arXiv subjects

Le Song

Publications and source records attributed to Le Song.

At least 19 recordsLinked to original sources

arXiv2026

Forecasting How RLHF Responds to Reward-Model Edits Before Training

Responses with headers, lists and greater length receive high scores from reward models (RMs), and RLHF policies learn to produce these features even when true quality does not improve. Practitioners therefore edit their RMs, but they learn whether an edit works only after an RL run. We show that the response of a policy to an RM edit can be forecast before training, from samples of the current policy and the scores of the old and new RM. If we read the RM as a set of prices, the first-order theory of KL-regularized RL implies that each feature moves in proportion to its within-prompt covariance with the change in reward. We implant controlled price changes into retrained RMs under a 2^(4-1) fractional factorial design with a self-distilled placebo, run 54 RL runs from six parent policies, and fix every forecast before the runs. With the covariance predictor, we predict the direction of all 20 changes in supply whose forecast has the same sign at every parent and explain 82% of the standardized change. With counterfactual prices, the classical alternative, we explain 50%. The forecast also holds under GRPO and for real RM upgrades, where we explain 66% out of sample with a coefficient frozen from the factorial runs. For rent, the gap between the proxy reward and a gold reward from stronger judges, we rank RM edits correctly with the same covariance over the first 30 steps (Spearman 0.94). This measures the horizon of the forecast: by step 200, the ranking of the factorial edits reverses under both RLOO and GRPO, while the real upgrades keep their order. When we vary the KL coefficient beta, the initial response does not depend on beta, and the response saturates below the KL equilibrium. In one experiment, the long-run response to a price rise is consistent with an additional implicit regularizer beta_0 of about 0.003 to 0.007.

cs.LG↗

arXiv2026

BioXArena: Benchmarking LLM Agents on Multi-Modal Biomedical Machine Learning Tasks

Large language model (LLM) agents increasingly automate machine-learning model building, yet biomedical benchmarks emphasize question answering, reasoning, and tool use or cover narrow slices of biomedical ML coding. We introduce BioXArena, a biomedical machine learning (BioML) coding benchmark for task-specific model building on heterogeneous, often multi-modal datasets. It contains 76 end-to-end tasks across 9 domains: sequence, single-cell, structure, network biology, chemical biology, perturbation dynamics, phenotype--disease, imaging, and text-integrated tasks. Each task packages primary-source data with hidden labels, held-out graders, and biology-aware metrics on a unified 0-to-100 scale; agents write runnable code, train models, and predict private test samples. BioXArena emphasizes realistic data interfaces: most tasks require agents to integrate multiple input sources, including 46 tasks that combine distinct modality families. We compare 18 harness--backbone configurations: general-purpose coding, biomedical, and ML agents plus our Minimal runner, all under the same controlled resource configuration. Codex with GPT-6 Astra achieves the highest task-level average score of 73.91 among 18 configurations, closely followed by Claude Code with Opus 5.5 (73.79). Matched-backbone comparisons show higher observed scores for mature coding systems than for Minimal; seven Minimal backends characterize model differences under a fixed runner. Beyond the main leaderboard, ablations, robustness checks, and scaling, runtime, and failure-mode analyses characterize how backbones, scaffolds, budgets, and domains affect BioML coding performance, exposing modeling and execution gaps across agent and LLM backbone families.

cs.CE↗

arXiv2026

Rent-Seeking Language Models: Reward Models Set the Prices, Frequent Audits Curb the Rent

Reward model overoptimization in RLHF is usually described as reward hacking. We recast it as rent-seeking: the policy, a firm, earns reward from a regulator, the proxy reward model, that true quality does not back. The lens turns overoptimization into measurable quantities, namely rent, a capture index and deadweight loss, and into testable predictions from the economics of regulation. In a fixed, version-controlled testbed with three model families, accuracy-matched proxy reward models and two gold reward models, RL turns 41% to 66% of its proxy gain into rent while gold reward plateaus. Rent follows each regulator's prices. Neither proxy verifies facts, but one pays for confident specifics and the other for displays of diligence, so RL policies learn to fabricate details about nonexistent entities (97% to 100% of probes) or to deflect factual questions (67% to 98%). Kinship between policy and regulator adds a fixed premium of about 0.1 standard deviations but gives the policy no extra leverage under optimization. At a fixed expected fine, frequent mild audits beat rare severe ones, and random audits are as efficient per audit as targeted ones. Bringing the bunching estimator of tax economics to RL training, we also find a first sign that policies learn to stay just below a targeted audit's threshold.

cs.LG↗

arXiv2026

BioDyad: Synchronize Biomedical Discovery and Machine Learning Engineering

Agentic biomedical machine learning (ML) draws on complementary advances in biomedical evidence acquisition and executable program search. Existing systems connect aspects of these capabilities, but coordinating them throughout program search remains challenging. New evidence must guide candidate construction, execution outcomes must inform subsequent discovery and reuse, and validation demands must fit the search budget. We introduce BioDyad, which couples biomedical discovery and ML engineering through two hierarchies within Monte Carlo graph search. Its scientific hierarchy combines prior biomedical guidance with iterative discovery, then links biomedical plans to execution outcomes in memory for reuse across candidates. Its engineering hierarchy moves candidate programs from smoke execution, through train/validation evaluation, to full-data retraining. We evaluate BioDyad on the 76-task BioXArena benchmark under a two-hour per-task budget with three matched LLM backends. It achieves the highest penalized all-task score and task success rate among four agent methods and a one-shot baseline under each backend. These results support coordinating biomedical discovery and ML engineering to integrate external knowledge into executable programs across heterogeneous biomedical tasks.

cs.AI↗

arXiv2026

MedKGent: A Large Language Model Agent Framework for Constructing Temporally Evolving Medical Knowledge Graph

The rapid expansion of medical literature challenges the scalable structuring of domain knowledge. Knowledge Graphs (KGs) offer a solution, yet current construction methods lack generalizability and ignore the temporal dynamics of evolving knowledge. To address this, we introduce MedKGent, a Large Language Model (LLM) agent framework for building temporally evolving medical KGs. Using over 10 million PubMed abstracts from 1975 to 2023, MedKGent incrementally constructs a KG daily via two specialized agents. The Extractor Agent identifies knowledge triples and assigns confidence scores, while the Constructor Agent integrates these triples into a temporal graph, reinforcing recurring knowledge and resolving conflicts. The resulting KG contains 156,275 entities and 2,971,384 triples, making it, to our knowledge, the largest LLM-derived medical KG to date. Automated and expert assessments showed triple-validity rates approaching 90%. In downstream evaluations, MedKGent-KG significantly improved retrieval-augmented generation for five LLMs across seven medical question-answering benchmarks. Together, these results position MedKGent as a scalable and temporally aware infrastructure for medical knowledge representation and literature-grounded AI research.

cs.CL↗

arXiv2026

HD-Prot: A Protein Language Model for Joint Sequence-Structure Modeling with Continuous Structure Tokens

Proteins inherently possess a consistent sequence-structure duality. The abundance of protein sequence data, which can be readily represented as discrete tokens, has driven fruitful developments in protein language models (pLMs). A key remaining challenge, however, is how to effectively integrate continuous structural knowledge into pLMs. Current methods often discretize protein structures to accommodate the language modeling framework, which inevitably results in the loss of fine-grained information and limits the performance potential of multimodal pLMs. In this paper, we argue that such concerns can be circumvented: a sequence-based pLM can be extended to incorporate the structure modality through continuous tokens, i.e., high-fidelity protein structure latents that avoid vector quantization. Specifically, we propose a hybrid diffusion protein language model, HD-Prot, which embeds a continuous-valued diffusion head atop a discrete pLM, enabling seamless operation with both discrete and continuous tokens for joint sequence-structure modeling. It captures inter-token dependencies across modalities through a unified absorbing diffusion process, and estimates per-token distributions via categorical prediction for sequences and continuous diffusion for structures. Extensive results demonstrate that HD-Prot achieves competitive performance in unconditional sequence-structure co-generation, motif-scaffolding, protein structure prediction, and inverse folding tasks. Furthermore, our method can perform on par with state-of-the-art multimodal pLMs, despite being developed under limited computational resources (i.e., less than one-tenth the budget for modality extension fine-tuning). It highlights the viability of simultaneously estimating categorical and continuous distributions within a unified language model architecture, offering a promising alternative direction for multimodal pLMs.

cs.CE↗

arXiv2025

MemR$^3$: Memory Retrieval via Reflective Reasoning for LLM Agents

Memory systems have been designed to leverage past experiences in Large Language Model (LLM) agents. However, many deployed memory systems primarily optimize compression and storage, with comparatively less emphasis on explicit, closed-loop control of memory retrieval. From this observation, we build memory retrieval as an autonomous, accurate, and compatible agent system, named MemR$^3$, which has two core mechanisms: 1) a router that selects among retrieve, reflect, and answer actions to optimize answer quality; 2) a global evidence-gap tracker that explicitly renders the answering process transparent and tracks the evidence collection process. This design departs from the standard retrieve-then-answer pipeline by introducing a closed-loop control mechanism that enables autonomous decision-making. Empirical results on the LoCoMo benchmark demonstrate that MemR$^3$ surpasses strong baselines on LLM-as-a-Judge score, and particularly, it improves existing retrievers across four categories with an overall improvement on RAG (+7.29%) and Zep (+1.94%) using GPT-4.1-mini backend, offering a plug-and-play controller for existing memory stores.

cs.AI↗

arXiv2025

Pruning Spurious Subgraphs for Graph Out-of-Distribution Generalization

Graph Neural Networks (GNNs) often encounter significant performance degradation under distribution shifts between training and test data, hindering their applicability in real-world scenarios. Recent studies have proposed various methods to address the out-of-distribution generalization challenge, with many methods in the graph domain focusing on directly identifying an invariant subgraph that is predictive of the target label. However, we argue that identifying the edges from the invariant subgraph directly is challenging and error-prone, especially when some spurious edges exhibit strong correlations with the targets. In this paper, we propose PrunE, the first pruning-based graph OOD method that eliminates spurious edges to improve OOD generalizability. By pruning spurious edges, PrunE retains the invariant subgraph more comprehensively, which is critical for OOD generalization. Specifically, PrunE employs two regularization terms to prune spurious edges: 1) graph size constraint to exclude uninformative spurious edges, and 2) $ε$-probability alignment to further suppress the occurrence of spurious edges. Through theoretical analysis and extensive experiments, we show that PrunE achieves superior OOD performance and outperforms previous state-of-the-art methods significantly. Codes are available at: \href{https://github.com/tianyao-aka/PrunE-GraphOOD}{https://github.com/tianyao-aka/PrunE-GraphOOD}.

cs.LG↗

arXiv2025

Beyond Profile: From Surface-Level Facts to Deep Persona Simulation in LLMs

Previous approaches to persona simulation large language models (LLMs) have typically relied on learning basic biographical information, or using limited role-play dialogue datasets to capture a character's responses. However, a holistic representation of an individual goes beyond surface-level facts or conversations to deeper thoughts and thinking. In this work, we introduce CharacterBot, a model designed to replicate both the linguistic patterns and distinctive thought patterns as manifested in the textual works of a character. Using Lu Xun, a renowned Chinese writer as a case study, we propose four training tasks derived from his 17 essay collections. These include a pre-training task focused on mastering external linguistic structures and knowledge, as well as three fine-tuning tasks: multiple-choice question answering, generative question answering, and style transfer, each aligning the LLM with Lu Xun's internal ideation and writing style. To optimize learning across these tasks, we introduce a CharLoRA parameter updating mechanism, where a general linguistic style expert collaborates with other task-specific experts to better study both the language style and the understanding of deeper thoughts. We evaluate CharacterBot on three tasks for linguistic accuracy and opinion comprehension, demonstrating that it significantly outperforms the baselines on our adapted metrics. We hope this work inspires future research on deep character persona simulation LLMs while considering the importance of ethical standards.

cs.CL↗

arXiv2025

From System 1 to System 2: A Survey of Reasoning Large Language Models

Achieving human-level intelligence requires refining the transition from the fast, intuitive System 1 to the slower, more deliberate System 2 reasoning. While System 1 excels in quick, heuristic decisions, System 2 relies on logical reasoning for more accurate judgments and reduced biases. Foundational Large Language Models (LLMs) excel at fast decision-making but lack the depth for complex reasoning, as they have not yet fully embraced the step-by-step analysis characteristic of true System 2 thinking. Recently, reasoning LLMs like OpenAI's o1/o3 and DeepSeek's R1 have demonstrated expert-level performance in fields such as mathematics and coding, closely mimicking the deliberate reasoning of System 2 and showcasing human-like cognitive abilities. This survey begins with a brief overview of the progress in foundational LLMs and the early development of System 2 technologies, exploring how their combination has paved the way for reasoning LLMs. Next, we discuss how to construct reasoning LLMs, analyzing their features, the core methods enabling advanced reasoning, and the evolution of various reasoning LLMs. Additionally, we provide an overview of reasoning benchmarks, offering an in-depth comparison of the performance of representative reasoning LLMs. Finally, we explore promising directions for advancing reasoning LLMs and maintain a real-time \href{https://github.com/zzli2022/Awesome-Slow-Reason-System}{GitHub Repository} to track the latest developments. We hope this survey will serve as a valuable resource to inspire innovation and drive progress in this rapidly evolving field.

cs.AI↗

arXiv2025

Protein Inverse Folding From Structure Feedback

The inverse folding problem, aiming to design amino acid sequences that fold into desired three-dimensional structures, is pivotal for various biotechnological applications. Here, we introduce a novel approach leveraging Direct Preference Optimization (DPO) to fine-tune an inverse folding model using feedback from a protein folding model. Given a target protein structure, we begin by sampling candidate sequences from the inverse-folding model, then predict the three-dimensional structure of each sequence with the folding model to generate pairwise structural-preference labels. These labels are used to fine-tune the inverse-folding model under the DPO objective. Our results on the CATH 4.2 test set demonstrate that DPO fine-tuning not only improves sequence recovery of baseline models but also leads to a significant improvement in average TM-Score from 0.77 to 0.81, indicating enhanced structure similarity. Furthermore, iterative application of our DPO-based method on challenging protein structures yields substantial gains, with an average TM-Score increase of 79.5\% with regard to the baseline model. This work establishes a promising direction for enhancing protein sequence design ability from structure feedback by effectively utilizing preference optimization.

cs.LG↗

arXiv2025

LifelongAgentBench: Evaluating LLM Agents as Lifelong Learners

Lifelong learning is essential for intelligent agents operating in dynamic environments. Current large language model (LLM)-based agents, however, remain stateless and unable to accumulate or transfer knowledge over time. Existing benchmarks treat agents as static systems and fail to evaluate lifelong learning capabilities. We present LifelongAgentBench, the first unified benchmark designed to systematically assess the lifelong learning ability of LLM agents. It provides skill-grounded, interdependent tasks across three interactive environments, Database, Operating System, and Knowledge Graph, with automatic label verification, reproducibility, and modular extensibility. Extensive experiments reveal that conventional experience replay has limited effectiveness for LLM agents due to irrelevant information and context length constraints. We further introduce a group self-consistency mechanism that significantly improves lifelong learning performance. We hope LifelongAgentBench will advance the development of adaptive, memory-capable LLM agents.

cs.AI↗

arXiv2025

Towards More Accurate Full-Atom Antibody Co-Design

Antibody co-design represents a critical frontier in drug development, where accurate prediction of both 1D sequence and 3D structure of complementarity-determining regions (CDRs) is essential for targeting specific epitopes. Despite recent advances in equivariant graph neural networks for antibody design, current approaches often fall short in capturing the intricate interactions that govern antibody-antigen recognition and binding specificity. In this work, we present Igformer, a novel end-to-end framework that addresses these limitations through innovative modeling of antibody-antigen binding interfaces. Our approach refines the inter-graph representation by integrating personalized propagation with global attention mechanisms, enabling comprehensive capture of the intricate interplay between local chemical interactions and global conformational dependencies that characterize effective antibody-antigen binding. Through extensive validation on epitope-binding CDR design and structure prediction tasks, Igformer demonstrates significant improvements over existing methods, suggesting that explicit modeling of multi-scale residue interactions can substantially advance computational antibody design for therapeutic applications.

q-bio.BM↗

arXiv2025

Computational Protein Science in the Era of Large Language Models (LLMs)

Considering the significance of proteins, computational protein science has always been a critical scientific field, dedicated to revealing knowledge and developing applications within the protein sequence-structure-function paradigm. In the last few decades, Artificial Intelligence (AI) has made significant impacts in computational protein science, leading to notable successes in specific protein modeling tasks. However, those previous AI models still meet limitations, such as the difficulty in comprehending the semantics of protein sequences, and the inability to generalize across a wide range of protein modeling tasks. Recently, LLMs have emerged as a milestone in AI due to their unprecedented language processing & generalization capability. They can promote comprehensive progress in fields rather than solving individual tasks. As a result, researchers have actively introduced LLM techniques in computational protein science, developing protein Language Models (pLMs) that skillfully grasp the foundational knowledge of proteins and can be effectively generalized to solve a diversity of sequence-structure-function reasoning problems. While witnessing prosperous developments, it's necessary to present a systematic overview of computational protein science empowered by LLM techniques. First, we summarize existing pLMs into categories based on their mastered protein knowledge, i.e., underlying sequence patterns, explicit structural and functional information, and external scientific languages. Second, we introduce the utilization and adaptation of pLMs, highlighting their remarkable achievements in promoting protein structure prediction, protein function prediction, and protein design studies. Then, we describe the practical application of pLMs in antibody design, enzyme design, and drug discovery. Finally, we specifically discuss the promising future directions in this fast-growing field.

cs.CE↗

arXiv2024

xTrimoPGLM: Unified 100B-Scale Pre-trained Transformer for Deciphering the Language of Protein

Protein language models have shown remarkable success in learning biological information from protein sequences. However, most existing models are limited by either autoencoding or autoregressive pre-training objectives, which makes them struggle to handle protein understanding and generation tasks concurrently. We propose a unified protein language model, xTrimoPGLM, to address these two types of tasks simultaneously through an innovative pre-training framework. Our key technical contribution is an exploration of the compatibility and the potential for joint optimization of the two types of objectives, which has led to a strategy for training xTrimoPGLM at an unprecedented scale of 100 billion parameters and 1 trillion training tokens. Our extensive experiments reveal that 1) xTrimoPGLM significantly outperforms other advanced baselines in 18 protein understanding benchmarks across four categories. The model also facilitates an atomic-resolution view of protein structures, leading to an advanced 3D structural prediction model that surpasses existing language model-based tools. 2) xTrimoPGLM not only can generate de novo protein sequences following the principles of natural ones, but also can perform programmable generation after supervised fine-tuning (SFT) on curated sequences. These results highlight the substantial capability and versatility of xTrimoPGLM in understanding and generating protein sequences, contributing to the evolving landscape of foundation models in protein science.

q-bio.QM↗

arXiv2024

Toward AI-Driven Digital Organism: Multiscale Foundation Models for Predicting, Simulating and Programming Biology at All Levels

We present an approach of using AI to model and simulate biology and life. Why is it important? Because at the core of medicine, pharmacy, public health, longevity, agriculture and food security, environmental protection, and clean energy, it is biology at work. Biology in the physical world is too complex to manipulate and always expensive and risky to tamper with. In this perspective, we layout an engineering viable approach to address this challenge by constructing an AI-Driven Digital Organism (AIDO), a system of integrated multiscale foundation models, in a modular, connectable, and holistic fashion to reflect biological scales, connectedness, and complexities. An AIDO opens up a safe, affordable and high-throughput alternative platform for predicting, simulating and programming biology at all levels from molecules to cells to individuals. We envision that an AIDO is poised to trigger a new wave of better-guided wet-lab experimentation and better-informed first-principle reasoning, which can eventually help us better decode and improve life.

cs.AI↗

arXiv2024

Training Compute-Optimal Protein Language Models

We explore optimally training protein language models, an area of significant interest in biological research where guidance on best practices is limited. Most models are trained with extensive compute resources until performance gains plateau, focusing primarily on increasing model sizes rather than optimizing the efficient compute frontier that balances performance and compute budgets. Our investigation is grounded in a massive dataset consisting of 939 million protein sequences. We trained over 300 models ranging from 3.5 million to 10.7 billion parameters on 5 to 200 billion unique tokens, to investigate the relations between model sizes, training token numbers, and objectives. First, we observed the effect of diminishing returns for the Causal Language Model (CLM) and that of overfitting for the Masked Language Model~(MLM) when repeating the commonly used Uniref database. To address this, we included metagenomic protein sequences in the training set to increase the diversity and avoid the plateau or overfitting effects. Second, we obtained the scaling laws of CLM and MLM on Transformer, tailored to the specific characteristics of protein sequence data. Third, we observe a transfer scaling phenomenon from CLM to MLM, further demonstrating the effectiveness of transfer through scaling behaviors based on estimated Effectively Transferred Tokens. Finally, to validate our scaling laws, we compare the large-scale versions of ESM-2 and PROGEN2 on downstream tasks, encompassing evaluations of protein generation as well as structure- and function-related tasks, all within less or equivalent pre-training compute budgets.

cs.LG↗

arXiv2024

MSAGPT: Neural Prompting Protein Structure Prediction via MSA Generative Pre-Training

Multiple Sequence Alignment (MSA) plays a pivotal role in unveiling the evolutionary trajectories of protein families. The accuracy of protein structure predictions is often compromised for protein sequences that lack sufficient homologous information to construct high quality MSA. Although various methods have been proposed to generate virtual MSA under these conditions, they fall short in comprehensively capturing the intricate coevolutionary patterns within MSA or require guidance from external oracle models. Here we introduce MSAGPT, a novel approach to prompt protein structure predictions via MSA generative pretraining in the low MSA regime. MSAGPT employs a simple yet effective 2D evolutionary positional encoding scheme to model complex evolutionary patterns. Endowed by this, its flexible 1D MSA decoding framework facilitates zero or few shot learning. Moreover, we demonstrate that leveraging the feedback from AlphaFold2 can further enhance the model capacity via Rejective Fine tuning (RFT) and Reinforcement Learning from AF2 Feedback (RLAF). Extensive experiments confirm the efficacy of MSAGPT in generating faithful virtual MSA to enhance the structure prediction accuracy. The transfer learning capabilities also highlight its great potential for facilitating other protein tasks.

q-bio.BM↗