, Stan Z. Li

Abstract: Estimating single-cell responses across various perturbations facilitates the identification of key genes and enhances drug screening, significantly boosting experimental efficiency. However, single-cell sequencing is a destructive process, making it impossible to capture the same cell's phenotype before and after perturbation. Consequently, data collected under perturbed and unperturbed condition… ▽ More Estimating single-cell responses across various perturbations facilitates the identification of key genes and enhances drug screening, significantly boosting experimental efficiency. However, single-cell sequencing is a destructive process, making it impossible to capture the same cell's phenotype before and after perturbation. Consequently, data collected under perturbed and unperturbed conditions are inherently unpaired, creating a critical yet unresolved problem in single-cell perturbation modeling. Moreover, the high dimensionality and sparsity of single-cell expression make direct modeling prone to focusing on zeros and neglecting meaningful patterns. To address these problems, we propose a new paradigm for single-cell perturbation modeling. Specifically, we leverage dual diffusion models to learn the control and perturbed distributions separately, and implicitly align them through a shared Gaussian latent space, without requiring explicit cell pairing. Furthermore, we introduce a sparsity masking strategy in which the mask model learns to predict zero-expressed genes, allowing the diffusion model to focus on capturing meaningful patterns among expressed genes and thereby preserving diversity in high-dimensional sparse data. We introduce \textbf{Doloris}, a generative framework that defines a new paradigm for modeling unpaired, high-dimensional, and sparse single-cell perturbation data. It leverages dual conditional diffusion models for separate learning of control and perturbed distributions, complemented by a sparsity masking strategy to enhance prediction of zero-valued genes. The results on publicly available datasets show that our model effectively captures the diversity of single-cell perturbations and achieves state-of-the-art performance. To facilitate reproducibility, we include the code in the supplementary materials. △ Less

Submitted 26 April, 2026; v1 submitted 26 June, 2025; originally announced June 2025.

PFMBench: Protein Foundation Model Benchmark

Authors: Zhangyang Gao, Hao Wang, Cheng Tan, Chenrui Xu, Mengdi Liu, Bozhen Hu, Linlin Chao, Xiaoming Zhang, Stan Z. Li

Abstract: This study investigates the current landscape and future directions of protein foundation model research. While recent advancements have transformed protein science and engineering, the field lacks a comprehensive benchmark for fair evaluation and in-depth understanding. Since ESM-1B, numerous protein foundation models have emerged, each with unique datasets and methodologies. However, evaluations… ▽ More This study investigates the current landscape and future directions of protein foundation model research. While recent advancements have transformed protein science and engineering, the field lacks a comprehensive benchmark for fair evaluation and in-depth understanding. Since ESM-1B, numerous protein foundation models have emerged, each with unique datasets and methodologies. However, evaluations often focus on limited tasks tailored to specific models, hindering insights into broader generalization and limitations. Specifically, researchers struggle to understand the relationships between tasks, assess how well current models perform across them, and determine the criteria in developing new foundation models. To fill this gap, we present PFMBench, a comprehensive benchmark evaluating protein foundation models across 38 tasks spanning 8 key areas of protein science. Through hundreds of experiments on 17 state-of-the-art models across 38 tasks, PFMBench reveals the inherent correlations between tasks, identifies top-performing models, and provides a streamlined evaluation protocol. Code is available at \href{https://github.com/biomap-research/PFMBench}{\textcolor{blue}{GitHub}}. △ Less

Submitted 1 June, 2025; originally announced June 2025.

AlphaFold Database Debiasing for Robust Inverse Folding

Authors: Cheng Tan, Zhenxiao Cao, Zhangyang Gao, Siyuan Li, Yufei Huang, Stan Z. Li

Abstract: The AlphaFold Protein Structure Database (AFDB) offers unparalleled structural coverage at near-experimental accuracy, positioning it as a valuable resource for data-driven protein design. However, its direct use in training deep models that are sensitive to fine-grained atomic geometry, such as inverse folding, exposes a critical limitation. Comparative analysis of structural feature distribution… ▽ More The AlphaFold Protein Structure Database (AFDB) offers unparalleled structural coverage at near-experimental accuracy, positioning it as a valuable resource for data-driven protein design. However, its direct use in training deep models that are sensitive to fine-grained atomic geometry, such as inverse folding, exposes a critical limitation. Comparative analysis of structural feature distributions reveals that AFDB structures exhibit distinct statistical regularities, reflecting a systematic geometric bias that deviates from the conformational diversity found in experimentally determined structures from the Protein Data Bank (PDB). While AFDB structures are cleaner and more idealized, PDB structures capture the intrinsic variability and physical realism essential for generalization in downstream tasks. To address this discrepancy, we introduce a Debiasing Structure AutoEncoder (DeSAE) that learns to reconstruct native-like conformations from intentionally corrupted backbone geometries. By training the model to recover plausible structural states, DeSAE implicitly captures a more robust and natural structural manifold. At inference, applying DeSAE to AFDB structures produces debiased structures that significantly improve inverse folding performance across multiple benchmarks. This work highlights the critical impact of subtle systematic biases in predicted structures and presents a principled framework for debiasing, significantly boosting the performance of structure-based learning tasks like inverse folding. △ Less

Submitted 9 June, 2025; originally announced June 2025.

Comments: Under review

Tokenizing Electron Cloud in Protein-Ligand Interaction Learning

Authors: Haitao Lin, Odin Zhang, Jia Xu, Yunfan Liu, Zheng Cheng, Lirong Wu, Yufei Huang, Zhifeng Gao, Stan Z. Li

Abstract: The affinity and specificity of protein-molecule binding directly impact functional outcomes, uncovering the mechanisms underlying biological regulation and signal transduction. Most deep-learning-based prediction approaches focus on structures of atoms or fragments. However, quantum chemical properties, such as electronic structures, are the key to unveiling interaction patterns but remain largel… ▽ More The affinity and specificity of protein-molecule binding directly impact functional outcomes, uncovering the mechanisms underlying biological regulation and signal transduction. Most deep-learning-based prediction approaches focus on structures of atoms or fragments. However, quantum chemical properties, such as electronic structures, are the key to unveiling interaction patterns but remain largely underexplored. To bridge this gap, we propose ECBind, a method for tokenizing electron cloud signals into quantized embeddings, enabling their integration into downstream tasks such as binding affinity prediction. By incorporating electron densities, ECBind helps uncover binding modes that cannot be fully represented by atom-level models. Specifically, to remove the redundancy inherent in electron cloud signals, a structure-aware transformer and hierarchical codebooks encode 3D binding sites enriched with electron structures into tokens. These tokenized codes are then used for specific tasks with labels. To extend its applicability to a wider range of scenarios, we utilize knowledge distillation to develop an electron-cloud-agnostic prediction model. Experimentally, ECBind demonstrates state-of-the-art performance across multiple tasks, achieving improvements of 6.42\% and 15.58\% in per-structure Pearson and Spearman correlation coefficients, respectively. △ Less

Submitted 31 May, 2025; v1 submitted 25 May, 2025; originally announced May 2025.

Comments: conference paper

GRAPE: Heterogeneous Graph Representation Learning for Genetic Perturbation with Coding and Non-Coding Biotype

Authors: Changxi Chi, Jun Xia, Jingbo Zhou, Jiabei Cheng, Chang Yu, Stan Z. Li

Abstract: Predicting genetic perturbations enables the identification of potentially crucial genes prior to wet-lab experiments, significantly improving overall experimental efficiency. Since genes are the foundation of cellular life, building gene regulatory networks (GRN) is essential to understand and predict the effects of genetic perturbations. However, current methods fail to fully leverage gene-relat… ▽ More Predicting genetic perturbations enables the identification of potentially crucial genes prior to wet-lab experiments, significantly improving overall experimental efficiency. Since genes are the foundation of cellular life, building gene regulatory networks (GRN) is essential to understand and predict the effects of genetic perturbations. However, current methods fail to fully leverage gene-related information, and solely rely on simple evaluation metrics to construct coarse-grained GRN. More importantly, they ignore functional differences between biotypes, limiting the ability to capture potential gene interactions. In this work, we leverage pre-trained large language model and DNA sequence model to extract features from gene descriptions and DNA sequence data, respectively, which serve as the initialization for gene representations. Additionally, we introduce gene biotype information for the first time in genetic perturbation, simulating the distinct roles of genes with different biotypes in regulating cellular processes, while capturing implicit gene relationships through graph structure learning (GSL). We propose GRAPE, a heterogeneous graph neural network (HGNN) that leverages gene representations initialized with features from descriptions and sequences, models the distinct roles of genes with different biotypes, and dynamically refines the GRN through GSL. The results on publicly available datasets show that our method achieves state-of-the-art performance. △ Less

Submitted 5 May, 2025; originally announced May 2025.

Adversarial Curriculum Graph-Free Knowledge Distillation for Graph Neural Networks

Authors: Yuang Jia, Xiaojuan Shan, Jun Xia, Guancheng Wan, Yuchen Zhang, Wenke Huang, Mang Ye, Stan Z. Li

Abstract: Data-free Knowledge Distillation (DFKD) is a method that constructs pseudo-samples using a generator without real data, and transfers knowledge from a teacher model to a student by enforcing the student to overcome dimensional differences and learn to mimic the teacher's outputs on these pseudo-samples. In recent years, various studies in the vision domain have made notable advancements in this ar… ▽ More Data-free Knowledge Distillation (DFKD) is a method that constructs pseudo-samples using a generator without real data, and transfers knowledge from a teacher model to a student by enforcing the student to overcome dimensional differences and learn to mimic the teacher's outputs on these pseudo-samples. In recent years, various studies in the vision domain have made notable advancements in this area. However, the varying topological structures and non-grid nature of graph data render the methods from the vision domain ineffective. Building upon prior research into differentiable methods for graph neural networks, we propose a fast and high-quality data-free knowledge distillation approach in this paper. Without compromising distillation quality, the proposed graph-free KD method (ACGKD) significantly reduces the spatial complexity of pseudo-graphs by leveraging the Binary Concrete distribution to model the graph structure and introducing a spatial complexity tuning parameter. This approach enables efficient gradient computation for the graph structure, thereby accelerating the overall distillation process. Additionally, ACGKD eliminates the dimensional ambiguity between the student and teacher models by increasing the student's dimensions and reusing the teacher's classifier. Moreover, it equips graph knowledge distillation with a CL-based strategy to ensure the student learns graph structures progressively. Extensive experiments demonstrate that ACGKD achieves state-of-the-art performance in distilling knowledge from GNNs without training data. △ Less

Submitted 2 April, 2025; v1 submitted 1 April, 2025; originally announced April 2025.

Efficient Inference for Large Reasoning Models: A Survey

Authors: Yue Liu, Jiaying Wu, Yufei He, Ruihan Gong, Jun Xia, Liang Li, Hongcheng Gao, Hongyu Chen, Baolong Bi, Jiaheng Zhang, Zhiqi Huang, Bryan Hooi, Stan Z. Li, Keqin Li

Abstract: Large Reasoning Models (LRMs) significantly improve the reasoning ability of Large Language Models (LLMs) by learning to reason, exhibiting promising performance in solving complex tasks. However, their deliberative reasoning process leads to inefficiencies in token usage, memory consumption, and inference time. Thus, this survey provides a review of efficient inference methods designed specifical… ▽ More Large Reasoning Models (LRMs) significantly improve the reasoning ability of Large Language Models (LLMs) by learning to reason, exhibiting promising performance in solving complex tasks. However, their deliberative reasoning process leads to inefficiencies in token usage, memory consumption, and inference time. Thus, this survey provides a review of efficient inference methods designed specifically for LRMs, focusing on mitigating token inefficiency while preserving the reasoning quality. The overview structure of this paper is shown in Figure~\ref{fig:paper_structure}. First, we introduce a taxonomy to group the recent methods into two main categories: (a) explicit compact Chain-of-Thought (CoT), which reduces tokens while keeping the explicit reasoning structure, and (b) implicit latent CoT, which encodes reasoning steps within hidden representations instead of explicit tokens. Meanwhile, we discuss their strengths and weaknesses. Then, we conduct empirical analyses on existing methods from reasoning scenarios, object functions, and performance \& efficiency aspects. Besides, we present open challenges in this field, including human-centric controllable reasoning, trade-off between interpretability and efficiency of reasoning, ensuring the safety of efficient reasoning, and broader applications of efficient reasoning. In addition, we highlight key insights for enhancing LRMs' inference efficiency via techniques such as model merging, new architectures, and agent routers. We hope this work serves as a valuable guide, helping researchers overcome challenges in this vibrant field. A collection of efficient reasoning methods for LRMs (papers and codes) is provided at this link: https://github.com/yueliu1999/Awesome-Efficient-Inference-for-LRMs. △ Less

Submitted 13 August, 2025; v1 submitted 29 March, 2025; originally announced March 2025.

dyAb: Flow Matching for Flexible Antibody Design with AlphaFold-driven Pre-binding Antigen

Authors: Cheng Tan, Yijie Zhang, Zhangyang Gao, Yufei Huang, Haitao Lin, Lirong Wu, Fandi Wu, Mathieu Blanchette, Stan. Z. Li

Abstract: The development of therapeutic antibodies heavily relies on accurate predictions of how antigens will interact with antibodies. Existing computational methods in antibody design often overlook crucial conformational changes that antigens undergo during the binding process, significantly impacting the reliability of the resulting antibodies. To bridge this gap, we introduce dyAb, a flexible framewo… ▽ More The development of therapeutic antibodies heavily relies on accurate predictions of how antigens will interact with antibodies. Existing computational methods in antibody design often overlook crucial conformational changes that antigens undergo during the binding process, significantly impacting the reliability of the resulting antibodies. To bridge this gap, we introduce dyAb, a flexible framework that incorporates AlphaFold2-driven predictions to model pre-binding antigen structures and specifically addresses the dynamic nature of antigen conformation changes. Our dyAb model leverages a unique combination of coarse-grained interface alignment and fine-grained flow matching techniques to simulate the interaction dynamics and structural evolution of the antigen-antibody complex, providing a realistic representation of the binding process. Extensive experiments show that dyAb significantly outperforms existing models in antibody design involving changing antigen conformations. These results highlight dyAb's potential to streamline the design process for therapeutic antibodies, promising more efficient development cycles and improved outcomes in clinical applications. △ Less

Submitted 28 February, 2025; originally announced March 2025.

Comments: AAAI 2025 Oral

Life-Code: Central Dogma Modeling with Multi-Omics Sequence Unification

Authors: Zicheng Liu, Siyuan Li, Zhiyuan Chen, Chang Yu, Qirong Yang, Yucheng Guo, Yujie Yang, Xiaoming Zhang, Stan Z. Li

Abstract: The interactions between DNA, RNA, and proteins are fundamental to biological processes, as illustrated by the central dogma of molecular biology. Although modern biological pre-trained models have achieved great success in analyzing these macromolecules individually, their interconnected nature remains underexplored. This paper follows the guidance of the central dogma to redesign both the data a… ▽ More The interactions between DNA, RNA, and proteins are fundamental to biological processes, as illustrated by the central dogma of molecular biology. Although modern biological pre-trained models have achieved great success in analyzing these macromolecules individually, their interconnected nature remains underexplored. This paper follows the guidance of the central dogma to redesign both the data and model pipeline and offers a comprehensive framework, Life-Code, that spans different biological functions. As for data flow, we propose a unified pipeline to integrate multi-omics data by reverse-transcribing RNA and reverse-translating amino acids into nucleotide-based sequences. As for the model, we design a codon tokenizer and a hybrid long-sequence architecture to encode the interactions between coding and non-coding regions through masked modeling pre-training. To model the translation and folding process with coding sequences, Life-Code learns protein structures of the corresponding amino acids by knowledge distillation from off-the-shelf protein language models. Such designs enable Life-Code to capture complex interactions within genetic sequences, providing a more comprehensive understanding of multi-omics with the central dogma. Extensive experiments show that Life-Code achieves state-of-the-art results on various tasks across three omics, highlighting its potential for advancing multi-omics analysis and interpretation. △ Less

Submitted 29 November, 2025; v1 submitted 11 February, 2025; originally announced February 2025.

Comments: Preprint V3 (10 pages main text)

A Simple yet Effective DDG Predictor is An Unsupervised Antibody Optimizer and Explainer

Authors: Lirong Wu, Yunfan Liu, Haitao Lin, Yufei Huang, Guojiang Zhao, Zhifeng Gao, Stan Z. Li

Abstract: The proteins that exist today have been optimized over billions of years of natural evolution, during which nature creates random mutations and selects them. The discovery of functionally promising mutations is challenged by the limited evolutionary accessible regions, i.e., only a small region on the fitness landscape is beneficial. There have been numerous priors used to constrain protein evolut… ▽ More The proteins that exist today have been optimized over billions of years of natural evolution, during which nature creates random mutations and selects them. The discovery of functionally promising mutations is challenged by the limited evolutionary accessible regions, i.e., only a small region on the fitness landscape is beneficial. There have been numerous priors used to constrain protein evolution to regions of landscapes with high-fitness variants, among which the change in binding free energy (DDG) of protein complexes upon mutations is one of the most commonly used priors. However, the huge mutation space poses two challenges: (1) how to improve the efficiency of DDG prediction for fast mutation screening; and (2) how to explain mutation preferences and efficiently explore accessible evolutionary regions. To address these challenges, we propose a lightweight DDG predictor (Light-DDG), which adopts a structure-aware Transformer as the backbone and enhances it by knowledge distilled from existing powerful but computationally heavy DDG predictors. Additionally, we augmented, annotated, and released a large-scale dataset containing millions of mutation data for pre-training Light-DDG. We find that such a simple yet effective Light-DDG can serve as a good unsupervised antibody optimizer and explainer. For the target antibody, we propose a novel Mutation Explainer to learn mutation preferences, which accounts for the marginal benefit of each mutation per residue. To further explore accessible evolutionary regions, we conduct preference-guided antibody optimization and evaluate antibody candidates quickly using Light-DDG to identify desirable mutations. △ Less

Submitted 13 February, 2025; v1 submitted 10 February, 2025; originally announced February 2025.

G2PDiffusion: Cross-Species Genotype-to-Phenotype Prediction via Evolutionary Diffusion

Authors: Mengdi Liu, Zhangyang Gao, Hong Chang, Stan Z. Li, Shiguang Shan, Xilin Chen

Abstract: Understanding how genes influence phenotype across species is a fundamental challenge in genetic engineering, which will facilitate advances in various fields such as crop breeding, conservation biology, and personalized medicine. However, current phenotype prediction models are limited to individual species and expensive phenotype labeling process, making the genotype-to-phenotype prediction a hi… ▽ More Understanding how genes influence phenotype across species is a fundamental challenge in genetic engineering, which will facilitate advances in various fields such as crop breeding, conservation biology, and personalized medicine. However, current phenotype prediction models are limited to individual species and expensive phenotype labeling process, making the genotype-to-phenotype prediction a highly domain-dependent and data-scarce problem. To this end, we suggest taking images as morphological proxies, facilitating cross-species generalization through large-scale multimodal pretraining. We propose the first genotype-to-phenotype diffusion model (G2PDiffusion) that generates morphological images from DNA considering two critical evolutionary signals, i.e., multiple sequence alignments (MSA) and environmental contexts. The model contains three novel components: 1) a MSA retrieval engine that identifies conserved and co-evolutionary patterns; 2) an environment-aware MSA conditional encoder that effectively models complex genotype-environment interactions; and 3) an adaptive phenomic alignment module to improve genotype-phenotype consistency. Extensive experiments show that integrating evolutionary signals with environmental context enriches the model's understanding of phenotype variability across species, thereby offering a valuable and promising exploration into advanced AI-assisted genomic analysis. △ Less

Submitted 9 March, 2025; v1 submitted 7 February, 2025; originally announced February 2025.

GuardReasoner: Towards Reasoning-based LLM Safeguards

Authors: Yue Liu, Hongcheng Gao, Shengfang Zhai, Yufei He, Jun Xia, Zhengyu Hu, Yulin Chen, Xihong Yang, Jiaheng Zhang, Stan Z. Li, Hui Xiong, Bryan Hooi

Abstract: As LLMs increasingly impact safety-critical applications, ensuring their safety using guardrails remains a key challenge. This paper proposes GuardReasoner, a new safeguard for LLMs, by guiding the guard model to learn to reason. Concretely, we first create the GuardReasonerTrain dataset, which consists of 127K samples with 460K detailed reasoning steps. Then, we introduce reasoning SFT to unlock… ▽ More As LLMs increasingly impact safety-critical applications, ensuring their safety using guardrails remains a key challenge. This paper proposes GuardReasoner, a new safeguard for LLMs, by guiding the guard model to learn to reason. Concretely, we first create the GuardReasonerTrain dataset, which consists of 127K samples with 460K detailed reasoning steps. Then, we introduce reasoning SFT to unlock the reasoning capability of guard models. In addition, we present hard sample DPO to further strengthen their reasoning ability. In this manner, GuardReasoner achieves better performance, explainability, and generalizability. Extensive experiments and analyses on 13 benchmarks of 3 guardrail tasks demonstrate its superiority. Remarkably, GuardReasoner 8B surpasses GPT-4o+CoT by 5.74% and LLaMA Guard 3 8B by 20.84% F1 score on average. We release the training data, code, and models with different scales (1B, 3B, 8B) of GuardReasoner : https://github.com/yueliu1999/GuardReasoner/. △ Less

Submitted 17 October, 2025; v1 submitted 30 January, 2025; originally announced January 2025.

Comments: 22 pages, 18 figures

Relation-Aware Equivariant Graph Networks for Epitope-Unknown Antibody Design and Specificity Optimization

Authors: Lirong Wu, Haitao Lin, Yufei Huang, Zhangyang Gao, Cheng Tan, Yunfan Liu, Tailin Wu, Stan Z. Li

Abstract: Antibodies are Y-shaped proteins that protect the host by binding to specific antigens, and their binding is mainly determined by the Complementary Determining Regions (CDRs) in the antibody. Despite the great progress made in CDR design, existing computational methods still encounter several challenges: 1) poor capability of modeling complex CDRs with long sequences due to insufficient contextual… ▽ More Antibodies are Y-shaped proteins that protect the host by binding to specific antigens, and their binding is mainly determined by the Complementary Determining Regions (CDRs) in the antibody. Despite the great progress made in CDR design, existing computational methods still encounter several challenges: 1) poor capability of modeling complex CDRs with long sequences due to insufficient contextual information; 2) conditioned on pre-given antigenic epitopes and their static interaction with the target antibody; 3) neglect of specificity during antibody optimization leads to non-specific antibodies. In this paper, we take into account a variety of node features, edge features, and edge relations to include more contextual and geometric information. We propose a novel Relation-Aware Antibody Design (RAAD) framework, which dynamically models antigen-antibody interactions for co-designing the sequences and structures of antigen-specific CDRs. Furthermore, we propose a new evaluation metric to better measure antibody specificity and develop a contrasting specificity-enhancing constraint to optimize the specificity of antibodies. Extensive experiments have demonstrated the superior capability of RAAD in terms of antibody modeling, generation, and optimization across different CDR types, sequence lengths, pre-training strategies, and input contexts. △ Less

Submitted 13 December, 2024; originally announced January 2025.

PhyloGen: Language Model-Enhanced Phylogenetic Inference via Graph Structure Generation

Authors: ChenRui Duan, Zelin Zang, Siyuan Li, Yongjie Xu, Stan Z. Li

Abstract: Phylogenetic trees elucidate evolutionary relationships among species, but phylogenetic inference remains challenging due to the complexity of combining continuous (branch lengths) and discrete parameters (tree topology). Traditional Markov Chain Monte Carlo methods face slow convergence and computational burdens. Existing Variational Inference methods, which require pre-generated topologies and t… ▽ More Phylogenetic trees elucidate evolutionary relationships among species, but phylogenetic inference remains challenging due to the complexity of combining continuous (branch lengths) and discrete parameters (tree topology). Traditional Markov Chain Monte Carlo methods face slow convergence and computational burdens. Existing Variational Inference methods, which require pre-generated topologies and typically treat tree structures and branch lengths independently, may overlook critical sequence features, limiting their accuracy and flexibility. We propose PhyloGen, a novel method leveraging a pre-trained genomic language model to generate and optimize phylogenetic trees without dependence on evolutionary models or aligned sequence constraints. PhyloGen views phylogenetic inference as a conditionally constrained tree structure generation problem, jointly optimizing tree topology and branch lengths through three core modules: (i) Feature Extraction, (ii) PhyloTree Construction, and (iii) PhyloTree Structure Modeling. Meanwhile, we introduce a Scoring Function to guide the model towards a more stable gradient descent. We demonstrate the effectiveness and robustness of PhyloGen on eight real-world benchmark datasets. Visualization results confirm PhyloGen provides deeper insights into phylogenetic relationships. △ Less

Submitted 25 December, 2024; originally announced December 2024.

DapPep: Domain Adaptive Peptide-agnostic Learning for Universal T-cell Receptor-antigen Binding Affinity Prediction

Authors: Jiangbin Zheng, Qianhui Xu, Ruichen Xia, Stan Z. Li

Abstract: Identifying T-cell receptors (TCRs) that interact with antigenic peptides provides the technical basis for developing vaccines and immunotherapies. The emergent deep learning methods excel at learning antigen binding patterns from known TCRs but struggle with novel or sparsely represented antigens. However, binding specificity for unseen antigens or exogenous peptides is critical. We introduce a d… ▽ More Identifying T-cell receptors (TCRs) that interact with antigenic peptides provides the technical basis for developing vaccines and immunotherapies. The emergent deep learning methods excel at learning antigen binding patterns from known TCRs but struggle with novel or sparsely represented antigens. However, binding specificity for unseen antigens or exogenous peptides is critical. We introduce a domain-adaptive peptide-agnostic learning framework DapPep for universal TCR-antigen binding affinity prediction to address this challenge. The lightweight self-attention architecture combines a pre-trained protein language model with an inner-loop self-supervised regime to enable robust TCR-peptide representations. Extensive experiments on various benchmarks demonstrate that DapPep consistently outperforms existing tools, showcasing robust generalization capability, especially for data-scarce settings and unseen peptides. Moreover, DapPep proves effective in challenging clinical tasks such as sorting reactive T cells in tumor neoantigen therapy and identifying key positions in 3D structures. △ Less

Submitted 26 November, 2024; originally announced November 2024.

Pan-protein Design Learning Enables Task-adaptive Generalization for Low-resource Enzyme Design

Authors: Jiangbin Zheng, Ge Wang, Han Zhang, Stan Z. Li

Abstract: Computational protein design (CPD) offers transformative potential for bioengineering, but current deep CPD models, focused on universal domains, struggle with function-specific designs. This work introduces a novel CPD paradigm tailored for functional design tasks, particularly for enzymes-a key protein class often lacking specific application efficiency. To address structural data scarcity, we p… ▽ More Computational protein design (CPD) offers transformative potential for bioengineering, but current deep CPD models, focused on universal domains, struggle with function-specific designs. This work introduces a novel CPD paradigm tailored for functional design tasks, particularly for enzymes-a key protein class often lacking specific application efficiency. To address structural data scarcity, we present CrossDesign, a domain-adaptive framework that leverages pretrained protein language models (PPLMs). By aligning protein structures with sequences, CrossDesign transfers pretrained knowledge to structure models, overcoming the limitations of limited structural data. The framework combines autoregressive (AR) and non-autoregressive (NAR) states in its encoder-decoder architecture, applying it to enzyme datasets and pan-proteins. Experimental results highlight CrossDesign's superior performance and robustness, especially with out-of-domain enzymes. Additionally, the model excels in fitness prediction when tested on large-scale mutation data, showcasing its stability. △ Less

Submitted 26 November, 2024; originally announced November 2024.

Revisiting Marr in Face: The Building of 2D--2.5D--3D Representations in Deep Neural Networks

Authors: Xiangyu Zhu, Chang Yu, Jiankuo Zhao, Zhaoxiang Zhang, Stan Z. Li, Zhen Lei

Abstract: David Marr's seminal theory of vision proposes that the human visual system operates through a sequence of three stages, known as the 2D sketch, the 2.5D sketch, and the 3D model. In recent years, Deep Neural Networks (DNN) have been widely thought to have reached a level comparable to human vision. However, the mechanisms by which DNNs accomplish this and whether they adhere to Marr's 2D--2.5D--3… ▽ More David Marr's seminal theory of vision proposes that the human visual system operates through a sequence of three stages, known as the 2D sketch, the 2.5D sketch, and the 3D model. In recent years, Deep Neural Networks (DNN) have been widely thought to have reached a level comparable to human vision. However, the mechanisms by which DNNs accomplish this and whether they adhere to Marr's 2D--2.5D--3D construction theory remain unexplored. In this paper, we delve into the perception task to explore these questions and find evidence supporting Marr's theory. We introduce a graphics probe, a sub-network crafted to reconstruct the original image from the network's intermediate layers. The key to the graphics probe is its flexible architecture that supports image in both 2D and 3D formats, as well as in a transitional state between them. By injecting graphics probes into neural networks, and analyzing their behavior in reconstructing images, we find that DNNs initially encode images as 2D representations in low-level layers, and finally construct 3D representations in high-level layers. Intriguingly, in mid-level layers, DNNs exhibit a hybrid state, building a geometric representation that s sur normals within a narrow depth range, akin to the appearance of a low-relief sculpture. This stage resembles the 2.5D representations, providing a view of how DNNs evolve from 2D to 3D in the perception process. The graphics probe therefore serves as a tool for peering into the mechanisms of DNN, providing empirical support for Marr's theory. △ Less

Submitted 25 November, 2024; originally announced November 2024.

FlowTS: Time Series Generation via Rectified Flow

Authors: Yang Hu, Xiao Wang, Zezhen Ding, Lirong Wu, Huatian Zhang, Stan Z. Li, Sheng Wang, Jiheng Zhang, Ziyun Li, Tianlong Chen

Abstract: Diffusion-based models have significant achievements in time series generation but suffer from inefficient computation: solving high-dimensional ODEs/SDEs via iterative numerical solvers demands hundreds to thousands of drift function evaluations per sample, incurring prohibitive costs. To resolve this, we propose FlowTS, an ODE-based model that leverages rectified flow with straight-line transpor… ▽ More Diffusion-based models have significant achievements in time series generation but suffer from inefficient computation: solving high-dimensional ODEs/SDEs via iterative numerical solvers demands hundreds to thousands of drift function evaluations per sample, incurring prohibitive costs. To resolve this, we propose FlowTS, an ODE-based model that leverages rectified flow with straight-line transport in probability space. By learning geodesic paths between distributions, FlowTS achieves computational efficiency through exact linear trajectory simulation, accelerating training and generation while improving performances. We further introduce an adaptive sampling strategy inspired by the exploration-exploitation trade-off, balancing noise adaptation and precision. Notably, FlowTS enables seamless adaptation from unconditional to conditional generation without retraining, ensuring efficient real-world deployment. Also, to enhance generation authenticity, FlowTS integrates trend and seasonality decomposition, attention registers (for global context aggregation), and Rotary Position Embedding (RoPE) (for position information). For unconditional setting, extensive experiments demonstrate that FlowTS achieves state-of-the-art performance, with context FID scores of 0.019 and 0.011 on Stock and ETTh datasets (prev. best: 0.067, 0.061). For conditional setting, we have achieved superior performance in solar forecasting (MSE 213, prev. best: 375) and MuJoCo imputation tasks (MSE 7e-5, prev. best 2.7e-4). The code is available at https://github.com/UNITES-Lab/FlowTS. △ Less

Submitted 8 February, 2025; v1 submitted 11 November, 2024; originally announced November 2024.

MeToken: Uniform Micro-environment Token Boosts Post-Translational Modification Prediction

Authors: Cheng Tan, Zhenxiao Cao, Zhangyang Gao, Lirong Wu, Siyuan Li, Yufei Huang, Jun Xia, Bozhen Hu, Stan Z. Li

Abstract: Post-translational modifications (PTMs) profoundly expand the complexity and functionality of the proteome, regulating protein attributes and interactions that are crucial for biological processes. Accurately predicting PTM sites and their specific types is therefore essential for elucidating protein function and understanding disease mechanisms. Existing computational approaches predominantly foc… ▽ More Post-translational modifications (PTMs) profoundly expand the complexity and functionality of the proteome, regulating protein attributes and interactions that are crucial for biological processes. Accurately predicting PTM sites and their specific types is therefore essential for elucidating protein function and understanding disease mechanisms. Existing computational approaches predominantly focus on protein sequences to predict PTM sites, driven by the recognition of sequence-dependent motifs. However, these approaches often overlook protein structural contexts. In this work, we first compile a large-scale sequence-structure PTM dataset, which serves as the foundation for fair comparison. We introduce the MeToken model, which tokenizes the micro-environment of each amino acid, integrating both sequence and structural information into unified discrete tokens. This model not only captures the typical sequence motifs associated with PTMs but also leverages the spatial arrangements dictated by protein tertiary structures, thus providing a holistic view of the factors influencing PTM sites. Designed to address the long-tail distribution of PTM types, MeToken employs uniform sub-codebooks that ensure even the rarest PTMs are adequately represented and distinguished. We validate the effectiveness and generalizability of MeToken across multiple datasets, demonstrating its superior performance in accurately identifying PTM types. The results underscore the importance of incorporating structural data and highlight MeToken's potential in facilitating accurate and comprehensive PTM predictions, which could significantly impact proteomics research. The code and datasets are available at https://github.com/A4Bio/MeToken. △ Less

Submitted 4 November, 2024; originally announced November 2024.

Comments: 26 pages, 20 figures, 10 tables

MoE-Enhanced Explainable Deep Manifold Transformation for Complex Data Embedding and Visualization

Authors: Zelin Zang, Yuhao Wang, Jinlin Wu, Hong Liu, Yue Shen, Zhen Lei, Stan Z. Li

Abstract: Dimensionality reduction (DR) plays a crucial role in various fields, including data engineering and visualization, by simplifying complex datasets while retaining essential information. However, achieving both high DR accuracy and strong explainability remains a fundamental challenge, especially for users dealing with high-dimensional data. Traditional DR methods often face a trade-off between pr… ▽ More Dimensionality reduction (DR) plays a crucial role in various fields, including data engineering and visualization, by simplifying complex datasets while retaining essential information. However, achieving both high DR accuracy and strong explainability remains a fundamental challenge, especially for users dealing with high-dimensional data. Traditional DR methods often face a trade-off between precision and transparency, where optimizing for performance can lead to reduced explainability, and vice versa. This limitation is especially prominent in real-world applications such as image, tabular, and text data analysis, where both accuracy and explainability are critical. To address these challenges, this work introduces the MoE-based Explainable Deep Manifold Transformation (DMT-ME). The proposed approach combines a geometry-aware hyperbolic mapper with Mixture of Experts (MoE) models, where sparse expert specialization provides the main representational gain and the hyperbolic component offers an additional refinement for structurally complex data. DMT-ME enhances DR accuracy primarily through MoE-based sparse routing and structure-aware matching, while also improving explainability by explicitly linking input data, embedding outcomes, and key features through the MoE structure. Extensive experiments demonstrate that DMT-ME consistently achieves superior performance in both DR accuracy and model explainability, making it a robust solution for complex data analysis. The code is available at https://github.com/zangzelin/code_dmtme. △ Less

Submitted 16 August, 2026; v1 submitted 25 October, 2024; originally announced October 2024.

Comments: 17 pages, 15 figures, accepted by IEEE Transactions on Pattern Analysis and Machine Intelligence (TPAMI)

Journal ref: IEEE Transactions on Pattern Analysis and Machine Intelligence, 2026

FlexMol: A Flexible Toolkit for Benchmarking Molecular Relational Learning

Authors: Sizhe Liu, Jun Xia, Lecheng Zhang, Yuchen Liu, Yue Liu, Wenjie Du, Zhangyang Gao, Bozhen Hu, Cheng Tan, Hongxin Xiang, Stan Z. Li

Abstract: Molecular relational learning (MRL) is crucial for understanding the interaction behaviors between molecular pairs, a critical aspect of drug discovery and development. However, the large feasible model space of MRL poses significant challenges to benchmarking, and existing MRL frameworks face limitations in flexibility and scope. To address these challenges, avoid repetitive coding efforts, and e… ▽ More Molecular relational learning (MRL) is crucial for understanding the interaction behaviors between molecular pairs, a critical aspect of drug discovery and development. However, the large feasible model space of MRL poses significant challenges to benchmarking, and existing MRL frameworks face limitations in flexibility and scope. To address these challenges, avoid repetitive coding efforts, and ensure fair comparison of models, we introduce FlexMol, a comprehensive toolkit designed to facilitate the construction and evaluation of diverse model architectures across various datasets and performance metrics. FlexMol offers a robust suite of preset model components, including 16 drug encoders, 13 protein sequence encoders, 9 protein structure encoders, and 7 interaction layers. With its easy-to-use API and flexibility, FlexMol supports the dynamic construction of over 70, 000 distinct combinations of model architectures. Additionally, we provide detailed benchmark results and code examples to demonstrate FlexMol's effectiveness in simplifying and standardizing MRL model development and comparison. △ Less

Submitted 19 October, 2024; originally announced October 2024.

Unveiling the Backbone-Optimizer Coupling Bias in Visual Representation Learning

Authors: Siyuan Li, Juanxi Tian, Zedong Wang, Luyuan Zhang, Zicheng Liu, Weiyang Jin, Yang Liu, Baigui Sun, Stan Z. Li

Abstract: This paper delves into the interplay between vision backbones and optimizers, unvealing an inter-dependent phenomenon termed \textit{\textbf{b}ackbone-\textbf{o}ptimizer \textbf{c}oupling \textbf{b}ias} (BOCB). We observe that canonical CNNs, such as VGG and ResNet, exhibit a marked co-dependency with SGD families, while recent architectures like ViTs and ConvNeXt share a tight coupling with the a… ▽ More This paper delves into the interplay between vision backbones and optimizers, unvealing an inter-dependent phenomenon termed \textit{\textbf{b}ackbone-\textbf{o}ptimizer \textbf{c}oupling \textbf{b}ias} (BOCB). We observe that canonical CNNs, such as VGG and ResNet, exhibit a marked co-dependency with SGD families, while recent architectures like ViTs and ConvNeXt share a tight coupling with the adaptive learning rate ones. We further show that BOCB can be introduced by both optimizers and certain backbone designs and may significantly impact the pre-training and downstream fine-tuning of vision models. Through in-depth empirical analysis, we summarize takeaways on recommended optimizers and insights into robust vision backbone architectures. We hope this work can inspire the community to question long-held assumptions on backbones and optimizers, stimulate further explorations, and thereby contribute to more robust vision systems. The source code and models are publicly available at https://bocb-ai.github.io/. △ Less

Submitted 8 October, 2024; originally announced October 2024.

Comments: Preprint V1. Online project at https://bocb-ai.github.io/

A Review of BioTree Construction in the Context of Information Fusion: Priors, Methods, Applications and Trends

Authors: Zelin Zang, Yongjie Xu, Chenrui Duan, Yue Yuan, Jinlin Wu, Zhen Lei, Stan Z. Li

Abstract: Biological tree (BioTree) analysis is a foundational tool in biology, enabling the exploration of evolutionary and differentiation relationships among organisms, genes, and cells. Traditional tree construction methods, while instrumental in early research, face significant challenges in handling the growing complexity and scale of modern biological data, particularly in integrating multimodal data… ▽ More Biological tree (BioTree) analysis is a foundational tool in biology, enabling the exploration of evolutionary and differentiation relationships among organisms, genes, and cells. Traditional tree construction methods, while instrumental in early research, face significant challenges in handling the growing complexity and scale of modern biological data, particularly in integrating multimodal datasets. Advances in deep learning (DL) offer transformative opportunities by enabling the fusion of biological prior knowledge with data-driven models. These approaches address key limitations of traditional methods, facilitating the construction of more accurate and interpretable BioTrees. This review highlights critical biological priors essential for phylogenetic and differentiation tree analyses and explores strategies for integrating these priors into DL models to enhance accuracy and interpretability. Additionally, the review systematically examines commonly used data modalities and databases, offering a valuable resource for developing and evaluating multimodal fusion models. Traditional tree construction methods are critically assessed, focusing on their biological assumptions, technical limitations, and scalability issues. Recent advancements in DL-based tree generation methods are reviewed, emphasizing their innovative approaches to multimodal integration and prior knowledge incorporation. Finally, the review discusses diverse applications of BioTrees in various biological disciplines, from phylogenetics to developmental biology, and outlines future trends in leveraging DL to advance BioTree research. By addressing the challenges of data complexity and prior knowledge integration, this review aims to inspire interdisciplinary innovation at the intersection of biology and DL. △ Less

Submitted 15 February, 2025; v1 submitted 7 October, 2024; originally announced October 2024.

Comments: 115 pages, 15 figures

Learning to Model Graph Structural Information on MLPs via Graph Structure Self-Contrasting

Authors: Lirong Wu, Haitao Lin, Guojiang Zhao, Cheng Tan, Stan Z. Li

Abstract: Recent years have witnessed great success in handling graph-related tasks with Graph Neural Networks (GNNs). However, most existing GNNs are based on message passing to perform feature aggregation and transformation, where the structural information is explicitly involved in the forward propagation by coupling with node features through graph convolution at each layer. As a result, subtle feature… ▽ More Recent years have witnessed great success in handling graph-related tasks with Graph Neural Networks (GNNs). However, most existing GNNs are based on message passing to perform feature aggregation and transformation, where the structural information is explicitly involved in the forward propagation by coupling with node features through graph convolution at each layer. As a result, subtle feature noise or structure perturbation may cause severe error propagation, resulting in extremely poor robustness. In this paper, we rethink the roles played by graph structural information in graph data training and identify that message passing is not the only path to modeling structural information. Inspired by this, we propose a simple but effective Graph Structure Self-Contrasting (GSSC) framework that learns graph structural information without message passing. The proposed framework is based purely on Multi-Layer Perceptrons (MLPs), where the structural information is only implicitly incorporated as prior knowledge to guide the computation of supervision signals, substituting the explicit message propagation as in GNNs. Specifically, it first applies structural sparsification to remove potentially uninformative or noisy edges in the neighborhood, and then performs structural self-contrasting in the sparsified neighborhood to learn robust node representations. Finally, structural sparsification and self-contrasting are formulated as a bi-level optimization problem and solved in a unified framework. Extensive experiments have qualitatively and quantitatively demonstrated that the GSSC framework can produce truly encouraging performance with better generalization and robustness than other leading competitors. △ Less

Submitted 9 September, 2024; originally announced September 2024.

A Survey on Mixup Augmentations and Beyond

Authors: Xin Jin, Hongyu Zhu, Siyuan Li, Zedong Wang, Zicheng Liu, Juanxi Tian, Chang Yu, Huafeng Qin, Stan Z. Li

Abstract: As Deep Neural Networks have achieved thrilling breakthroughs in the past decade, data augmentations have garnered increasing attention as regularization techniques when massive labeled data are unavailable. Among existing augmentations, Mixup and relevant data-mixing methods that convexly combine selected samples and the corresponding labels are widely adopted because they yield high performances… ▽ More As Deep Neural Networks have achieved thrilling breakthroughs in the past decade, data augmentations have garnered increasing attention as regularization techniques when massive labeled data are unavailable. Among existing augmentations, Mixup and relevant data-mixing methods that convexly combine selected samples and the corresponding labels are widely adopted because they yield high performances by generating data-dependent virtual data while easily migrating to various domains. This survey presents a comprehensive review of foundational mixup methods and their applications. We first elaborate on the training pipeline with mixup augmentations as a unified framework containing modules. A reformulated framework could contain various mixup methods and give intuitive operational procedures. Then, we systematically investigate the applications of mixup augmentations on vision downstream tasks, various data modalities, and some analysis \& theorems of mixup. Meanwhile, we conclude the current status and limitations of mixup research and point out further work for effective and efficient mixup augmentations. This survey can provide researchers with the current state of the art in mixup methods and provide some insights and guidance roles in the mixup arena. An online project with this survey is available at https://github.com/Westlake-AI/Awesome-Mixup. △ Less

Submitted 23 April, 2025; v1 submitted 8 September, 2024; originally announced September 2024.

Comments: Preprint V2 with 30 pages main text. Online project at https://github.com/Westlake-AI/Awesome-Mixup

MetaEnzyme: Meta Pan-Enzyme Learning for Task-Adaptive Redesign

Authors: Jiangbin Zheng, Han Zhang, Qianqing Xu, An-Ping Zeng, Stan Z. Li

Abstract: Enzyme design plays a crucial role in both industrial production and biology. However, this field faces challenges due to the lack of comprehensive benchmarks and the complexity of enzyme design tasks, leading to a dearth of systematic research. Consequently, computational enzyme design is relatively overlooked within the broader protein domain and remains in its early stages. In this work, we add… ▽ More Enzyme design plays a crucial role in both industrial production and biology. However, this field faces challenges due to the lack of comprehensive benchmarks and the complexity of enzyme design tasks, leading to a dearth of systematic research. Consequently, computational enzyme design is relatively overlooked within the broader protein domain and remains in its early stages. In this work, we address these challenges by introducing MetaEnzyme, a staged and unified enzyme design framework. We begin by employing a cross-modal structure-to-sequence transformation architecture, as the feature-driven starting point to obtain initial robust protein representation. Subsequently, we leverage domain adaptive techniques to generalize specific enzyme design tasks under low-resource conditions. MetaEnzyme focuses on three fundamental low-resource enzyme redesign tasks: functional design (FuncDesign), mutation design (MutDesign), and sequence generation design (SeqDesign). Through novel unified paradigm and enhanced representation capabilities, MetaEnzyme demonstrates adaptability to diverse enzyme design tasks, yielding outstanding results. Wet lab experiments further validate these findings, reinforcing the efficacy of the redesign process. △ Less

Submitted 5 August, 2024; originally announced August 2024.

Comments: Accepted to ACM Multimedia 2024

SSPA: Split-and-Synthesize Prompting with Gated Alignments for Multi-Label Image Recognition

Authors: Hao Tan, Zichang Tan, Jun Li, Jun Wan, Zhen Lei, Stan Z. Li

Abstract: Multi-label image recognition is a fundamental task in computer vision. Recently, Vision-Language Models (VLMs) have made notable advancements in this area. However, previous methods fail to effectively leverage the rich knowledge in language models and often incorporate label semantics into visual features unidirectionally. To overcome these problems, we propose a Split-and-Synthesize Prompting w… ▽ More Multi-label image recognition is a fundamental task in computer vision. Recently, Vision-Language Models (VLMs) have made notable advancements in this area. However, previous methods fail to effectively leverage the rich knowledge in language models and often incorporate label semantics into visual features unidirectionally. To overcome these problems, we propose a Split-and-Synthesize Prompting with Gated Alignments (SSPA) framework to amplify the potential of VLMs. Specifically, we develop an in-context learning approach to associate the inherent knowledge from LLMs. Then we propose a novel Split-and-Synthesize Prompting (SSP) strategy to first model the generic knowledge and downstream label semantics individually and then aggregate them carefully through the quaternion network. Moreover, we present Gated Dual-Modal Alignments (GDMA) to bidirectionally interact visual and linguistic modalities while eliminating redundant cross-modal information, enabling more efficient region-level alignments. Rather than making the final prediction by a sharp manner in previous works, we propose a soft aggregator to jointly consider results from all image regions. With the help of flexible prompting and gated alignments, SSPA is generalizable to specific domains. Extensive experiments on nine datasets from three domains (i.e., natural, pedestrian attributes and remote sensing) demonstrate the state-of-the-art performance of SSPA. Further analyses verify the effectiveness of SSP and the interpretability of GDMA. The code will be made public. △ Less

Submitted 30 July, 2024; originally announced July 2024.

Comments: 13 pages, 8 figures

Teach Harder, Learn Poorer: Rethinking Hard Sample Distillation for GNN-to-MLP Knowledge Distillation

Authors: Lirong Wu, Yunfan Liu, Haitao Lin, Yufei Huang, Stan Z. Li

Abstract: To bridge the gaps between powerful Graph Neural Networks (GNNs) and lightweight Multi-Layer Perceptron (MLPs), GNN-to-MLP Knowledge Distillation (KD) proposes to distill knowledge from a well-trained teacher GNN into a student MLP. In this paper, we revisit the knowledge samples (nodes) in teacher GNNs from the perspective of hardness, and identify that hard sample distillation may be a major per… ▽ More To bridge the gaps between powerful Graph Neural Networks (GNNs) and lightweight Multi-Layer Perceptron (MLPs), GNN-to-MLP Knowledge Distillation (KD) proposes to distill knowledge from a well-trained teacher GNN into a student MLP. In this paper, we revisit the knowledge samples (nodes) in teacher GNNs from the perspective of hardness, and identify that hard sample distillation may be a major performance bottleneck of existing graph KD algorithms. The GNN-to-MLP KD involves two different types of hardness, one student-free knowledge hardness describing the inherent complexity of GNN knowledge, and the other student-dependent distillation hardness describing the difficulty of teacher-to-student distillation. However, most of the existing work focuses on only one of these aspects or regards them as one thing. This paper proposes a simple yet effective Hardness-aware GNN-to-MLP Distillation (HGMD) framework, which decouples the two hardnesses and estimates them using a non-parametric approach. Finally, two hardness-aware distillation schemes (i.e., HGMD-weight and HGMD-mixup) are further proposed to distill hardness-aware knowledge from teacher GNNs into the corresponding nodes of student MLPs. As non-parametric distillation, HGMD does not involve any additional learnable parameters beyond the student MLPs, but it still outperforms most of the state-of-the-art competitors. HGMD-mixup improves over the vanilla MLPs by 12.95% and outperforms its teacher GNNs by 2.48% averaged over seven real-world datasets. △ Less

Submitted 20 July, 2024; originally announced July 2024.

The Heterophilic Graph Learning Handbook: Benchmarks, Models, Theoretical Analysis, Applications and Challenges

Authors: Sitao Luan, Chenqing Hua, Qincheng Lu, Liheng Ma, Lirong Wu, Xinyu Wang, Minkai Xu, Xiao-Wen Chang, Doina Precup, Rex Ying, Stan Z. Li, Jian Tang, Guy Wolf, Stefanie Jegelka

Abstract: Homophily principle, \ie{} nodes with the same labels or similar attributes are more likely to be connected, has been commonly believed to be the main reason for the superiority of Graph Neural Networks (GNNs) over traditional Neural Networks (NNs) on graph-structured data, especially on node-level tasks. However, recent work has identified a non-trivial set of datasets where GNN's performance com… ▽ More Homophily principle, \ie{} nodes with the same labels or similar attributes are more likely to be connected, has been commonly believed to be the main reason for the superiority of Graph Neural Networks (GNNs) over traditional Neural Networks (NNs) on graph-structured data, especially on node-level tasks. However, recent work has identified a non-trivial set of datasets where GNN's performance compared to the NN's is not satisfactory. Heterophily, i.e. low homophily, has been considered the main cause of this empirical observation. People have begun to revisit and re-evaluate most existing graph models, including graph transformer and its variants, in the heterophily scenario across various kinds of graphs, e.g. heterogeneous graphs, temporal graphs and hypergraphs. Moreover, numerous graph-related applications are found to be closely related to the heterophily problem. In the past few years, considerable effort has been devoted to studying and addressing the heterophily issue. In this survey, we provide a comprehensive review of the latest progress on heterophilic graph learning, including an extensive summary of benchmark datasets and evaluation of homophily metrics on synthetic graphs, meticulous classification of the most updated supervised and unsupervised learning methods, thorough digestion of the theoretical analysis on homophily/heterophily, and broad exploration of the heterophily-related applications. Notably, through detailed experiments, we are the first to categorize benchmark heterophilic datasets into three sub-categories: malignant, benign and ambiguous heterophily. Malignant and ambiguous datasets are identified as the real challenging datasets to test the effectiveness of new models on the heterophily challenge. Finally, we propose several challenges and future directions for heterophilic graph representation learning. △ Less

Submitted 12 July, 2024; originally announced July 2024.

Comments: Suggestions and comments are welcomed at sitao.luan@mail.mcgill.ca!

BioKGBench: A Knowledge Graph Checking Benchmark of AI Agent for Biomedical Science

Authors: Xinna Lin, Siqi Ma, Junjie Shan, Xiaojing Zhang, Shell Xu Hu, Tiannan Guo, Stan Z. Li, Kaicheng Yu

Abstract: Pursuing artificial intelligence for biomedical science, a.k.a. AI Scientist, draws increasing attention, where one common approach is to build a copilot agent driven by Large Language Models (LLMs). However, to evaluate such systems, people either rely on direct Question-Answering (QA) to the LLM itself, or in a biomedical experimental manner. How to precisely benchmark biomedical agents from an… ▽ More Pursuing artificial intelligence for biomedical science, a.k.a. AI Scientist, draws increasing attention, where one common approach is to build a copilot agent driven by Large Language Models (LLMs). However, to evaluate such systems, people either rely on direct Question-Answering (QA) to the LLM itself, or in a biomedical experimental manner. How to precisely benchmark biomedical agents from an AI Scientist perspective remains largely unexplored. To this end, we draw inspiration from one most important abilities of scientists, understanding the literature, and introduce BioKGBench. In contrast to traditional evaluation benchmark that only focuses on factual QA, where the LLMs are known to have hallucination issues, we first disentangle "Understanding Literature" into two atomic abilities, i) "Understanding" the unstructured text from research papers by performing scientific claim verification, and ii) Ability to interact with structured Knowledge-Graph Question-Answering (KGQA) as a form of "Literature" grounding. We then formulate a novel agent task, dubbed KGCheck, using KGQA and domain-based Retrieval-Augmented Generation (RAG) to identify the factual errors of existing large-scale knowledge graph databases. We collect over two thousand data for two atomic tasks and 225 high-quality annotated data for the agent task. Surprisingly, we discover that state-of-the-art agents, both daily scenarios and biomedical ones, have either failed or inferior performance on our benchmark. We then introduce a simple yet effective baseline, dubbed BKGAgent. On the widely used popular knowledge graph, we discover over 90 factual errors which provide scenarios for agents to make discoveries and demonstrate the effectiveness of our approach. The code and data are available at https://github.com/westlake-autolab/BioKGBench. △ Less

Submitted 29 June, 2024; originally announced July 2024.