Reflection Pretraining Enables Token-Level Self-Correction in Biological Sequence Models

Chain-of-Thought (CoT) prompting has significantly advanced task-solving capabilities in natural language processing with large language models. Unlike standard prompting, CoT encourages the model to generate intermediate reasoning steps, non-answer tokens, that help guide the model toward more accurate final outputs. These intermediate steps enable more complex reasoning processes such as error correction, memory management, future planning, and self-reflection. However, applying CoT to non-natural language domains, such as protein and RNA language models, is not yet possible, primarily due to the limited expressiveness of their token spaces (e.g., amino acid tokens). In this work, we propose and define the concept of language expressiveness: the ability of a given language, using its tokens and grammar, to encode information. We show that the limited expressiveness of protein language severely restricts the applicability of CoT-style reasoning. To overcome this, we introduce reflection pretraining, for the first time in a biological sequence model, which enables the model to engage in intermediate reasoning through the generation of auxiliary "thinking tokens" beyond simple answer tokens. Theoretically, we demonstrate that our augmented token set significantly enhances biological language expressiveness, thereby improving the overall reasoning capacity of the model. Experimentally, our pretraining approach teaches protein models to self-correct and leads to substantial performance gains compared to standard pretraining.

Accurate de novo sequencing of the modified proteome with OmniNovo

Post-translational modifications (PTMs) serve as a dynamic chemical language regulating protein function, yet current proteomic methods remain blind to a vast portion of the modified proteome. Standard database search algorithms suffer from a combinatorial explosion of search spaces, limiting the identification of uncharacterized or complex modifications. Here we introduce OmniNovo, a unified deep learning framework for reference-free sequencing of unmodified and modified peptides directly from tandem mass spectra. Unlike existing tools restricted to specific modification types, OmniNovo learns universal fragmentation rules to decipher diverse PTMs within a single coherent model. By integrating a mass-constrained decoding algorithm with rigorous false discovery rate estimation, OmniNovo achieves state-of-the-art accuracy, identifying 51\% more peptides than standard approaches at a 1\% false discovery rate. Crucially, the model generalizes to biological sites unseen during training, illuminating the dark matter of the proteome and enabling unbiased comprehensive analysis of cellular regulation.

Inference-Time Alignment Control for Diffusion Models with Reinforcement Learning Guidance

Denoising-based generative models, particularly diffusion and flow matching algorithms, have achieved remarkable success. However, aligning their output distributions with complex downstream objectives, such as human preferences, compositional accuracy, or data compressibility, remains challenging. While reinforcement learning (RL) fine-tuning methods, inspired by advances in RL from human feedback (RLHF) for large language models, have been adapted to these generative frameworks, current RL approaches are suboptimal for diffusion models and offer limited flexibility in controlling alignment strength after fine-tuning. In this work, we reinterpret RL fine-tuning for diffusion models through the lens of stochastic differential equations and implicit reward conditioning. We introduce Reinforcement Learning Guidance (RLG), an inference-time method that adapts Classifier-Free Guidance (CFG) by combining the outputs of the base and RL fine-tuned models via a geometric average. Our theoretical analysis shows that RLG's guidance scale is mathematically equivalent to adjusting the KL-regularization coefficient in standard RL objectives, enabling dynamic control over the alignment-quality trade-off without further training. Extensive experiments demonstrate that RLG consistently improves the performance of RL fine-tuned models across various architectures, RL algorithms, and downstream tasks, including human preferences, compositional control, compressibility, and text rendering. Furthermore, RLG supports both interpolation and extrapolation, thereby offering unprecedented flexibility in controlling generative alignment. Our approach provides a practical and theoretically sound solution for enhancing and controlling diffusion model alignment at inference. The source code for RLG is publicly available at the Github: https://github.com/jinluo12345/Reinforcement-learning-guidance.

Curriculum Learning for Biological Sequence Prediction: The Case of De Novo Peptide Sequencing

Peptide sequencing-the process of identifying amino acid sequences from mass spectrometry data-is a fundamental task in proteomics. Non-Autoregressive Transformers (NATs) have proven highly effective for this task, outperforming traditional methods. Unlike autoregressive models, which generate tokens sequentially, NATs predict all positions simultaneously, leveraging bidirectional context through unmasked self-attention. However, existing NAT approaches often rely on Connectionist Temporal Classification (CTC) loss, which presents significant optimization challenges due to CTC's complexity and increases the risk of training failures. To address these issues, we propose an improved non-autoregressive peptide sequencing model that incorporates a structured protein sequence curriculum learning strategy. This approach adjusts protein's learning difficulty based on the model's estimated protein generational capabilities through a sampling process, progressively learning peptide generation from simple to complex sequences. Additionally, we introduce a self-refining inference-time module that iteratively enhances predictions using learned NAT token embeddings, improving sequence accuracy at a fine-grained level. Our curriculum learning strategy reduces NAT training failures frequency by more than 90% based on sampled training over various data distributions. Evaluations on nine benchmark species demonstrate that our approach outperforms all previous methods across multiple metrics and species.

Universal Biological Sequence Reranking for Improved De Novo Peptide Sequencing

De novo peptide sequencing is a critical task in proteomics. However, the performance of current deep learning-based methods is limited by the inherent complexity of mass spectrometry data and the heterogeneous distribution of noise signals, leading to data-specific biases. We present RankNovo, the first deep reranking framework that enhances de novo peptide sequencing by leveraging the complementary strengths of multiple sequencing models. RankNovo employs a list-wise reranking approach, modeling candidate peptides as multiple sequence alignments and utilizing axial attention to extract informative features across candidates. Additionally, we introduce two new metrics, PMD (Peptide Mass Deviation) and RMD (residual Mass Deviation), which offer delicate supervision by quantifying mass differences between peptides at both the sequence and residue levels. Extensive experiments demonstrate that RankNovo not only surpasses its base models used to generate training candidates for reranking pre-training, but also sets a new state-of-the-art benchmark. Moreover, RankNovo exhibits strong zero-shot generalization to unseen models whose generations were not exposed during training, highlighting its robustness and potential as a universal reranking framework for peptide sequencing. Our work presents a novel reranking strategy that fundamentally challenges existing single-model paradigms and advances the frontier of accurate de novo sequencing. Our source code is provided on GitHub.

AlignRAG: An Adaptable Framework for Resolving Misalignments in Retrieval-Aware Reasoning of RAG

Retrieval-augmented generation (RAG) has emerged as a foundational paradigm for knowledge-grounded text generation. However, existing RAG pipelines often fail to ensure that the reasoning trajectories align with the evidential constraints imposed by retrieved content. In this paper, we reframe RAG as a problem of retrieval-aware reasoning and identify a core challenge: reasoning misalignment-the mismatch between a model's reasoning trajectory and the retrieved evidence. To address this challenge, we propose AlignRAG, a novel test-time framework that mitigates reasoning misalignment through iterative Critique-Driven Alignment (CDA) steps. In contrast to prior approaches that rely on static training or post-hoc selection, AlignRAG actively refines reasoning trajectories during inference by enforcing fine-grained alignment with evidence. Our framework introduces a new paradigm for retrieval-aware reasoning by: (1) constructing context-rich training corpora; (2) generating contrastive critiques from preference-aware reasoning trajectories; (3) training a dedicated \textit{Critic Language Model (CLM)} to identify reasoning misalignments; and (4) applying CDA steps to optimize reasoning trajectories iteratively. Empirical results demonstrate that AlignRAG consistently outperforms all baselines and could integrate as a plug-and-play module into existing RAG pipelines without further changes. By reconceptualizing RAG as a structured reasoning trajectory and establishing the test-time framework for correcting reasoning misalignments in RAG, AlignRAG provides practical advancements for retrieval-aware generation.