Daily Papers

Cis-regulatory elements (CREs), such as promoters and enhancers, are relatively short DNA sequences that directly regulate gene expression. The fitness of CREs, measured by their ability to modulate gene expression, highly depends on the nucleotide sequences, especially specific motifs known as transcription factor binding sites (TFBSs). Designing high-fitness CREs is crucial for therapeutic and bioengineering applications. Current CRE design methods are limited by two major drawbacks: (1) they typically rely on iterative optimization strategies that modify existing sequences and are prone to local optima, and (2) they lack the guidance of biological prior knowledge in sequence optimization. In this paper, we address these limitations by proposing a generative approach that leverages reinforcement learning (RL) to fine-tune a pre-trained autoregressive (AR) model. Our method incorporates data-driven biological priors by deriving computational inference-based rewards that simulate the addition of activator TFBSs and removal of repressor TFBSs, which are then integrated into the RL process. We evaluate our method on promoter design tasks in two yeast media conditions and enhancer design tasks for three human cell types, demonstrating its ability to generate high-fitness CREs while maintaining sequence diversity. The code is available at https://github.com/yangzhao1230/TACO.

We consider controllable DNA sequence design, where sequences are generated by conditioning on specific biological properties. While language models (LMs) such as GPT and BERT have achieved remarkable success in natural language generation, their application to DNA sequence generation remains largely underexplored. In this work, we introduce ATGC-Gen, an Automated Transformer Generator for Controllable Generation, which leverages cross-modal encoding to integrate diverse biological signals. ATGC-Gen is instantiated with both decoder-only and encoder-only transformer architectures, allowing flexible training and generation under either autoregressive or masked recovery objectives. We evaluate ATGC-Gen on representative tasks including promoter and enhancer sequence design, and further introduce a new dataset based on ChIP-Seq experiments for modeling protein binding specificity. Our experiments demonstrate that ATGC-Gen can generate fluent, diverse, and biologically relevant sequences aligned with the desired properties. Compared to prior methods, our model achieves notable improvements in controllability and functional relevance, highlighting the potential of language models in advancing programmable genomic design. The source code is released at (https://github.com/divelab/AIRS/blob/main/OpenBio/ATGC_Gen).

Discrete diffusion or flow models could enable faster and more controllable sequence generation than autoregressive models. We show that na\"ive linear flow matching on the simplex is insufficient toward this goal since it suffers from discontinuities in the training target and further pathologies. To overcome this, we develop Dirichlet flow matching on the simplex based on mixtures of Dirichlet distributions as probability paths. In this framework, we derive a connection between the mixtures' scores and the flow's vector field that allows for classifier and classifier-free guidance. Further, we provide distilled Dirichlet flow matching, which enables one-step sequence generation with minimal performance hits, resulting in O(L) speedups compared to autoregressive models. On complex DNA sequence generation tasks, we demonstrate superior performance compared to all baselines in distributional metrics and in achieving desired design targets for generated sequences. Finally, we show that our classifier-free guidance approach improves unconditional generation and is effective for generating DNA that satisfies design targets. Code is available at https://github.com/HannesStark/dirichlet-flow-matching.

Designing biological sequences that satisfy multiple, often conflicting, functional and biophysical criteria remains a central challenge in biomolecule engineering. While discrete flow matching models have recently shown promise for efficient sampling in high-dimensional sequence spaces, existing approaches address only single objectives or require continuous embeddings that can distort discrete distributions. We present Multi-Objective-Guided Discrete Flow Matching (MOG-DFM), a general framework to steer any pretrained discrete-time flow matching generator toward Pareto-efficient trade-offs across multiple scalar objectives. At each sampling step, MOG-DFM computes a hybrid rank-directional score for candidate transitions and applies an adaptive hypercone filter to enforce consistent multi-objective progression. We also trained two unconditional discrete flow matching models, PepDFM for diverse peptide generation and EnhancerDFM for functional enhancer DNA generation, as base generation models for MOG-DFM. We demonstrate MOG-DFM's effectiveness in generating peptide binders optimized across five properties (hemolysis, non-fouling, solubility, half-life, and binding affinity), and in designing DNA sequences with specific enhancer classes and DNA shapes. In total, MOG-DFM proves to be a powerful tool for multi-property-guided biomolecule sequence design.

Offline model-based optimization aims to maximize a black-box objective function with a static dataset of designs and their scores. In this paper, we focus on biological sequence design to maximize some sequence score. A recent approach employs bidirectional learning, combining a forward mapping for exploitation and a backward mapping for constraint, and it relies on the neural tangent kernel (NTK) of an infinitely wide network to build a proxy model. Though effective, the NTK cannot learn features because of its parametrization, and its use prevents the incorporation of powerful pre-trained Language Models (LMs) that can capture the rich biophysical information in millions of biological sequences. We adopt an alternative proxy model, adding a linear head to a pre-trained LM, and propose a linearization scheme. This yields a closed-form loss and also takes into account the biophysical information in the pre-trained LM. In addition, the forward mapping and the backward mapping play different roles and thus deserve different weights during sequence optimization. To achieve this, we train an auxiliary model and leverage its weak supervision signal via a bi-level optimization framework to effectively learn how to balance the two mappings. Further, by extending the framework, we develop the first learning rate adaptation module Adaptive-eta, which is compatible with all gradient-based algorithms for offline model-based optimization. Experimental results on DNA/protein sequence design tasks verify the effectiveness of our algorithm. Our code is available~https://anonymous.4open.science/r/BIB-ICLR2023-Submission/README.md{here.}

Designing antibody sequences to better resemble those observed in natural human repertoires is a key challenge in biologics development. We introduce IgCraft: a multi-purpose model for paired human antibody sequence generation, built on Bayesian Flow Networks. IgCraft presents one of the first unified generative modeling frameworks capable of addressing multiple antibody sequence design tasks with a single model, including unconditional sampling, sequence inpainting, inverse folding, and CDR motif scaffolding. Our approach achieves competitive results across the full spectrum of these tasks while constraining generation to the space of human antibody sequences, exhibiting particular strengths in CDR motif scaffolding (grafting) where we achieve state-of-the-art performance in terms of humanness and preservation of structural properties. By integrating previously separate tasks into a single scalable generative model, IgCraft provides a versatile platform for sampling human antibody sequences under a variety of contexts relevant to antibody discovery and engineering. Model code and weights are publicly available at github.com/mgreenig/IgCraft.

The motif-scaffolding problem is a central task in computational protein design: Given the coordinates of atoms in a geometry chosen to confer a desired biochemical function (a motif), the task is to identify diverse protein structures (scaffolds) that include the motif and maintain its geometry. Significant recent progress on motif-scaffolding has been made due to computational evaluation with reliable protein structure prediction and fixed-backbone sequence design methods. However, significant variability in evaluation strategies across publications has hindered comparability of results, challenged reproducibility, and impeded robust progress. In response we introduce MotifBench, comprising (1) a precisely specified pipeline and evaluation metrics, (2) a collection of 30 benchmark problems, and (3) an implementation of this benchmark and leaderboard at github.com/blt2114/MotifBench. The MotifBench test cases are more difficult compared to earlier benchmarks, and include protein design problems for which solutions are known but on which, to the best of our knowledge, state-of-the-art methods fail to identify any solution.

Peptides, short chains of amino acid residues, play a vital role in numerous biological processes by interacting with other target molecules, offering substantial potential in drug discovery. In this work, we present PepFlow, the first multi-modal deep generative model grounded in the flow-matching framework for the design of full-atom peptides that target specific protein receptors. Drawing inspiration from the crucial roles of residue backbone orientations and side-chain dynamics in protein-peptide interactions, we characterize the peptide structure using rigid backbone frames within the SE(3) manifold and side-chain angles on high-dimensional tori. Furthermore, we represent discrete residue types in the peptide sequence as categorical distributions on the probability simplex. By learning the joint distributions of each modality using derived flows and vector fields on corresponding manifolds, our method excels in the fine-grained design of full-atom peptides. Harnessing the multi-modal paradigm, our approach adeptly tackles various tasks such as fix-backbone sequence design and side-chain packing through partial sampling. Through meticulously crafted experiments, we demonstrate that PepFlow exhibits superior performance in comprehensive benchmarks, highlighting its significant potential in computational peptide design and analysis.

Flow matching in the continuous simplex has emerged as a promising strategy for DNA sequence design, but struggles to scale to higher simplex dimensions required for peptide and protein generation. We introduce Gumbel-Softmax Flow and Score Matching, a generative framework on the simplex based on a novel Gumbel-Softmax interpolant with a time-dependent temperature. Using this interpolant, we introduce Gumbel-Softmax Flow Matching by deriving a parameterized velocity field that transports from smooth categorical distributions to distributions concentrated at a single vertex of the simplex. We alternatively present Gumbel-Softmax Score Matching which learns to regress the gradient of the probability density. Our framework enables high-quality, diverse generation and scales efficiently to higher-dimensional simplices. To enable training-free guidance, we propose Straight-Through Guided Flows (STGFlow), a classifier-based guidance method that leverages straight-through estimators to steer the unconditional velocity field toward optimal vertices of the simplex. STGFlow enables efficient inference-time guidance using classifiers pre-trained on clean sequences, and can be used with any discrete flow method. Together, these components form a robust framework for controllable de novo sequence generation. We demonstrate state-of-the-art performance in conditional DNA promoter design, sequence-only protein generation, and target-binding peptide design for rare disease treatment.

Designing biological sequences is an important challenge that requires satisfying complex constraints and thus is a natural problem to address with deep generative modeling. Diffusion generative models have achieved considerable success in many applications. Score-based generative stochastic differential equations (SDE) model is a continuous-time diffusion model framework that enjoys many benefits, but the originally proposed SDEs are not naturally designed for modeling discrete data. To develop generative SDE models for discrete data such as biological sequences, here we introduce a diffusion process defined in the probability simplex space with stationary distribution being the Dirichlet distribution. This makes diffusion in continuous space natural for modeling discrete data. We refer to this approach as Dirchlet diffusion score model. We demonstrate that this technique can generate samples that satisfy hard constraints using a Sudoku generation task. This generative model can also solve Sudoku, including hard puzzles, without additional training. Finally, we applied this approach to develop the first human promoter DNA sequence design model and showed that designed sequences share similar properties with natural promoter sequences.

Reparameterized diffusion models (RDMs) have recently matched autoregressive methods in protein generation, motivating their use for challenging tasks such as designing membrane proteins, which possess interleaved soluble and transmembrane (TM) regions. We introduce the Membrane Diffusion Language Model (MemDLM), a fine-tuned RDM-based protein language model that enables controllable membrane protein sequence design. MemDLM-generated sequences recapitulate the TM residue density and structural features of natural membrane proteins, achieving comparable biological plausibility and outperforming state-of-the-art diffusion baselines in motif scaffolding tasks by producing lower perplexity, higher BLOSUM-62 scores, and improved pLDDT confidence. To enhance controllability, we develop Per-Token Guidance (PET), a novel classifier-guided sampling strategy that selectively solubilizes residues while preserving conserved TM domains, yielding sequences with reduced TM density but intact functional cores. Importantly, MemDLM designs validated in TOXCAT beta-lactamase growth assays demonstrate successful TM insertion, distinguishing high-quality generated sequences from poor ones. Together, our framework establishes the first experimentally-validated diffusion-based model for rational membrane protein generation, integrating de novo design, motif scaffolding, and targeted property optimization.

3D scene understanding from single images is a pivotal problem in computer vision with numerous downstream applications in graphics, augmented reality, and robotics. While diffusion-based modeling approaches have shown promise, they often struggle to maintain object and scene consistency, especially in complex real-world scenarios. To address these limitations, we propose an autoregressive generative approach called Local Random Access Sequence (LRAS) modeling, which uses local patch quantization and randomly ordered sequence generation. By utilizing optical flow as an intermediate representation for 3D scene editing, our experiments demonstrate that LRAS achieves state-of-the-art novel view synthesis and 3D object manipulation capabilities. Furthermore, we show that our framework naturally extends to self-supervised depth estimation through a simple modification of the sequence design. By achieving strong performance on multiple 3D scene understanding tasks, LRAS provides a unified and effective framework for building the next generation of 3D vision models.

Designing sequences that satisfy multiple, often conflicting, objectives is a central challenge in therapeutic and biomolecular engineering. Existing generative frameworks largely operate in continuous spaces with single-objective guidance, while discrete approaches lack guarantees for multi-objective Pareto optimality. We introduce AReUReDi (Annealed Rectified Updates for Refining Discrete Flows), a discrete optimization algorithm with theoretical guarantees of convergence to the Pareto front. Building on Rectified Discrete Flows (ReDi), AReUReDi combines Tchebycheff scalarization, locally balanced proposals, and annealed Metropolis-Hastings updates to bias sampling toward Pareto-optimal states while preserving distributional invariance. Applied to peptide and SMILES sequence design, AReUReDi simultaneously optimizes up to five therapeutic properties (including affinity, solubility, hemolysis, half-life, and non-fouling) and outperforms both evolutionary and diffusion-based baselines. These results establish AReUReDi as a powerful, sequence-based framework for multi-property biomolecule generation.

Autoregressive models have achieved promising results in natural language processing. However, for image generation tasks, they encounter substantial challenges in effectively capturing long-range dependencies, managing computational costs, and most crucially, defining meaningful autoregressive sequences that reflect natural image hierarchies. To address these issues, we present Next-Frequency Image Generation (NFIG), a novel framework that decomposes the image generation process into multiple frequency-guided stages. Our approach first generates low-frequency components to establish global structure with fewer tokens, then progressively adds higher-frequency details, following the natural spectral hierarchy of images. This principled autoregressive sequence not only improves the quality of generated images by better capturing true causal relationships between image components, but also significantly reduces computational overhead during inference. Extensive experiments demonstrate that NFIG achieves state-of-the-art performance with fewer steps, offering a more efficient solution for image generation, with 1.25times speedup compared to VAR-d20 while achieving better performance (FID: 2.81) on the ImageNet-256 benchmark. We hope that our insight of incorporating frequency-domain knowledge to guide autoregressive sequence design will shed light on future research. We will make our code publicly available upon acceptance of the paper.

Large Language Models (LLMs) have revolutionized the field of natural language processing, but they fall short in comprehending biological sequences such as proteins. To address this challenge, we propose InstructProtein, an innovative LLM that possesses bidirectional generation capabilities in both human and protein languages: (i) taking a protein sequence as input to predict its textual function description and (ii) using natural language to prompt protein sequence generation. To achieve this, we first pre-train an LLM on both protein and natural language corpora, enabling it to comprehend individual languages. Then supervised instruction tuning is employed to facilitate the alignment of these two distinct languages. Herein, we introduce a knowledge graph-based instruction generation framework to construct a high-quality instruction dataset, addressing annotation imbalance and instruction deficits in existing protein-text corpus. In particular, the instructions inherit the structural relations between proteins and function annotations in knowledge graphs, which empowers our model to engage in the causal modeling of protein functions, akin to the chain-of-thought processes in natural languages. Extensive experiments on bidirectional protein-text generation tasks show that InstructProtein outperforms state-of-the-art LLMs by large margins. Moreover, InstructProtein serves as a pioneering step towards text-based protein function prediction and sequence design, effectively bridging the gap between protein and human language understanding.

Diffusion models have shown promising generative capabilities across diverse domains, yet aligning their outputs with desired reward functions remains a challenge, particularly in cases where reward functions are non-differentiable. Some gradient-free guidance methods have been developed, but they often struggle to achieve optimal inference-time alignment. In this work, we newly frame inference-time alignment in diffusion as a search problem and propose Dynamic Search for Diffusion (DSearch), which subsamples from denoising processes and approximates intermediate node rewards. It also dynamically adjusts beam width and tree expansion to efficiently explore high-reward generations. To refine intermediate decisions, DSearch incorporates adaptive scheduling based on noise levels and a lookahead heuristic function. We validate DSearch across multiple domains, including biological sequence design, molecular optimization, and image generation, demonstrating superior reward optimization compared to existing approaches.

With the growing prominence of antibody-based therapeutics, antibody engineering has gained increasing attention as a critical area of research and development. Recent progress in transformer-based protein large language models (LLMs) has demonstrated promising applications in protein sequence design and structural prediction. Moreover, the availability of large-scale antibody datasets such as the Observed Antibody Space (OAS) database has opened new avenues for the development of LLMs specialized for processing antibody sequences. Among these, RoBERTa has demonstrated improved performance relative to BERT, while maintaining a smaller parameter count (125M) compared to the BERT-based protein model, ProtBERT (420M). This reduced model size enables more efficient deployment in antibody-related applications. However, despite the numerous advantages of the RoBERTa architecture, antibody-specific foundational models built upon it have remained inaccessible to the research community. In this study, we introduce Ab-RoBERTa, a RoBERTa-based antibody-specific LLM, which is publicly available at https://huggingface.co/mogam-ai/Ab-RoBERTa. This resource is intended to support a wide range of antibody-related research applications including paratope prediction or humanness assessment.

We propose UniTAB that Unifies Text And Box outputs for grounded vision-language (VL) modeling. Grounded VL tasks such as grounded captioning require the model to generate a text description and align predicted words with object regions. To achieve this, models must generate desired text and box outputs together, and meanwhile indicate the alignments between words and boxes. In contrast to existing solutions that use multiple separate modules for different outputs, UniTAB represents both text and box outputs with a shared token sequence, and introduces a special <obj> token to naturally indicate word-box alignments in the sequence. UniTAB thus could provide a more comprehensive and interpretable image description, by freely grounding generated words to object regions. On grounded captioning, UniTAB presents a simpler solution with a single output head, and significantly outperforms state of the art in both grounding and captioning evaluations. On general VL tasks that have different desired output formats (i.e., text, box, or their combination), UniTAB with a single network achieves better or comparable performance than task-specific state of the art. Experiments cover 7 VL benchmarks, including grounded captioning, visual grounding, image captioning, and visual question answering. Furthermore, UniTAB's unified multi-task network and the task-agnostic output sequence design make the model parameter efficient and generalizable to new tasks.

The rapid advancements in transformer-based language models have revolutionized natural language processing, yet understanding the internal mechanisms of these models remains a significant challenge. This paper explores the application of sparse autoencoders (SAE) to interpret the internal representations of protein language models, specifically focusing on the ESM-2 8M parameter model. By performing a statistical analysis on each latent component's relevance to distinct protein annotations, we identify potential interpretations linked to various protein characteristics, including transmembrane regions, binding sites, and specialized motifs. We then leverage these insights to guide sequence generation, shortlisting the relevant latent components that can steer the model towards desired targets such as zinc finger domains. This work contributes to the emerging field of mechanistic interpretability in biological sequence models, offering new perspectives on model steering for sequence design.

Generative modeling of discrete variables is challenging yet crucial for applications in natural language processing and biological sequence design. We introduce the Shortlisting Model (SLM), a novel simplex-based diffusion model inspired by progressive candidate pruning. SLM operates on simplex centroids, reducing generation complexity and enhancing scalability. Additionally, SLM incorporates a flexible implementation of classifier-free guidance, enhancing unconditional generation performance. Extensive experiments on DNA promoter and enhancer design, protein design, character-level and large-vocabulary language modeling demonstrate the competitive performance and strong potential of SLM. Our code can be found at https://github.com/GenSI-THUAIR/SLM

MRI is an indispensable clinical tool, offering a rich variety of tissue contrasts to support broad diagnostic and research applications. Clinical exams routinely acquire multiple structural sequences that provide complementary information for differential diagnosis, while research protocols often incorporate advanced functional, diffusion, spectroscopic, and relaxometry sequences to capture multidimensional insights into tissue structure and composition. However, these capabilities come at the cost of prolonged scan times, which reduce patient throughput, increase susceptibility to motion artifacts, and may require trade-offs in image quality or diagnostic scope. Over the last two decades, advances in image reconstruction algorithms--alongside improvements in hardware and pulse sequence design--have made it possible to accelerate acquisitions while preserving diagnostic quality. Central to this progress is the ability to incorporate prior information to regularize the solutions to the reconstruction problem. In this tutorial, we overview the basics of MRI reconstruction and highlight state-of-the-art approaches, beginning with classical methods that rely on explicit hand-crafted priors, and then turning to deep learning methods that leverage a combination of learned and crafted priors to further push the performance envelope. We also explore the translational aspects and eventual clinical implications of these methods. We conclude by discussing future directions to address remaining challenges in MRI reconstruction. The tutorial is accompanied by a Python toolbox (https://github.com/tutorial-MRI-recon/tutorial) to demonstrate select methods discussed in the article.

Peptide therapeutics, a major class of medicines, have achieved remarkable success across diseases such as diabetes and cancer, with landmark examples such as GLP-1 receptor agonists revolutionizing the treatment of type-2 diabetes and obesity. Despite their success, designing peptides that satisfy multiple conflicting objectives, such as target binding affinity, solubility, and membrane permeability, remains a major challenge. Classical drug development and structure-based design are ineffective for such tasks, as they fail to optimize global functional properties critical for therapeutic efficacy. Existing generative frameworks are largely limited to continuous spaces, unconditioned outputs, or single-objective guidance, making them unsuitable for discrete sequence optimization across multiple properties. To address this, we present PepTune, a multi-objective discrete diffusion model for the simultaneous generation and optimization of therapeutic peptide SMILES. Built on the Masked Discrete Language Model (MDLM) framework, PepTune ensures valid peptide structures with state-dependent masking schedules and penalty-based objectives. To guide the diffusion process, we propose a Monte Carlo Tree Search (MCTS)-based strategy that balances exploration and exploitation to iteratively refine Pareto-optimal sequences. MCTS integrates classifier-based rewards with search-tree expansion, overcoming gradient estimation challenges and data sparsity inherent to discrete spaces. Using PepTune, we generate diverse, chemically-modified peptides optimized for multiple therapeutic properties, including target binding affinity, membrane permeability, solubility, hemolysis, and non-fouling characteristics on various disease-relevant targets. In total, our results demonstrate that MCTS-guided discrete diffusion is a powerful and modular approach for multi-objective sequence design in discrete state spaces.

Recent advances in quantum information science enabled the development of quantum communication network prototypes and created an opportunity to study full-stack quantum network architectures. This work develops SeQUeNCe, a comprehensive, customizable quantum network simulator. Our simulator consists of five modules: Hardware models, Entanglement Management protocols, Resource Management, Network Management, and Application. This framework is suitable for simulation of quantum network prototypes that capture the breadth of current and future hardware technologies and protocols. We implement a comprehensive suite of network protocols and demonstrate the use of SeQUeNCe by simulating a photonic quantum network with nine routers equipped with quantum memories. The simulation capabilities are illustrated in three use cases. We show the dependence of quantum network throughput on several key hardware parameters and study the impact of classical control message latency. We also investigate quantum memory usage efficiency in routers and demonstrate that redistributing memory according to anticipated load increases network capacity by 69.1% and throughput by 6.8%. We design SeQUeNCe to enable comparisons of alternative quantum network technologies, experiment planning, and validation and to aid with new protocol design. We are releasing SeQUeNCe as an open source tool and aim to generate community interest in extending it.

Linear Sequence Modeling (LSM) like linear attention, state space models and linear RNNs, and Mixture-of-Experts (MoE) have recently emerged as significant architectural improvements. In this paper, we introduce Linear-MoE, a production-level system for modeling and training large-scale models that integrate LSM with MoE. Linear-MoE leverages the advantages of both LSM modules for linear-complexity sequence modeling and MoE layers for sparsely activation, aiming to offer high performance with efficient training. The Linear-MoE system comprises: 1) Modeling subsystem, which provides a unified framework supporting all instances of LSM. and 2) Training subsystem, which facilitates efficient training by incorporating various advanced parallelism technologies, particularly Sequence Parallelism designed for Linear-MoE models. Additionally, we explore hybrid models that combine Linear-MoE layers with standard Transformer-MoE layers with its Sequence Parallelism to further enhance model flexibility and performance. Evaluations on two model series, A0.3B-2B and A1B-7B, demonstrate Linear-MoE achieves efficiency gains while maintaining competitive performance on various benchmarks, showcasing its potential as a next-generation foundational model architecture. Code: https://github.com/OpenSparseLLMs/Linear-MoE.

Content-aware visual-textual presentation layout aims at arranging spatial space on the given canvas for pre-defined elements, including text, logo, and underlay, which is a key to automatic template-free creative graphic design. In practical applications, e.g., poster designs, the canvas is originally non-empty, and both inter-element relationships as well as inter-layer relationships should be concerned when generating a proper layout. A few recent works deal with them simultaneously, but they still suffer from poor graphic performance, such as a lack of layout variety or spatial non-alignment. Since content-aware visual-textual presentation layout is a novel task, we first construct a new dataset named PosterLayout, which consists of 9,974 poster-layout pairs and 905 images, i.e., non-empty canvases. It is more challenging and useful for greater layout variety, domain diversity, and content diversity. Then, we propose design sequence formation (DSF) that reorganizes elements in layouts to imitate the design processes of human designers, and a novel CNN-LSTM-based conditional generative adversarial network (GAN) is presented to generate proper layouts. Specifically, the discriminator is design-sequence-aware and will supervise the "design" process of the generator. Experimental results verify the usefulness of the new benchmark and the effectiveness of the proposed approach, which achieves the best performance by generating suitable layouts for diverse canvases.

Recently, diffusion models have emerged as a new paradigm for generative models. Despite the success in domains using continuous signals such as vision and audio, adapting diffusion models to natural language is under-explored due to the discrete nature of texts, especially for conditional generation. We tackle this challenge by proposing DiffuSeq: a diffusion model designed for sequence-to-sequence (Seq2Seq) text generation tasks. Upon extensive evaluation over a wide range of Seq2Seq tasks, we find DiffuSeq achieving comparable or even better performance than six established baselines, including a state-of-the-art model that is based on pre-trained language models. Apart from quality, an intriguing property of DiffuSeq is its high diversity during generation, which is desired in many Seq2Seq tasks. We further include a theoretical analysis revealing the connection between DiffuSeq and autoregressive/non-autoregressive models. Bringing together theoretical analysis and empirical evidence, we demonstrate the great potential of diffusion models in complex conditional language generation tasks. Code is available at https://github.com/Shark-NLP/DiffuSeq

In recent years, substantial advancements in pre-trained language models have paved the way for the development of numerous non-English language versions, with a particular focus on encoder-only and decoder-only architectures. While Spanish language models encompassing BERT, RoBERTa, and GPT have exhibited prowess in natural language understanding and generation, there remains a scarcity of encoder-decoder models designed for sequence-to-sequence tasks involving input-output pairs. This paper breaks new ground by introducing the implementation and evaluation of renowned encoder-decoder architectures, exclusively pre-trained on Spanish corpora. Specifically, we present Spanish versions of BART, T5, and BERT2BERT-style models and subject them to a comprehensive assessment across a diverse range of sequence-to-sequence tasks, spanning summarization, rephrasing, and generative question answering. Our findings underscore the competitive performance of all models, with BART and T5 emerging as top performers across all evaluated tasks. As an additional contribution, we have made all models publicly available to the research community, fostering future exploration and development in Spanish language processing.

In healthcare, medical image segmentation is crucial for accurate disease diagnosis and the development of effective treatment strategies. Early detection can significantly aid in managing diseases and potentially prevent their progression. Machine learning, particularly deep convolutional neural networks, has emerged as a promising approach to addressing segmentation challenges. Traditional methods like U-Net use encoding blocks for local representation modeling and decoding blocks to uncover semantic relationships. However, these models often struggle with multi-scale objects exhibiting significant variations in texture and shape, and they frequently fail to capture long-range dependencies in the input data. Transformers designed for sequence-to-sequence predictions have been proposed as alternatives, utilizing global self-attention mechanisms. Yet, they can sometimes lack precise localization due to insufficient granular details. To overcome these limitations, we introduce TransDAE: a novel approach that reimagines the self-attention mechanism to include both spatial and channel-wise associations across the entire feature space, while maintaining computational efficiency. Additionally, TransDAE enhances the skip connection pathway with an inter-scale interaction module, promoting feature reuse and improving localization accuracy. Remarkably, TransDAE outperforms existing state-of-the-art methods on the Synaps multi-organ dataset, even without relying on pre-trained weights.

A central goal of sequence modeling is designing a single principled model that can address sequence data across a range of modalities and tasks, particularly on long-range dependencies. Although conventional models including RNNs, CNNs, and Transformers have specialized variants for capturing long dependencies, they still struggle to scale to very long sequences of 10000 or more steps. A promising recent approach proposed modeling sequences by simulating the fundamental state space model (SSM) \( x'(t) = Ax(t) + Bu(t), y(t) = Cx(t) + Du(t) \), and showed that for appropriate choices of the state matrix \( A \), this system could handle long-range dependencies mathematically and empirically. However, this method has prohibitive computation and memory requirements, rendering it infeasible as a general sequence modeling solution. We propose the Structured State Space sequence model (S4) based on a new parameterization for the SSM, and show that it can be computed much more efficiently than prior approaches while preserving their theoretical strengths. Our technique involves conditioning \( A \) with a low-rank correction, allowing it to be diagonalized stably and reducing the SSM to the well-studied computation of a Cauchy kernel. S4 achieves strong empirical results across a diverse range of established benchmarks, including (i) 91\% accuracy on sequential CIFAR-10 with no data augmentation or auxiliary losses, on par with a larger 2-D ResNet, (ii) substantially closing the gap to Transformers on image and language modeling tasks, while performing generation 60times faster (iii) SoTA on every task from the Long Range Arena benchmark, including solving the challenging Path-X task of length 16k that all prior work fails on, while being as efficient as all competitors.

Music is an integral part of human culture, embodying human intelligence and creativity, of which songs compose an essential part. While various aspects of song generation have been explored by previous works, such as singing voice, vocal composition and instrumental arrangement, etc., generating songs with both vocals and accompaniment given lyrics remains a significant challenge, hindering the application of music generation models in the real world. In this light, we propose SongCreator, a song-generation system designed to tackle this challenge. The model features two novel designs: a meticulously designed dual-sequence language model (DSLM) to capture the information of vocals and accompaniment for song generation, and an additional attention mask strategy for DSLM, which allows our model to understand, generate and edit songs, making it suitable for various song-related generation tasks. Extensive experiments demonstrate the effectiveness of SongCreator by achieving state-of-the-art or competitive performances on all eight tasks. Notably, it surpasses previous works by a large margin in lyrics-to-song and lyrics-to-vocals. Additionally, it is able to independently control the acoustic conditions of the vocals and accompaniment in the generated song through different prompts, exhibiting its potential applicability. Our samples are available at https://songcreator.github.io/.

Neural scaling laws offer valuable insights for designing robust sequence processing architectures. While these laws have been extensively characterized in other modalities, their behavior in speech remains comparatively underexplored. In this work, we introduce OWLS, an open-access, reproducible suite of multilingual speech recognition and translation models spanning 0.25B to 18B parameters, with the 18B version being the largest speech model, to the best of our knowledge. OWLS leverages up to 360K hours of public speech data across 150 languages, enabling a systematic investigation into how data, model, and compute scaling each influence performance in multilingual speech tasks. We use OWLS to derive neural scaling laws, showing how final performance can be reliably predicted when scaling. One of our key findings is that scaling enhances performance on low-resource languages/dialects, helping to mitigate bias and improve the accessibility of speech technologies. Finally, we show how OWLS can be used to power new research directions by discovering emergent abilities in large-scale speech models. Model checkpoints will be released on https://huggingface.co/collections/espnet/owls-scaling-laws-for-speech-recognition-and-translation-67ab7f991c194065f057ce8d for future studies.

Medical image segmentation is an essential prerequisite for developing healthcare systems, especially for disease diagnosis and treatment planning. On various medical image segmentation tasks, the u-shaped architecture, also known as U-Net, has become the de-facto standard and achieved tremendous success. However, due to the intrinsic locality of convolution operations, U-Net generally demonstrates limitations in explicitly modeling long-range dependency. Transformers, designed for sequence-to-sequence prediction, have emerged as alternative architectures with innate global self-attention mechanisms, but can result in limited localization abilities due to insufficient low-level details. In this paper, we propose TransUNet, which merits both Transformers and U-Net, as a strong alternative for medical image segmentation. On one hand, the Transformer encodes tokenized image patches from a convolution neural network (CNN) feature map as the input sequence for extracting global contexts. On the other hand, the decoder upsamples the encoded features which are then combined with the high-resolution CNN feature maps to enable precise localization. We argue that Transformers can serve as strong encoders for medical image segmentation tasks, with the combination of U-Net to enhance finer details by recovering localized spatial information. TransUNet achieves superior performances to various competing methods on different medical applications including multi-organ segmentation and cardiac segmentation. Code and models are available at https://github.com/Beckschen/TransUNet.

This paper describes our submission to CoNLL 2018 UD Shared Task. We have extended an LSTM-based neural network designed for sequence tagging to additionally generate character-level sequences. The network was jointly trained to produce lemmas, part-of-speech tags and morphological features. Sentence segmentation, tokenization and dependency parsing were handled by UDPipe 1.2 baseline. The results demonstrate the viability of the proposed multitask architecture, although its performance still remains far from state-of-the-art.

Deep learning research for binary analysis faces a critical infrastructure gap. Today, existing datasets target single platforms, require specialized tooling, or provide only hand-engineered features incompatible with modern neural architectures; no single dataset supports accessible research and pedagogy on realistic use cases. To solve this, we introduce Binary-30K, the first heterogeneous binary dataset designed for sequence-based models like transformers. Critically, Binary-30K covers Windows, Linux, macOS, and Android across 15+ CPU architectures. With 29,793 binaries and approximately 26.93% malware representation, Binary-30K enables research on platform-invariant detection, cross-target transfer learning, and long-context binary understanding. The dataset provides pre-computed byte-level BPE tokenization alongside comprehensive structural metadata, supporting both sequence modeling and structure-aware approaches. Platform-first stratified sampling ensures representative coverage across operating systems and architectures, while distribution via Hugging Face with official train/validation/test splits enables reproducible benchmarking. The dataset is publicly available at https://huggingface.co/datasets/mjbommar/binary-30k, providing an accessible resource for researchers, practitioners, and students alike.

We present a scientific reasoning foundation model that aligns natural language with heterogeneous scientific representations. The model is pretrained on a 206B-token corpus spanning scientific text, pure sequences, and sequence-text pairs, then aligned via SFT on 40M instructions, annealed cold-start bootstrapping to elicit long-form chain-of-thought, and reinforcement learning with task-specific reward shaping, which instills deliberate scientific reasoning. It supports four capability families, covering up to 103 tasks across workflows: (i) faithful translation between text and scientific formats, (ii) text/knowledge extraction, (iii) property prediction, (iv) property classification, (v) unconditional and conditional sequence generation and design. Compared with specialist systems, our approach broadens instruction coverage, improves cross-domain generalization, and enhances fidelity. We detail data curation and training and show that cross-discipline learning strengthens transfer and downstream reliability. The model, instruct tuning datasets and the evaluation code are open-sourced at https://huggingface.co/SciReason and https://github.com/open-sciencelab/SciReason.

We propose a design pattern for tackling text ranking problems, dubbed "Expando-Mono-Duo", that has been empirically validated for a number of ad hoc retrieval tasks in different domains. At the core, our design relies on pretrained sequence-to-sequence models within a standard multi-stage ranking architecture. "Expando" refers to the use of document expansion techniques to enrich keyword representations of texts prior to inverted indexing. "Mono" and "Duo" refer to components in a reranking pipeline based on a pointwise model and a pairwise model that rerank initial candidates retrieved using keyword search. We present experimental results from the MS MARCO passage and document ranking tasks, the TREC 2020 Deep Learning Track, and the TREC-COVID challenge that validate our design. In all these tasks, we achieve effectiveness that is at or near the state of the art, in some cases using a zero-shot approach that does not exploit any training data from the target task. To support replicability, implementations of our design pattern are open-sourced in the Pyserini IR toolkit and PyGaggle neural reranking library.

Enlarging the context window of large language models (LLMs) has become a crucial research area, particularly for applications involving extremely long texts. In this work, we propose a novel training-free framework for processing long texts, utilizing a divide-and-conquer strategy to achieve comprehensive document understanding. The proposed LLMtimesMapReduce framework splits the entire document into several chunks for LLMs to read and then aggregates the intermediate answers to produce the final output. The main challenge for divide-and-conquer long text processing frameworks lies in the risk of losing essential long-range information when splitting the document, which can lead the model to produce incomplete or incorrect answers based on the segmented texts. Disrupted long-range information can be classified into two categories: inter-chunk dependency and inter-chunk conflict. We design a structured information protocol to better cope with inter-chunk dependency and an in-context confidence calibration mechanism to resolve inter-chunk conflicts. Experimental results demonstrate that LLMtimesMapReduce can outperform representative open-source and commercial long-context LLMs, and is applicable to several different models.

Large language models (LLMs) have shown remarkable potential in processing long sequences, yet efficiently serving these long-context models remains challenging due to the quadratic computational complexity of attention in the prefilling stage and the large memory footprint of the KV cache in the decoding stage. To address these issues, we introduce LServe, an efficient system that accelerates long-sequence LLM serving via hybrid sparse attention. This method unifies different hardware-friendly, structured sparsity patterns for both prefilling and decoding attention into a single framework, where computations on less important tokens are skipped block-wise. LServe demonstrates the compatibility of static and dynamic sparsity in long-context LLM attention. This design enables multiplicative speedups by combining these optimizations. Specifically, we convert half of the attention heads to nearly free streaming heads in both the prefilling and decoding stages. Additionally, we find that only a constant number of KV pages is required to preserve long-context capabilities, irrespective of context length. We then design a hierarchical KV page selection policy that dynamically prunes KV pages based on query-centric similarity. On average, LServe accelerates LLM prefilling by up to 2.9x and decoding by 1.3-2.1x over vLLM, maintaining long-context accuracy. Code is released at https://github.com/mit-han-lab/omniserve.

Computer-Aided Design (CAD) generative modeling is driving significant innovations across industrial applications. Recent works have shown remarkable progress in creating solid models from various inputs such as point clouds, meshes, and text descriptions. However, these methods fundamentally diverge from traditional industrial workflows that begin with 2D engineering drawings. The automatic generation of parametric CAD models from these 2D vector drawings remains underexplored despite being a critical step in engineering design. To address this gap, our key insight is to reframe CAD generation as a sequence-to-sequence learning problem where vector drawing primitives directly inform the generation of parametric CAD operations, preserving geometric precision and design intent throughout the transformation process. We propose Drawing2CAD, a framework with three key technical components: a network-friendly vector primitive representation that preserves precise geometric information, a dual-decoder transformer architecture that decouples command type and parameter generation while maintaining precise correspondence, and a soft target distribution loss function accommodating inherent flexibility in CAD parameters. To train and evaluate Drawing2CAD, we create CAD-VGDrawing, a dataset of paired engineering drawings and parametric CAD models, and conduct thorough experiments to demonstrate the effectiveness of our method. Code and dataset are available at https://github.com/lllssc/Drawing2CAD.

Large language models (LLMs) with long sequences begin to power more and more fundamentally new applications we use every day. Existing methods for long-sequence LLM training are neither efficient nor compatible with commonly-used training algorithms such as FlashAttention. We design Buff to address these issues. Buff decouples all of the sharding dimensions into a new hierarchical space, and systematically analyzes the memory and communication cost of LLM training. Then, it generates an effective hybrid parallelism strategy. We design a new selective overlap mechanism to mitigate the communication overhead introduced by the hybrid parallelism. We also implement memory management techniques to reduce GPU memory fragmentation. Evaluation results show that Buff generates parallelization strategies that match or outperform existing methods in model FLOPs utilization.

Human organs constantly undergo anatomical changes due to a complex mix of short-term (e.g., heartbeat) and long-term (e.g., aging) factors. Evidently, prior knowledge of these factors will be beneficial when modeling their future state, i.e., via image generation. However, most of the medical image generation tasks only rely on the input from a single image, thus ignoring the sequential dependency even when longitudinal data is available. Sequence-aware deep generative models, where model input is a sequence of ordered and timestamped images, are still underexplored in the medical imaging domain that is featured by several unique challenges: 1) Sequences with various lengths; 2) Missing data or frame, and 3) High dimensionality. To this end, we propose a sequence-aware diffusion model (SADM) for the generation of longitudinal medical images. Recently, diffusion models have shown promising results in high-fidelity image generation. Our method extends this new technique by introducing a sequence-aware transformer as the conditional module in a diffusion model. The novel design enables learning longitudinal dependency even with missing data during training and allows autoregressive generation of a sequence of images during inference. Our extensive experiments on 3D longitudinal medical images demonstrate the effectiveness of SADM compared with baselines and alternative methods. The code is available at https://github.com/ubc-tea/SADM-Longitudinal-Medical-Image-Generation.

Linear attention Transformers and their gated variants, celebrated for enabling parallel training and efficient recurrent inference, still fall short in recall-intensive tasks compared to traditional Transformers and demand significant resources for training from scratch. This paper introduces Gated Slot Attention (GSA), which enhances Attention with Bounded-memory-Control (ABC) by incorporating a gating mechanism inspired by Gated Linear Attention (GLA). Essentially, GSA comprises a two-layer GLA linked via softmax, utilizing context-aware memory reading and adaptive forgetting to improve memory capacity while maintaining compact recurrent state size. This design greatly enhances both training and inference efficiency through GLA's hardware-efficient training algorithm and reduced state size. Additionally, retaining the softmax operation is particularly beneficial in "finetuning pretrained Transformers to RNNs" (T2R) settings, reducing the need for extensive training from scratch. Extensive experiments confirm GSA's superior performance in scenarios requiring in-context recall and in T2R settings.

Training native 3D texture generative models remains a fundamental yet challenging problem, largely due to the limited availability of large-scale, high-quality 3D texture datasets. This scarcity hinders generalization to real-world scenarios. To address this, most existing methods finetune foundation image generative models to exploit their learned visual priors. However, these approaches typically generate only multi-view images and rely on post-processing to produce UV texture maps -- an essential representation in modern graphics pipelines. Such two-stage pipelines often suffer from error accumulation and spatial inconsistencies across the 3D surface. In this paper, we introduce SeqTex, a novel end-to-end framework that leverages the visual knowledge encoded in pretrained video foundation models to directly generate complete UV texture maps. Unlike previous methods that model the distribution of UV textures in isolation, SeqTex reformulates the task as a sequence generation problem, enabling the model to learn the joint distribution of multi-view renderings and UV textures. This design effectively transfers the consistent image-space priors from video foundation models into the UV domain. To further enhance performance, we propose several architectural innovations: a decoupled multi-view and UV branch design, geometry-informed attention to guide cross-domain feature alignment, and adaptive token resolution to preserve fine texture details while maintaining computational efficiency. Together, these components allow SeqTex to fully utilize pretrained video priors and synthesize high-fidelity UV texture maps without the need for post-processing. Extensive experiments show that SeqTex achieves state-of-the-art performance on both image-conditioned and text-conditioned 3D texture generation tasks, with superior 3D consistency, texture-geometry alignment, and real-world generalization.

In the field of graphic design, automating the integration of design elements into a cohesive multi-layered artwork not only boosts productivity but also paves the way for the democratization of graphic design. One existing practice is Graphic Layout Generation (GLG), which aims to layout sequential design elements. It has been constrained by the necessity for a predefined correct sequence of layers, thus limiting creative potential and increasing user workload. In this paper, we present Hierarchical Layout Generation (HLG) as a more flexible and pragmatic setup, which creates graphic composition from unordered sets of design elements. To tackle the HLG task, we introduce Graphist, the first layout generation model based on large multimodal models. Graphist efficiently reframes the HLG as a sequence generation problem, utilizing RGB-A images as input, outputs a JSON draft protocol, indicating the coordinates, size, and order of each element. We develop new evaluation metrics for HLG. Graphist outperforms prior arts and establishes a strong baseline for this field. Project homepage: https://github.com/graphic-design-ai/graphist

Antibodies comprise the most versatile class of binding molecules, with numerous applications in biomedicine. Computational design of antibodies involves generating novel and diverse sequences, while maintaining structural consistency. Unique to antibodies, designing the complementarity-determining region (CDR), which determines the antigen binding affinity and specificity, creates its own unique challenges. Recent deep learning models have shown impressive results, however the limited number of known antibody sequence/structure pairs frequently leads to degraded performance, particularly lacking diversity in the generated sequences. In our work we address this challenge by leveraging Model Reprogramming (MR), which repurposes pretrained models on a source language to adapt to the tasks that are in a different language and have scarce data - where it may be difficult to train a high-performing model from scratch or effectively fine-tune an existing pre-trained model on the specific task. Specifically, we introduce ReprogBert in which a pretrained English language model is repurposed for protein sequence infilling - thus considers cross-language adaptation using less data. Results on antibody design benchmarks show that our model on low-resourced antibody sequence dataset provides highly diverse CDR sequences, up to more than a two-fold increase of diversity over the baselines, without losing structural integrity and naturalness. The generated sequences also demonstrate enhanced antigen binding specificity and virus neutralization ability. Code is available at https://github.com/IBM/ReprogBERT

The alignment between RNA sequences and structures in foundation models (FMs) has yet to be thoroughly investigated. Existing FMs have struggled to establish sequence-structure alignment, hindering the free flow of genomic information between RNA sequences and structures. In this study, we introduce OmniGenome, an RNA FM trained to align RNA sequences with respect to secondary structures based on structure-contextualised modelling. The alignment enables free and bidirectional mappings between sequences and structures by utilising the flexible RNA modelling paradigm that supports versatile input and output modalities, i.e., sequence and/or structure as input/output. We implement RNA design and zero-shot secondary structure prediction as case studies to evaluate the Seq2Str and Str2Seq mapping capacity of OmniGenome. Results on the EternaV2 benchmark show that OmniGenome solved 74% of puzzles, whereas existing FMs only solved up to 3% of the puzzles due to the oversight of sequence-structure alignment. We leverage four comprehensive in-silico genome modelling benchmarks to evaluate performance across a diverse set of genome downstream tasks, where the results show that OmniGenome achieves state-of-the-art performance on RNA and DNA benchmarks, even without any training on DNA genomes.

In the rapidly evolving landscape of deep learning, the quest for models that balance expressivity with computational efficiency has never been more critical. This paper introduces Orchid, a novel architecture that reimagines sequence modeling by incorporating a new data-dependent convolution mechanism. Orchid is designed to address the inherent limitations of traditional attention mechanisms, particularly their quadratic complexity, without compromising the ability to capture long-range dependencies and in-context learning. At the core of Orchid lies the data-dependent convolution layer, which dynamically adjusts its kernel conditioned on input data using a dedicated conditioning neural network. We design two simple conditioning networks that maintain shift equivariance in the adaptive convolution operation. The dynamic nature of data-dependent convolution kernel, coupled with gating operations, grants Orchid high expressivity while maintaining efficiency and quasilinear scalability for long sequences. We rigorously evaluate Orchid across multiple domains, including language modeling and image classification, to showcase its performance and generality. Our experiments demonstrate that Orchid architecture not only outperforms traditional attention-based architectures such as BERT and Vision Transformers with smaller model sizes, but also extends the feasible sequence length beyond the limitations of the dense attention layers. This achievement represents a significant step towards more efficient and scalable deep learning models for sequence modeling.

Target proteins that lack accessible binding pockets and conformational stability have posed increasing challenges for drug development. Induced proximity strategies, such as PROTACs and molecular glues, have thus gained attention as pharmacological alternatives, but still require small molecule docking at binding pockets for targeted protein degradation (TPD). The computational design of protein-based binders presents unique opportunities to access undruggable targets, but have often relied on stable 3D structures or predictions for effective binder generation. Recently, we have leveraged the expressive latent spaces of protein language models (pLMs) for the prioritization of peptide binders from sequence alone, which we have then fused to E3 ubiquitin ligase domains, creating a CRISPR-analogous TPD system for target proteins. However, our methods rely on training discriminator models for ranking heuristically or unconditionally-derived guide peptides for their target binding capability. In this work, we introduce PepMLM, a purely target sequence-conditioned de novo generator of linear peptide binders. By employing a novel masking strategy that uniquely positions cognate peptide sequences at the terminus of target protein sequences, PepMLM tasks the state-of-the-art ESM-2 pLM to fully reconstruct the binder region, achieving low perplexities matching or improving upon previously-validated peptide-protein sequence pairs. After successful in silico benchmarking with AlphaFold-Multimer, we experimentally verify PepMLM's efficacy via fusion of model-derived peptides to E3 ubiquitin ligase domains, demonstrating endogenous degradation of target substrates in cellular models. In total, PepMLM enables the generative design of candidate binders to any target protein, without the requirement of target structure, empowering downstream programmable proteome editing applications.

Transformer has achieved remarkable success in language, image, and speech processing. Recently, various efficient attention architectures have been proposed to improve transformer's efficiency while largely preserving its efficacy, especially in modeling long sequences. A widely-used benchmark to test these efficient methods' capability on long-range modeling is Long Range Arena (LRA). However, LRA only focuses on the standard bidirectional (or noncausal) self attention, and completely ignores cross attentions and unidirectional (or causal) attentions, which are equally important to downstream applications. Although designing cross and causal variants of an attention method is straightforward for vanilla attention, it is often challenging for efficient attentions with subquadratic time and memory complexity. In this paper, we propose Comprehensive Attention Benchmark (CAB) under a fine-grained attention taxonomy with four distinguishable attention patterns, namely, noncausal self, causal self, noncausal cross, and causal cross attentions. CAB collects seven real-world tasks from different research areas to evaluate efficient attentions under the four attention patterns. Among these tasks, CAB validates efficient attentions in eight backbone networks to show their generalization across neural architectures. We conduct exhaustive experiments to benchmark the performances of nine widely-used efficient attention architectures designed with different philosophies on CAB. Extensive experimental results also shed light on the fundamental problems of efficient attentions, such as efficiency length against vanilla attention, performance consistency across attention patterns, the benefit of attention mechanisms, and interpolation/extrapolation on long-context language modeling.

Human motion generation stands as a significant pursuit in generative computer vision, while achieving long-sequence and efficient motion generation remains challenging. Recent advancements in state space models (SSMs), notably Mamba, have showcased considerable promise in long sequence modeling with an efficient hardware-aware design, which appears to be a promising direction to build motion generation model upon it. Nevertheless, adapting SSMs to motion generation faces hurdles since the lack of a specialized design architecture to model motion sequence. To address these challenges, we propose Motion Mamba, a simple and efficient approach that presents the pioneering motion generation model utilized SSMs. Specifically, we design a Hierarchical Temporal Mamba (HTM) block to process temporal data by ensemble varying numbers of isolated SSM modules across a symmetric U-Net architecture aimed at preserving motion consistency between frames. We also design a Bidirectional Spatial Mamba (BSM) block to bidirectionally process latent poses, to enhance accurate motion generation within a temporal frame. Our proposed method achieves up to 50% FID improvement and up to 4 times faster on the HumanML3D and KIT-ML datasets compared to the previous best diffusion-based method, which demonstrates strong capabilities of high-quality long sequence motion modeling and real-time human motion generation. See project website https://steve-zeyu-zhang.github.io/MotionMamba/

Multimodal protein language models (PLMs) integrate sequence and token-based structural information, serving as a powerful foundation for protein modeling, generation, and design. However, the reliance on tokenizing 3D structures into discrete tokens causes substantial loss of fidelity about fine-grained structural details and correlations. In this paper, we systematically elucidate the design space of multimodal PLMs to overcome their limitations. We identify tokenization loss and inaccurate structure token predictions by the PLMs as major bottlenecks. To address these, our proposed design space covers improved generative modeling, structure-aware architectures and representation learning, and data exploration. Our advancements approach finer-grained supervision, demonstrating that token-based multimodal PLMs can achieve robust structural modeling. The effective design methods dramatically improve the structure generation diversity, and notably, folding abilities of our 650M model by reducing the RMSD from 5.52 to 2.36 on PDB testset, even outperforming 3B baselines and on par with the specialized folding models.

We present trellis networks, a new architecture for sequence modeling. On the one hand, a trellis network is a temporal convolutional network with special structure, characterized by weight tying across depth and direct injection of the input into deep layers. On the other hand, we show that truncated recurrent networks are equivalent to trellis networks with special sparsity structure in their weight matrices. Thus trellis networks with general weight matrices generalize truncated recurrent networks. We leverage these connections to design high-performing trellis networks that absorb structural and algorithmic elements from both recurrent and convolutional models. Experiments demonstrate that trellis networks outperform the current state of the art methods on a variety of challenging benchmarks, including word-level language modeling and character-level language modeling tasks, and stress tests designed to evaluate long-term memory retention. The code is available at https://github.com/locuslab/trellisnet .

Computer-aided design (CAD) significantly enhances the efficiency, accuracy, and innovation of design processes by enabling precise 2D and 3D modeling, extensive analysis, and optimization. Existing methods for creating CAD models rely on latent vectors or point clouds, which are difficult to obtain and costly to store. Recent advances in Multimodal Large Language Models (MLLMs) have inspired researchers to use natural language instructions and images for CAD model construction. However, these models still struggle with inferring accurate 3D spatial location and orientation, leading to inaccuracies in determining the spatial 3D starting points and extrusion directions for constructing geometries. This work introduces CAD-GPT, a CAD synthesis method with spatial reasoning-enhanced MLLM that takes either a single image or a textual description as input. To achieve precise spatial inference, our approach introduces a 3D Modeling Spatial Mechanism. This method maps 3D spatial positions and 3D sketch plane rotation angles into a 1D linguistic feature space using a specialized spatial unfolding mechanism, while discretizing 2D sketch coordinates into an appropriate planar space to enable precise determination of spatial starting position, sketch orientation, and 2D sketch coordinate translations. Extensive experiments demonstrate that CAD-GPT consistently outperforms existing state-of-the-art methods in CAD model synthesis, both quantitatively and qualitatively.

This paper demonstrates that language models are strong structure-based protein designers. We present LM-Design, a generic approach to reprogramming sequence-based protein language models (pLMs), that have learned massive sequential evolutionary knowledge from the universe of natural protein sequences, to acquire an immediate capability to design preferable protein sequences for given folds. We conduct a structural surgery on pLMs, where a lightweight structural adapter is implanted into pLMs and endows it with structural awareness. During inference, iterative refinement is performed to effectively optimize the generated protein sequences. Experiments show that LM-Design improves the state-of-the-art results by a large margin, leading to up to 4% to 12% accuracy gains in sequence recovery (e.g., 55.65%/56.63% on CATH 4.2/4.3 single-chain benchmarks, and >60% when designing protein complexes). We provide extensive and in-depth analyses, which verify that LM-Design can (1) indeed leverage both structural and sequential knowledge to accurately handle structurally non-deterministic regions, (2) benefit from scaling data and model size, and (3) generalize to other proteins (e.g., antibodies and de novo proteins)

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.

State-based sequence models like RWKV-7 offer a compelling alternative to Transformer architectures, achieving linear complexity while demonstrating greater expressive power in short-context scenarios and enabling state tracking beyond the \(TC^0\) complexity class. However, RWKV-7 lacks mechanisms for token-parameter interactions and native scalability, limiting its adaptability and growth without retraining. In this paper, we propose Meta-State, a novel extension to RWKV-7 that replaces attention mechanisms with a fully state-driven approach, integrating token-parameter interactions through a Self-State Encoder (SSE) mechanism. The SSE repurposes a portion of the RWKV-7 Weighted Key-Value (WKV) state as transformation weights to encode token-parameter interactions in a linear, state-driven manner without introducing new trainable matrices or softmax operations, while preserving the autoregressive property of token processing. Meta-State supports progressive model scaling by expanding the WKV state and parameter tokens, reusing existing parameters without retraining. Our approach bridges the gap between state-based modeling, token-parameter interactions, and scalable architectures, offering a flexible framework for efficient and adaptable sequence modeling with linear complexity and constant memory usage.

Designing control policies whose performance level is guaranteed to remain above a given threshold in a span of environments is a critical feature for the adoption of reinforcement learning (RL) in real-world applications. The search for such robust policies is a notoriously difficult problem, related to the so-called dynamic model of transition function uncertainty, where the environment dynamics are allowed to change at each time step. But in practical cases, one is rather interested in robustness to a span of static transition models throughout interaction episodes. The static model is known to be harder to solve than the dynamic one, and seminal algorithms, such as robust value iteration, as well as most recent works on deep robust RL, build upon the dynamic model. In this work, we propose to revisit the static model. We suggest an analysis of why solving the static model under some mild hypotheses is a reasonable endeavor, based on an equivalence with the dynamic model, and formalize the general intuition that robust MDPs can be solved by tackling a series of static problems. We introduce a generic meta-algorithm called IWOCS, which incrementally identifies worst-case transition models so as to guide the search for a robust policy. Discussion on IWOCS sheds light on new ways to decouple policy optimization and adversarial transition functions and opens new perspectives for analysis. We derive a deep RL version of IWOCS and demonstrate it is competitive with state-of-the-art algorithms on classical benchmarks.

Automatic black-and-white image sequence colorization while preserving character and object identity (ID) is a complex task with significant market demand, such as in cartoon or comic series colorization. Despite advancements in visual colorization using large-scale generative models like diffusion models, challenges with controllability and identity consistency persist, making current solutions unsuitable for industrial application.To address this, we propose ColorFlow, a three-stage diffusion-based framework tailored for image sequence colorization in industrial applications. Unlike existing methods that require per-ID finetuning or explicit ID embedding extraction, we propose a novel robust and generalizable Retrieval Augmented Colorization pipeline for colorizing images with relevant color references. Our pipeline also features a dual-branch design: one branch for color identity extraction and the other for colorization, leveraging the strengths of diffusion models. We utilize the self-attention mechanism in diffusion models for strong in-context learning and color identity matching. To evaluate our model, we introduce ColorFlow-Bench, a comprehensive benchmark for reference-based colorization. Results show that ColorFlow outperforms existing models across multiple metrics, setting a new standard in sequential image colorization and potentially benefiting the art industry. We release our codes and models on our project page: https://zhuang2002.github.io/ColorFlow/.

Despite significant popularity, Large-language Models (LLMs) require explicit, contextual facts to support domain-specific knowledge-intensive tasks in the design process. The applications built using LLMs should hence adopt Retrieval-Augmented Generation (RAG) to better suit the design process. In this article, we present a data-driven method to identify explicit facts from patent documents that provide standard descriptions of over 8 million artefacts. In our method, we train roBERTa Transformer-based sequence classification models using our dataset of 44,227 sentences and facts. Upon classifying tokens in a sentence as entities or relationships, our method uses another classifier to identify specific relationship tokens for a given pair of entities so that explicit facts of the form head entity :: relationship :: tail entity are identified. In the benchmark approaches for constructing facts, we use linear classifiers and Graph Neural Networks (GNNs) both incorporating BERT Transformer-based token embeddings to predict associations among the entities and relationships. We apply our method to 4,870 fan system related patents and populate a knowledge base of around 3 million facts. Upon retrieving the facts representing generalisable domain knowledge and the knowledge of specific subsystems and issues, we demonstrate how these facts contextualise LLMs for generating text that is more relevant to the design process.

We study the problem of extrapolative controlled generation, i.e., generating sequences with attribute values beyond the range seen in training. This task is of significant importance in automated design, especially drug discovery, where the goal is to design novel proteins that are better (e.g., more stable) than existing sequences. Thus, by definition, the target sequences and their attribute values are out of the training distribution, posing challenges to existing methods that aim to directly generate the target sequence. Instead, in this work, we propose Iterative Controlled Extrapolation (ICE) which iteratively makes local edits to a sequence to enable extrapolation. We train the model on synthetically generated sequence pairs that demonstrate small improvement in the attribute value. Results on one natural language task (sentiment analysis) and two protein engineering tasks (ACE2 stability and AAV fitness) show that ICE considerably outperforms state-of-the-art approaches despite its simplicity. Our code and models are available at: https://github.com/vishakhpk/iter-extrapolation.

Models using structured state space sequence (S4) layers have achieved state-of-the-art performance on long-range sequence modeling tasks. An S4 layer combines linear state space models (SSMs), the HiPPO framework, and deep learning to achieve high performance. We build on the design of the S4 layer and introduce a new state space layer, the S5 layer. Whereas an S4 layer uses many independent single-input, single-output SSMs, the S5 layer uses one multi-input, multi-output SSM. We establish a connection between S5 and S4, and use this to develop the initialization and parameterization used by the S5 model. The result is a state space layer that can leverage efficient and widely implemented parallel scans, allowing S5 to match the computational efficiency of S4, while also achieving state-of-the-art performance on several long-range sequence modeling tasks. S5 averages 87.4% on the long range arena benchmark, and 98.5% on the most difficult Path-X task.

Recent advancements in sequence prediction have significantly improved the accuracy of video data interpretation; however, existing models often overlook the potential of attention-based mechanisms for next-frame prediction. This study introduces the Vision Augmentation Prediction Autoencoder with Attention Design (VAPAAD), an innovative approach that integrates attention mechanisms into sequence prediction, enabling nuanced analysis and understanding of temporal dynamics in video sequences. Utilizing the Moving MNIST dataset, we demonstrate VAPAAD's robust performance and superior handling of complex temporal data compared to traditional methods. VAPAAD combines data augmentation, ConvLSTM2D layers, and a custom-built self-attention mechanism to effectively focus on salient features within a sequence, enhancing predictive accuracy and context-aware analysis. This methodology not only adheres to human cognitive processes during video interpretation but also addresses limitations in conventional models, which often struggle with the variability inherent in video sequences. The experimental results confirm that VAPAAD outperforms existing models, especially in integrating attention mechanisms, which significantly improve predictive performance.

We introduce MeshPad, a generative approach that creates 3D meshes from sketch inputs. Building on recent advances in artistic-designed triangle mesh generation, our approach addresses the need for interactive artistic mesh creation. To this end, we focus on enabling consistent edits by decomposing editing into 'deletion' of regions of a mesh, followed by 'addition' of new mesh geometry. Both operations are invoked by simple user edits of a sketch image, facilitating an iterative content creation process and enabling the construction of complex 3D meshes. Our approach is based on a triangle sequence-based mesh representation, exploiting a large Transformer model for mesh triangle addition and deletion. In order to perform edits interactively, we introduce a vertex-aligned speculative prediction strategy on top of our additive mesh generator. This speculator predicts multiple output tokens corresponding to a vertex, thus significantly reducing the computational cost of inference and accelerating the editing process, making it possible to execute each editing step in only a few seconds. Comprehensive experiments demonstrate that MeshPad outperforms state-of-the-art sketch-conditioned mesh generation methods, achieving more than 22% mesh quality improvement in Chamfer distance, and being preferred by 90% of participants in perceptual evaluations.

Many large language models (LLMs) for medicine have largely been evaluated on short texts, and their ability to handle longer sequences such as a complete electronic health record (EHR) has not been systematically explored. Assessing these models on long sequences is crucial since prior work in the general domain has demonstrated performance degradation of LLMs on longer texts. Motivated by this, we introduce LongBoX, a collection of seven medical datasets in text-to-text format, designed to investigate model performance on long sequences. Preliminary experiments reveal that both medical LLMs (e.g., BioGPT) and strong general domain LLMs (e.g., FLAN-T5) struggle on this benchmark. We further evaluate two techniques designed for long-sequence handling: (i) local-global attention, and (ii) Fusion-in-Decoder (FiD). Our results demonstrate mixed results with long-sequence handling - while scores on some datasets increase, there is substantial room for improvement. We hope that LongBoX facilitates the development of more effective long-sequence techniques for the medical domain. Data and source code are available at https://github.com/Mihir3009/LongBoX.

Neural text generation models are typically trained by maximizing log-likelihood with the sequence cross entropy (CE) loss, which encourages an exact token-by-token match between a target sequence with a generated sequence. Such training objective is sub-optimal when the target sequence is not perfect, e.g., when the target sequence is corrupted with noises, or when only weak sequence supervision is available. To address the challenge, we propose a novel Edit-Invariant Sequence Loss (EISL), which computes the matching loss of a target n-gram with all n-grams in the generated sequence. EISL is designed to be robust to various noises and edits in the target sequences. Moreover, the EISL computation is essentially an approximate convolution operation with target n-grams as kernels, which is easy to implement and efficient to compute with existing libraries. To demonstrate the effectiveness of EISL, we conduct experiments on a wide range of tasks, including machine translation with noisy target sequences, unsupervised text style transfer with only weak training signals, and non-autoregressive generation with non-predefined generation order. Experimental results show our method significantly outperforms the common CE loss and other strong baselines on all the tasks. EISL has a simple API that can be used as a drop-in replacement of the CE loss: https://github.com/guangyliu/EISL.

Pre-trained large language models demonstrate potential in extracting information from DNA sequences, yet adapting to a variety of tasks and data modalities remains a challenge. To address this, we propose DNAGPT, a generalized DNA pre-training model trained on over 200 billion base pairs from all mammals. By enhancing the classic GPT model with a binary classification task (DNA sequence order), a numerical regression task (guanine-cytosine content prediction), and a comprehensive token language, DNAGPT can handle versatile DNA analysis tasks while processing both sequence and numerical data. Our evaluation of genomic signal and region recognition, mRNA abundance regression, and artificial genomes generation tasks demonstrates DNAGPT's superior performance compared to existing models designed for specific downstream tasks, benefiting from pre-training using the newly designed model structure.

Sequence Parallel (SP) serves as a prevalent strategy to handle long sequences that exceed the memory limit of a single GPU. However, existing SP methods do not take advantage of linear attention features, resulting in sub-optimal parallelism efficiency and usability for linear attention-based language models. In this paper, we introduce Linear Attention Sequence Parallel (LASP), an efficient SP method tailored to linear attention-based language models. Specifically, we design an efficient point-to-point communication mechanism to leverage the right-product kernel trick of linear attention, which sharply decreases the communication overhead of SP. We also enhance the practical efficiency of LASP by performing kernel fusion and intermediate state caching, making the implementation of LASP hardware-friendly on GPU clusters. Furthermore, we meticulously ensure the compatibility of sequence-level LASP with all types of batch-level data parallel methods, which is vital for distributed training on large clusters with long sequences and large batches. We conduct extensive experiments on two linear attention-based models with varying sequence lengths and GPU cluster sizes. LASP scales sequence length up to 4096K using 128 A100 80G GPUs on 1B models, which is 8 times longer than existing SP methods while being significantly faster. The code is available at https://github.com/OpenNLPLab/LASP.

Reinforcement learning (RL) is typically concerned with estimating stationary policies or single-step models, leveraging the Markov property to factorize problems in time. However, we can also view RL as a generic sequence modeling problem, with the goal being to produce a sequence of actions that leads to a sequence of high rewards. Viewed in this way, it is tempting to consider whether high-capacity sequence prediction models that work well in other domains, such as natural-language processing, can also provide effective solutions to the RL problem. To this end, we explore how RL can be tackled with the tools of sequence modeling, using a Transformer architecture to model distributions over trajectories and repurposing beam search as a planning algorithm. Framing RL as sequence modeling problem simplifies a range of design decisions, allowing us to dispense with many of the components common in offline RL algorithms. We demonstrate the flexibility of this approach across long-horizon dynamics prediction, imitation learning, goal-conditioned RL, and offline RL. Further, we show that this approach can be combined with existing model-free algorithms to yield a state-of-the-art planner in sparse-reward, long-horizon tasks.

Linear State Space Models (SSMs) have demonstrated strong performance in a variety of sequence modeling tasks due to their efficient encoding of the recurrent structure. However, in more comprehensive tasks like language modeling and machine translation, self-attention-based models still outperform SSMs. Hybrid models employing both SSM and self-attention generally show promising performance, but current approaches apply attention modules statically and uniformly to all elements in the input sequences, leading to sub-optimal quality-efficiency trade-offs. In this work, we introduce Sparse Modular Activation (SMA), a general mechanism enabling neural networks to sparsely and dynamically activate sub-modules for sequence elements in a differentiable manner. Through allowing each element to skip non-activated sub-modules, SMA reduces computation and memory consumption at both training and inference stages of sequence modeling. As a specific instantiation of SMA, we design a novel neural architecture, SeqBoat, which employs SMA to sparsely activate a Gated Attention Unit (GAU) based on the state representations learned from an SSM. By constraining the GAU to only conduct local attention on the activated inputs, SeqBoat can achieve linear inference complexity with theoretically infinite attention span, and provide substantially better quality-efficiency trade-off than the chunking-based models. With experiments on a wide range of tasks, including language modeling, speech classification and long-range arena, SeqBoat brings new state-of-the-art results among hybrid models with linear complexity and reveals the amount of attention needed for each task through the learned sparse activation patterns.

Blind Omnidirectional Image Quality Assessment (BOIQA) aims to objectively assess the human perceptual quality of omnidirectional images (ODIs) without relying on pristine-quality image information. It is becoming more significant with the increasing advancement of virtual reality (VR) technology. However, the quality assessment of ODIs is severely hampered by the fact that the existing BOIQA pipeline lacks the modeling of the observer's browsing process. To tackle this issue, we propose a novel multi-sequence network for BOIQA called Assessor360, which is derived from the realistic multi-assessor ODI quality assessment procedure. Specifically, we propose a generalized Recursive Probability Sampling (RPS) method for the BOIQA task, combining content and details information to generate multiple pseudo-viewport sequences from a given starting point. Additionally, we design a Multi-scale Feature Aggregation (MFA) module with a Distortion-aware Block (DAB) to fuse distorted and semantic features of each viewport. We also devise Temporal Modeling Module (TMM) to learn the viewport transition in the temporal domain. Extensive experimental results demonstrate that Assessor360 outperforms state-of-the-art methods on multiple OIQA datasets. The code and models are available at https://github.com/TianheWu/Assessor360.

Large language models are increasingly capable of handling long-context inputs, but the memory overhead of key-value (KV) cache remains a major bottleneck for general-purpose deployment. While various compression strategies have been explored, sequence-level compression, which drops the full KV caches for certain tokens, is particularly challenging as it can lead to the loss of important contextual information. To address this, we introduce UniGist, a sequence-level long-context compression framework that efficiently preserves context information by replacing raw tokens with special compression tokens (gists) in a fine-grained manner. We adopt a chunk-free training strategy and design an efficient kernel with a gist shift trick, enabling optimized GPU training. Our scheme also supports flexible inference by allowing the actual removal of compressed tokens, resulting in real-time memory savings. Experiments across multiple long-context tasks demonstrate that UniGist significantly improves compression quality, with especially strong performance in detail-recalling tasks and long-range dependency modeling.

In this work, we propose sequence-level certainty as a common theme over hallucination in Knowledge Grounded Dialogue Generation (KGDG). We explore the correlation between the level of hallucination and two types of sequence-level certainty: probabilistic certainty and semantic certainty. Empirical results reveal that a higher level of both types of sequence-level certainty in model responses is correlated with a lower level of hallucination. We further propose Certainty-based Response Ranking (CRR), a decoding-time hallucination mitigation method that ranks response candidates based on their sequence-level certainty and outputs the answer with the highest certainty level. Aligning with our definitions of sequence-level certainty, we design 2 types of CRR approaches: Probabilistic CRR (P-CRR) and Semantic CRR (S-CRR). P-CRR ranks individually sampled model responses using the arithmetic mean log-probability of the entire sequence. S-CRR approaches certainty estimation from meaning-space, and ranks model response candidates based on their semantic certainty level as measured by an entailment-based Agreement Score (AS). Through extensive experiments across 3 KGDG datasets, 3 decoding methods, and 4 different models, we validate the effectiveness of the CRR methods in reducing model hallucination.

Innovations like protein diffusion have enabled significant progress in de novo protein design, which is a vital topic in life science. These methods typically depend on protein structure encoders to model residue backbone frames, where atoms do not exist. Most prior encoders rely on atom-wise features, such as angles and distances between atoms, which are not available in this context. Thus far, only several simple encoders, such as IPA, have been proposed for this scenario, exposing the frame modeling as a bottleneck. In this work, we proffer the Vector Field Network (VFN), which enables network layers to perform learnable vector computations between coordinates of frame-anchored virtual atoms, thus achieving a higher capability for modeling frames. The vector computation operates in a manner similar to a linear layer, with each input channel receiving 3D virtual atom coordinates instead of scalar values. The multiple feature vectors output by the vector computation are then used to update the residue representations and virtual atom coordinates via attention aggregation. Remarkably, VFN also excels in modeling both frames and atoms, as the real atoms can be treated as the virtual atoms for modeling, positioning VFN as a potential universal encoder. In protein diffusion (frame modeling), VFN exhibits an impressive performance advantage over IPA, excelling in terms of both designability (67.04% vs. 53.58%) and diversity (66.54% vs. 51.98%). In inverse folding (frame and atom modeling), VFN outperforms the previous SoTA model, PiFold (54.7% vs. 51.66%), on sequence recovery rate. We also propose a method of equipping VFN with the ESM model, which significantly surpasses the previous ESM-based SoTA (62.67% vs. 55.65%), LM-Design, by a substantial margin.

Traditional molecular string representations, such as SMILES, often pose challenges for AI-driven molecular design due to their non-sequential depiction of molecular substructures. To address this issue, we introduce Sequential Attachment-based Fragment Embedding (SAFE), a novel line notation for chemical structures. SAFE reimagines SMILES strings as an unordered sequence of interconnected fragment blocks while maintaining full compatibility with existing SMILES parsers. It streamlines complex generative tasks, including scaffold decoration, fragment linking, polymer generation, and scaffold hopping, while facilitating autoregressive generation for fragment-constrained design, thereby eliminating the need for intricate decoding or graph-based models. We demonstrate the effectiveness of SAFE by training an 87-million-parameter GPT2-like model on a dataset containing 1.1 billion SAFE representations. Through extensive experimentation, we show that our SAFE-GPT model exhibits versatile and robust optimization performance. SAFE opens up new avenues for the rapid exploration of chemical space under various constraints, promising breakthroughs in AI-driven molecular design.

Computational RNA design tasks are often posed as inverse problems, where sequences are designed based on adopting a single desired secondary structure without considering 3D geometry and conformational diversity. We introduce gRNAde, a geometric RNA design pipeline operating on 3D RNA backbones to design sequences that explicitly account for structure and dynamics. Under the hood, gRNAde is a multi-state Graph Neural Network that generates candidate RNA sequences conditioned on one or more 3D backbone structures where the identities of the bases are unknown. On a single-state fixed backbone re-design benchmark of 14 RNA structures from the PDB identified by Das et al. [2010], gRNAde obtains higher native sequence recovery rates (56% on average) compared to Rosetta (45% on average), taking under a second to produce designs compared to the reported hours for Rosetta. We further demonstrate the utility of gRNAde on a new benchmark of multi-state design for structurally flexible RNAs, as well as zero-shot ranking of mutational fitness landscapes in a retrospective analysis of a recent ribozyme. Open source code: https://github.com/chaitjo/geometric-rna-design

While artificial intelligence has made remarkable strides in revealing the relationship between biological macromolecules' primary sequence and tertiary structure, designing RNA sequences based on specified tertiary structures remains challenging. Though existing approaches in protein design have thoroughly explored structure-to-sequence dependencies in proteins, RNA design still confronts difficulties due to structural complexity and data scarcity. Moreover, direct transplantation of protein design methodologies into RNA design fails to achieve satisfactory outcomes although sharing similar structural components. In this study, we aim to systematically construct a data-driven RNA design pipeline. We crafted a large, well-curated benchmark dataset and designed a comprehensive structural modeling approach to represent the complex RNA tertiary structure. More importantly, we proposed a hierarchical data-efficient representation learning framework that learns structural representations through contrastive learning at both cluster-level and sample-level to fully leverage the limited data. By constraining data representations within a limited hyperspherical space, the intrinsic relationships between data points could be explicitly imposed. Moreover, we incorporated extracted secondary structures with base pairs as prior knowledge to facilitate the RNA design process. Extensive experiments demonstrate the effectiveness of our proposed method, providing a reliable baseline for future RNA design tasks. The source code and benchmark dataset are available at https://github.com/A4Bio/RDesign.

The transformer model is known to be computationally demanding, and prohibitively costly for long sequences, as the self-attention module uses a quadratic time and space complexity with respect to sequence length. Many researchers have focused on designing new forms of self-attention or introducing new parameters to overcome this limitation, however a large portion of them prohibits the model to inherit weights from large pretrained models. In this work, the transformer's inefficiency has been taken care of from another perspective. We propose Fourier Transformer, a simple yet effective approach by progressively removing redundancies in hidden sequence using the ready-made Fast Fourier Transform (FFT) operator to perform Discrete Cosine Transformation (DCT). Fourier Transformer is able to significantly reduce computational costs while retain the ability to inherit from various large pretrained models. Experiments show that our model achieves state-of-the-art performances among all transformer-based models on the long-range modeling benchmark LRA with significant improvement in both speed and space. For generative seq-to-seq tasks including CNN/DailyMail and ELI5, by inheriting the BART weights our model outperforms the standard BART and other efficient models. Our code is publicly available at \url{https://github.com/LUMIA-Group/FourierTransformer}

Recent advancements in specialized large-scale architectures for training image and language have profoundly impacted the field of computer vision and natural language processing (NLP). Language models, such as the recent ChatGPT and GPT4 have demonstrated exceptional capabilities in processing, translating, and generating human languages. These breakthroughs have also been reflected in protein research, leading to the rapid development of numerous new methods in a short time, with unprecedented performance. Language models, in particular, have seen widespread use in protein research, as they have been utilized to embed proteins, generate novel ones, and predict tertiary structures. In this book chapter, we provide an overview of the use of protein generative models, reviewing 1) language models for the design of novel artificial proteins, 2) works that use non-Transformer architectures, and 3) applications in directed evolution approaches.

Modern sequence models (e.g., Transformers, linear RNNs, etc.) emerged as dominant backbones of recent deep learning frameworks, mainly due to their efficiency, representational power, and/or ability to capture long-range dependencies. Adopting these sequence models for graph-structured data has recently gained popularity as the alternative to Message Passing Neural Networks (MPNNs). There is, however, a lack of a common foundation about what constitutes a good graph sequence model, and a mathematical description of the benefits and deficiencies in adopting different sequence models for learning on graphs. To this end, we first present Graph Sequence Model (GSM), a unifying framework for adopting sequence models for graphs, consisting of three main steps: (1) Tokenization, which translates the graph into a set of sequences; (2) Local Encoding, which encodes local neighborhoods around each node; and (3) Global Encoding, which employs a scalable sequence model to capture long-range dependencies within the sequences. This framework allows us to understand, evaluate, and compare the power of different sequence model backbones in graph tasks. Our theoretical evaluations of the representation power of Transformers and modern recurrent models through the lens of global and local graph tasks show that there are both negative and positive sides for both types of models. Building on this observation, we present GSM++, a fast hybrid model that uses the Hierarchical Affinity Clustering (HAC) algorithm to tokenize the graph into hierarchical sequences, and then employs a hybrid architecture of Transformer to encode these sequences. Our theoretical and experimental results support the design of GSM++, showing that GSM++ outperforms baselines in most benchmark evaluations.

Proteins are fundamental to biology, executing diverse functions through complex physicochemical interactions, and they hold transformative potential across medicine, materials science, and environmental applications. Protein Language Models (pLMs) aim to unlock insights from the vast space of unlabeled protein sequences by learning rich, semantic representations from primary sequences via masked language modeling. However, these models typically exhibit limited generative capacity. In this work, we introduce the Diffusion Sequence Model (DSM), a novel pLM trained with masked diffusion to enable both high-quality representation learning and generative protein design. DSM builds upon the ESM2 architecture by incorporating a masked forward diffusion process inspired by the LLaDA framework. After training, DSM is capable of generating diverse, biomimetic sequences that align with expected amino acid compositions, secondary structures, and predicted functions, even with 90\% token corruption. Furthermore, DSM's learned representations match or exceed those of similarly sized pLMs on downstream tasks. We also introduce DSM(ppi), a variant fine-tuned to generate protein binders by attending to target sequences. We demonstrate DSM(ppi)'s effectiveness on the challenging Bench-tested Binder Benchmark (BenchBB), where both DSM and DSM(ppi) produce candidates with superior predicted binding affinity compared to known binders. Our results establish masked diffusion as a powerful paradigm for unifying protein representation and generation in a single framework.

We study the problem of optimizing biological sequences, e.g., proteins, DNA, and RNA, to maximize a black-box score function that is only evaluated in an offline dataset. We propose a novel solution, bootstrapped training of score-conditioned generator (BootGen) algorithm. Our algorithm repeats a two-stage process. In the first stage, our algorithm trains the biological sequence generator with rank-based weights to enhance the accuracy of sequence generation based on high scores. The subsequent stage involves bootstrapping, which augments the training dataset with self-generated data labeled by a proxy score function. Our key idea is to align the score-based generation with a proxy score function, which distills the knowledge of the proxy score function to the generator. After training, we aggregate samples from multiple bootstrapped generators and proxies to produce a diverse design. Extensive experiments show that our method outperforms competitive baselines on biological sequential design tasks. We provide reproducible source code: https://github.com/kaist-silab/bootgen{https://github.com/kaist-silab/bootgen}.

Predicting protein function from amino acid sequence remains a central challenge in data-scarce (low-N) regimes, limiting machine learning-guided protein design when only small amounts of assay-labeled sequence-function data are available. Protein language models (pLMs) have advanced the field by providing evolutionary-informed embeddings and sparse autoencoders (SAEs) have enabled decomposition of these embeddings into interpretable latent variables that capture structural and functional features. However, the effectiveness of SAEs for low-N function prediction and protein design has not been systematically studied. Herein, we evaluate SAEs trained on fine-tuned ESM2 embeddings across diverse fitness extrapolation and protein engineering tasks. We show that SAEs, with as few as 24 sequences, consistently outperform or compete with their ESM2 baselines in fitness prediction, indicating that their sparse latent space encodes compact and biologically meaningful representations that generalize more effectively from limited data. Moreover, steering predictive latents exploits biological motifs in pLM representations, yielding top-fitness variants in 83% of cases compared to designing with ESM2 alone.

Extending the context length (i.e., the maximum supported sequence length) of LLMs is of paramount significance. To facilitate long context training of LLMs, sequence parallelism has emerged as an essential technique, which scatters each input sequence across multiple devices and necessitates communication to process the sequence. In essence, existing sequence parallelism methods assume homogeneous sequence lengths (i.e., all input sequences are equal in length) and therefore leverages a single, static scattering strategy for all input sequences. However, in reality, the sequence lengths in LLM training corpora exhibit substantial variability, often following a long-tail distribution, which leads to workload heterogeneity. In this paper, we show that employing a single, static strategy results in inefficiency and resource under-utilization, highlighting the need for adaptive approaches to handle the heterogeneous workloads across sequences. To address this, we propose a heterogeneity-adaptive sequence parallelism method. For each training step, our approach captures the variability in sequence lengths and assigns the optimal combination of scattering strategies based on workload characteristics. We model this problem as a linear programming optimization and design an efficient and effective solver to find the optimal solution. Furthermore, we implement our method in a high-performance system that supports adaptive parallelization in distributed LLM training. Experimental results demonstrate that our system outperforms state-of-the-art training frameworks by up to 1.98x.

Paper is a cheap, recyclable, and clean material that is often used to make practical tools. Traditional tool design either relies on simulation or physical analysis, which is often inaccurate and time-consuming. In this paper, we propose PaperBot, an approach that directly learns to design and use a tool in the real world using paper without human intervention. We demonstrated the effectiveness and efficiency of PaperBot on two tool design tasks: 1. learning to fold and throw paper airplanes for maximum travel distance 2. learning to cut paper into grippers that exert maximum gripping force. We present a self-supervised learning framework that learns to perform a sequence of folding, cutting, and dynamic manipulation actions in order to optimize the design and use of a tool. We deploy our system to a real-world two-arm robotic system to solve challenging design tasks that involve aerodynamics (paper airplane) and friction (paper gripper) that are impossible to simulate accurately.

Antibodies are Y-shaped proteins that neutralize pathogens and constitute the core of our adaptive immune system. De novo generation of new antibodies that target specific antigens holds the key to accelerating vaccine discovery. However, this co-design of the amino acid sequence and the 3D structure subsumes and accentuates some central challenges from multiple tasks, including protein folding (sequence to structure), inverse folding (structure to sequence), and docking (binding). We strive to surmount these challenges with a new generative model AbODE that extends graph PDEs to accommodate both contextual information and external interactions. Unlike existing approaches, AbODE uses a single round of full-shot decoding and elicits continuous differential attention that encapsulates and evolves with latent interactions within the antibody as well as those involving the antigen. We unravel fundamental connections between AbODE and temporal networks as well as graph-matching networks. The proposed model significantly outperforms existing methods on standard metrics across benchmarks.

Many real-world applications require the prediction of long sequence time-series, such as electricity consumption planning. Long sequence time-series forecasting (LSTF) demands a high prediction capacity of the model, which is the ability to capture precise long-range dependency coupling between output and input efficiently. Recent studies have shown the potential of Transformer to increase the prediction capacity. However, there are several severe issues with Transformer that prevent it from being directly applicable to LSTF, including quadratic time complexity, high memory usage, and inherent limitation of the encoder-decoder architecture. To address these issues, we design an efficient transformer-based model for LSTF, named Informer, with three distinctive characteristics: (i) a ProbSparse self-attention mechanism, which achieves O(L log L) in time complexity and memory usage, and has comparable performance on sequences' dependency alignment. (ii) the self-attention distilling highlights dominating attention by halving cascading layer input, and efficiently handles extreme long input sequences. (iii) the generative style decoder, while conceptually simple, predicts the long time-series sequences at one forward operation rather than a step-by-step way, which drastically improves the inference speed of long-sequence predictions. Extensive experiments on four large-scale datasets demonstrate that Informer significantly outperforms existing methods and provides a new solution to the LSTF problem.

The task of Grammatical Error Correction (GEC) has received remarkable attention with wide applications in Natural Language Processing (NLP) in recent years. While one of the key principles of GEC is to keep the correct parts unchanged and avoid over-correction, previous sequence-to-sequence (seq2seq) models generate results from scratch, which are not guaranteed to follow the original sentence structure and may suffer from the over-correction problem. In the meantime, the recently proposed sequence tagging models can overcome the over-correction problem by only generating edit operations, but are conditioned on human designed language-specific tagging labels. In this paper, we combine the pros and alleviate the cons of both models by proposing a novel Sequence-to-Action~(S2A) module. The S2A module jointly takes the source and target sentences as input, and is able to automatically generate a token-level action sequence before predicting each token, where each action is generated from three choices named SKIP, COPY and GENerate. Then the actions are fused with the basic seq2seq framework to provide final predictions. We conduct experiments on the benchmark datasets of both English and Chinese GEC tasks. Our model consistently outperforms the seq2seq baselines, while being able to significantly alleviate the over-correction problem as well as holding better generality and diversity in the generation results compared to the sequence tagging models.

This paper introduces Group Sequence Policy Optimization (GSPO), our stable, efficient, and performant reinforcement learning algorithm for training large language models. Unlike previous algorithms that adopt token-level importance ratios, GSPO defines the importance ratio based on sequence likelihood and performs sequence-level clipping, rewarding, and optimization. We demonstrate that GSPO achieves superior training efficiency and performance compared to the GRPO algorithm, notably stabilizes Mixture-of-Experts (MoE) RL training, and has the potential for simplifying the design of RL infrastructure. These merits of GSPO have contributed to the remarkable improvements in the latest Qwen3 models.

As the field of artificial intelligence progresses, assistive technologies are becoming more widely used across all industries. The healthcare industry is no different, with numerous studies being done to develop assistive tools for healthcare professionals. Automatic diagnostic systems are one such beneficial tool that can assist with a variety of tasks, including collecting patient information, analyzing test results, and diagnosing patients. However, the idea of developing systems that can provide a differential diagnosis has been largely overlooked in most of these research studies. In this study, we propose a transformer-based approach for providing differential diagnoses based on a patient's age, sex, medical history, and symptoms. We use the DDXPlus dataset, which provides differential diagnosis information for patients based on 49 disease types. Firstly, we propose a method to process the tabular patient data from the dataset and engineer them into patient reports to make them suitable for our research. In addition, we introduce two data modification modules to diversify the training data and consequently improve the robustness of the models. We approach the task as a multi-label classification problem and conduct extensive experiments using four transformer models. All the models displayed promising results by achieving over 97% F1 score on the held-out test set. Moreover, we design additional behavioral tests to get a broader understanding of the models. In particular, for one of our test cases, we prepared a custom test set of 100 samples with the assistance of a doctor. The results on the custom set showed that our proposed data modification modules improved the model's generalization capabilities. We hope our findings will provide future researchers with valuable insights and inspire them to develop reliable systems for automatic differential diagnosis.

We present significant extensions to diffusion-based sequence generation models, blurring the line with autoregressive language models. We introduce hyperschedules, which assign distinct noise schedules to individual token positions, generalizing both autoregressive models (e.g., GPT) and conventional diffusion models (e.g., SEDD, MDLM) as special cases. Second, we propose two hybrid token-wise noising processes that interpolate between absorbing and uniform processes, enabling the model to fix past mistakes, and we introduce a novel inference algorithm that leverages this new feature in a simplified context inspired from MDLM. To support efficient training and inference, we design attention masks compatible with KV-caching. Our methods achieve state-of-the-art perplexity and generate diverse, high-quality sequences across standard benchmarks, suggesting a promising path for autoregressive diffusion-based sequence generation.

Proteins are dynamic molecular machines whose biological functions, spanning enzymatic catalysis, signal transduction, and structural adaptation, are intrinsically linked to their motions. Designing proteins with targeted dynamic properties, however, remains a challenge due to the complex, degenerate relationships between sequence, structure, and molecular motion. Here, we introduce VibeGen, a generative AI framework that enables end-to-end de novo protein design conditioned on normal mode vibrations. VibeGen employs an agentic dual-model architecture, comprising a protein designer that generates sequence candidates based on specified vibrational modes and a protein predictor that evaluates their dynamic accuracy. This approach synergizes diversity, accuracy, and novelty during the design process. Via full-atom molecular simulations as direct validation, we demonstrate that the designed proteins accurately reproduce the prescribed normal mode amplitudes across the backbone while adopting various stable, functionally relevant structures. Notably, generated sequences are de novo, exhibiting no significant similarity to natural proteins, thereby expanding the accessible protein space beyond evolutionary constraints. Our work integrates protein dynamics into generative protein design, and establishes a direct, bidirectional link between sequence and vibrational behavior, unlocking new pathways for engineering biomolecules with tailored dynamical and functional properties. This framework holds broad implications for the rational design of flexible enzymes, dynamic scaffolds, and biomaterials, paving the way toward dynamics-informed AI-driven protein engineering.

Artefact descriptions are the primary carriers of engineering design knowledge that is both an outcome and a driver of the design process. While an artefact could be described in different connotations, the design process requires a description to embody engineering design knowledge, which is expressed in the text through intricate placement of entities and relationships. As large-language models learn from all kinds of text merely as a sequence of characters/tokens, these are yet to generate text that embodies explicit engineering design facts. Existing ontological design theories are less likely to guide the large-language models whose applications are currently limited to ideation and learning purposes. In this article, we explicate engineering design knowledge as knowledge graphs from a large sample of 33,881 patent documents. We examine the constituents of these knowledge graphs to understand the linguistic and structural basis of engineering design knowledge. In terms of linguistic basis, we observe that entities and relationships could be generalised to 64 and 24 linguistic syntaxes. While relationships mainly capture attributes ('of'), structure ('in', 'with'), purpose ('to', 'for'), hierarchy ('include'), exemplification ('such as'), and behaviour ('to', 'from'), the hierarchical relationships could specifically be identified using 75 unique syntaxes. To understand the structural basis, we draw inspiration from various studies on biological/ecological networks and discover motifs from patent knowledge graphs. We identify four 3-node and four 4-node patterns that could further be converged and simplified into sequence [->...->], aggregation [->...<-], and hierarchy [<-...->]. Expected to guide large-language model based design tools, we propose few regulatory precepts for concretising abstract entities and relationships within subgraphs, while explicating hierarchical structures.

Proteins power a vast array of functional processes in living cells. The capability to create new proteins with designed structures and functions would thus enable the engineering of cellular behavior and development of protein-based therapeutics and materials. Structure-based protein design aims to find structures that are designable (can be realized by a protein sequence), novel (have dissimilar geometry from natural proteins), and diverse (span a wide range of geometries). While advances in protein structure prediction have made it possible to predict structures of novel protein sequences, the combinatorially large space of sequences and structures limits the practicality of search-based methods. Generative models provide a compelling alternative, by implicitly learning the low-dimensional structure of complex data distributions. Here, we leverage recent advances in denoising diffusion probabilistic models and equivariant neural networks to develop Genie, a generative model of protein structures that performs discrete-time diffusion using a cloud of oriented reference frames in 3D space. Through in silico evaluations, we demonstrate that Genie generates protein backbones that are more designable, novel, and diverse than existing models. This indicates that Genie is capturing key aspects of the distribution of protein structure space and facilitates protein design with high success rates. Code for generating new proteins and training new versions of Genie is available at https://github.com/aqlaboratory/genie.

Long sequence modeling has gained broad interest as large language models (LLMs) continue to advance. Recent research has identified that a large portion of hidden states within the key-value caches of Transformer models can be discarded (also termed evicted) without affecting the perplexity performance in generating long sequences. However, we show that these methods, despite preserving perplexity performance, often drop information that is important for solving downstream tasks, a problem which we call information neglect. To address this issue, we introduce Chunked Instruction-aware State Eviction (CItruS), a novel modeling technique that integrates the attention preferences useful for a downstream task into the eviction process of hidden states. In addition, we design a method for chunked sequence processing to further improve efficiency. Our training-free method exhibits superior performance on long sequence comprehension and retrieval tasks over several strong baselines under the same memory budget, while preserving language modeling perplexity.

Keyphrase Generation (KPG) is a longstanding task in NLP with widespread applications. The advent of sequence-to-sequence (seq2seq) pre-trained language models (PLMs) has ushered in a transformative era for KPG, yielding promising performance improvements. However, many design decisions remain unexplored and are often made arbitrarily. This paper undertakes a systematic analysis of the influence of model selection and decoding strategies on PLM-based KPG. We begin by elucidating why seq2seq PLMs are apt for KPG, anchored by an attention-driven hypothesis. We then establish that conventional wisdom for selecting seq2seq PLMs lacks depth: (1) merely increasing model size or performing task-specific adaptation is not parameter-efficient; (2) although combining in-domain pre-training with task adaptation benefits KPG, it does partially hinder generalization. Regarding decoding, we demonstrate that while greedy search achieves strong F1 scores, it lags in recall compared with sampling-based methods. Based on these insights, we propose DeSel, a likelihood-based decode-select algorithm for seq2seq PLMs. DeSel improves greedy search by an average of 4.7% semantic F1 across five datasets. Our collective findings pave the way for deeper future investigations into PLM-based KPG.

Scene text recognition has attracted a great many researches due to its importance to various applications. Existing methods mainly adopt recurrence or convolution based networks. Though have obtained good performance, these methods still suffer from two limitations: slow training speed due to the internal recurrence of RNNs, and high complexity due to stacked convolutional layers for long-term feature extraction. This paper, for the first time, proposes a no-recurrence sequence-to-sequence text recognizer, named NRTR, that dispenses with recurrences and convolutions entirely. NRTR follows the encoder-decoder paradigm, where the encoder uses stacked self-attention to extract image features, and the decoder applies stacked self-attention to recognize texts based on encoder output. NRTR relies solely on self-attention mechanism thus could be trained with more parallelization and less complexity. Considering scene image has large variation in text and background, we further design a modality-transform block to effectively transform 2D input images to 1D sequences, combined with the encoder to extract more discriminative features. NRTR achieves state-of-the-art or highly competitive performance on both regular and irregular benchmarks, while requires only a small fraction of training time compared to the best model from the literature (at least 8 times faster).

Modern large language models (LLMs) are inherently auto-regressive, requiring input to be serialized into flat sequences regardless of their structural dependencies. This serialization hinders the model's ability to leverage structural inductive biases, especially in tasks such as retrieval-augmented generation (RAG) and reasoning on data with native graph structures, where inter-segment dependencies are crucial. We introduce Graph-KV with the potential to overcome this limitation. Graph-KV leverages the KV-cache of text segments as condensed representations and governs their interaction through structural inductive biases. In this framework, 'target' segments selectively attend only to the KV-caches of their designated 'source' segments, rather than all preceding segments in a serialized sequence. This approach induces a graph-structured block mask, sparsifying attention and enabling a message-passing-like step within the LLM. Furthermore, strategically allocated positional encodings for source and target segments reduce positional bias and context window consumption. We evaluate Graph-KV across three scenarios: (1) seven RAG benchmarks spanning direct inference, multi-hop reasoning, and long-document understanding; (2) Arxiv-QA, a novel academic paper QA task with full-text scientific papers structured as citation ego-graphs; and (3) paper topic classification within a citation network. By effectively reducing positional bias and harnessing structural inductive biases, Graph-KV substantially outperforms baselines, including standard costly sequential encoding, across various settings. Code and the Graph-KV data are publicly available.

Reinforcement learning (RL) is rapidly reaching and surpassing human-level control capabilities. However, state-of-the-art RL algorithms often require timesteps and reaction times significantly faster than human capabilities, which is impractical in real-world settings and typically necessitates specialized hardware. Such speeds are difficult to achieve in the real world and often requires specialized hardware. We introduce Sequence Reinforcement Learning (SRL), an RL algorithm designed to produce a sequence of actions for a given input state, enabling effective control at lower decision frequencies. SRL addresses the challenges of learning action sequences by employing both a model and an actor-critic architecture operating at different temporal scales. We propose a "temporal recall" mechanism, where the critic uses the model to estimate intermediate states between primitive actions, providing a learning signal for each individual action within the sequence. Once training is complete, the actor can generate action sequences independently of the model, achieving model-free control at a slower frequency. We evaluate SRL on a suite of continuous control tasks, demonstrating that it achieves performance comparable to state-of-the-art algorithms while significantly reducing actor sample complexity. To better assess performance across varying decision frequencies, we introduce the Frequency-Averaged Score (FAS) metric. Our results show that SRL significantly outperforms traditional RL algorithms in terms of FAS, making it particularly suitable for applications requiring variable decision frequencies. Additionally, we compare SRL with model-based online planning, showing that SRL achieves superior FAS while leveraging the same model during training that online planners use for planning.

Semantic future prediction is important for autonomous systems navigating dynamic environments. This paper introduces FUTURIST, a method for multimodal future semantic prediction that uses a unified and efficient visual sequence transformer architecture. Our approach incorporates a multimodal masked visual modeling objective and a novel masking mechanism designed for multimodal training. This allows the model to effectively integrate visible information from various modalities, improving prediction accuracy. Additionally, we propose a VAE-free hierarchical tokenization process, which reduces computational complexity, streamlines the training pipeline, and enables end-to-end training with high-resolution, multimodal inputs. We validate FUTURIST on the Cityscapes dataset, demonstrating state-of-the-art performance in future semantic segmentation for both short- and mid-term forecasting. We provide the implementation code at https://github.com/Sta8is/FUTURIST .

In this work we introduce RITA: a suite of autoregressive generative models for protein sequences, with up to 1.2 billion parameters, trained on over 280 million protein sequences belonging to the UniRef-100 database. Such generative models hold the promise of greatly accelerating protein design. We conduct the first systematic study of how capabilities evolve with model size for autoregressive transformers in the protein domain: we evaluate RITA models in next amino acid prediction, zero-shot fitness, and enzyme function prediction, showing benefits from increased scale. We release the RITA models openly, to the benefit of the research community.

Foundation models, now powering most of the exciting applications in deep learning, are almost universally based on the Transformer architecture and its core attention module. Many subquadratic-time architectures such as linear attention, gated convolution and recurrent models, and structured state space models (SSMs) have been developed to address Transformers' computational inefficiency on long sequences, but they have not performed as well as attention on important modalities such as language. We identify that a key weakness of such models is their inability to perform content-based reasoning, and make several improvements. First, simply letting the SSM parameters be functions of the input addresses their weakness with discrete modalities, allowing the model to selectively propagate or forget information along the sequence length dimension depending on the current token. Second, even though this change prevents the use of efficient convolutions, we design a hardware-aware parallel algorithm in recurrent mode. We integrate these selective SSMs into a simplified end-to-end neural network architecture without attention or even MLP blocks (Mamba). Mamba enjoys fast inference (5times higher throughput than Transformers) and linear scaling in sequence length, and its performance improves on real data up to million-length sequences. As a general sequence model backbone, Mamba achieves state-of-the-art performance across several modalities such as language, audio, and genomics. On language modeling, our Mamba-3B model outperforms Transformers of the same size and matches Transformers twice its size, both in pretraining and downstream evaluation.

The success of Transformer language models is widely credited to their dot-product attention mechanism, which interweaves a set of key design principles: mixing information across positions (enabling multi-token interactions), sequence-dependent activations (where attention weights adapt to each input), a specific mathematical form (dot-product similarities plus softmax weighting), and coupling of queries and keys to evolving hidden states (grounding attention in the current layer). However, the necessity of each of these principles remains largely untested. In this work, we systematically deconstruct attention by designing controlled variants that selectively relax these principles, applied both uniformly across all layers and in hybrid architectures where only some layers retain standard attention. Our empirical analysis reveals that mechanisms for mixing tokens are indispensable, as their absence collapses models to near-random behavior, while the exact mathematical form and sequence dependency can be substantially relaxed, especially when preserved in just a subset of layers. Surprisingly, even variants that fail in isolation can achieve robust performance when interleaved with standard attention, highlighting a cooperative effect. These findings deepen our understanding of what truly underpins attention's effectiveness and open new avenues for simplifying language models without sacrificing performance.

Unified generation of sequence and structure for scientific data (e.g., materials, molecules, proteins) is a critical task. Existing approaches primarily rely on either autoregressive sequence models or diffusion models, each offering distinct advantages and facing notable limitations. Autoregressive models, such as GPT, Llama, and Phi-4, have demonstrated remarkable success in natural language generation and have been extended to multimodal tasks (e.g., image, video, and audio) using advanced encoders like VQ-VAE to represent complex modalities as discrete sequences. However, their direct application to scientific domains is challenging due to the high precision requirements and the diverse nature of scientific data. On the other hand, diffusion models excel at generating high-dimensional scientific data, such as protein, molecule, and material structures, with remarkable accuracy. Yet, their inability to effectively model sequences limits their potential as general-purpose multimodal foundation models. To address these challenges, we propose UniGenX, a unified framework that combines autoregressive next-token prediction with conditional diffusion models. This integration leverages the strengths of autoregressive models to ease the training of conditional diffusion models, while diffusion-based generative heads enhance the precision of autoregressive predictions. We validate the effectiveness of UniGenX on material and small molecule generation tasks, achieving a significant leap in state-of-the-art performance for material crystal structure prediction and establishing new state-of-the-art results for small molecule structure prediction, de novo design, and conditional generation. Notably, UniGenX demonstrates significant improvements, especially in handling long sequences for complex structures, showcasing its efficacy as a versatile tool for scientific data generation.

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

Creating CAD digital twins from the physical world is crucial for manufacturing, design, and simulation. However, current methods typically rely on costly 3D scanning with labor-intensive post-processing. To provide a user-friendly design process, we explore the problem of reverse engineering from unconstrained real-world CAD images that can be easily captured by users of all experiences. However, the scarcity of real-world CAD data poses challenges in directly training such models. To tackle these challenges, we propose CADCrafter, an image-to-parametric CAD model generation framework that trains solely on synthetic textureless CAD data while testing on real-world images. To bridge the significant representation disparity between images and parametric CAD models, we introduce a geometry encoder to accurately capture diverse geometric features. Moreover, the texture-invariant properties of the geometric features can also facilitate the generalization to real-world scenarios. Since compiling CAD parameter sequences into explicit CAD models is a non-differentiable process, the network training inherently lacks explicit geometric supervision. To impose geometric validity constraints, we employ direct preference optimization (DPO) to fine-tune our model with the automatic code checker feedback on CAD sequence quality. Furthermore, we collected a real-world dataset, comprised of multi-view images and corresponding CAD command sequence pairs, to evaluate our method. Experimental results demonstrate that our approach can robustly handle real unconstrained CAD images, and even generalize to unseen general objects.

In recent years, while natural language processing and multimodal learning have seen rapid advancements, the field of de novo protein design has also experienced significant growth. However, most current methods rely on proprietary datasets and evaluation rubrics, making fair comparisons between different approaches challenging. Moreover, these methods often employ evaluation metrics that capture only a subset of the desired properties of designed proteins, lacking a comprehensive assessment framework. To address these, we introduce PDFBench, the first comprehensive benchmark for evaluating de novo protein design from function. PDFBench supports two tasks: description-guided design and keyword-guided design. To ensure fair and multifaceted evaluation, we compile 22 metrics covering sequence plausibility, structural fidelity, and language-protein alignment, along with measures of novelty and diversity. We evaluate five state-of-the-art baselines, revealing their respective strengths and weaknesses across tasks. Finally, we analyze inter-metric correlations, exploring the relationships between four categories of metrics, and offering guidelines for metric selection. PDFBench establishes a unified framework to drive future advances in function-driven de novo protein design.

Protein family design emerges as a promising alternative by combining the advantages of de novo protein design and mutation-based directed evolution.In this paper, we propose ProfileBFN, the Profile Bayesian Flow Networks, for specifically generative modeling of protein families. ProfileBFN extends the discrete Bayesian Flow Network from an MSA profile perspective, which can be trained on single protein sequences by regarding it as a degenerate profile, thereby achieving efficient protein family design by avoiding large-scale MSA data construction and training. Empirical results show that ProfileBFN has a profound understanding of proteins. When generating diverse and novel family proteins, it can accurately capture the structural characteristics of the family. The enzyme produced by this method is more likely than the previous approach to have the corresponding function, offering better odds of generating diverse proteins with the desired functionality.

Deep generative models of 3D shapes have received a great deal of research interest. Yet, almost all of them generate discrete shape representations, such as voxels, point clouds, and polygon meshes. We present the first 3D generative model for a drastically different shape representation --- describing a shape as a sequence of computer-aided design (CAD) operations. Unlike meshes and point clouds, CAD models encode the user creation process of 3D shapes, widely used in numerous industrial and engineering design tasks. However, the sequential and irregular structure of CAD operations poses significant challenges for existing 3D generative models. Drawing an analogy between CAD operations and natural language, we propose a CAD generative network based on the Transformer. We demonstrate the performance of our model for both shape autoencoding and random shape generation. To train our network, we create a new CAD dataset consisting of 178,238 models and their CAD construction sequences. We have made this dataset publicly available to promote future research on this topic.

Audio restoration has become increasingly significant in modern society, not only due to the demand for high-quality auditory experiences enabled by advanced playback devices, but also because the growing capabilities of generative audio models necessitate high-fidelity audio. Typically, audio restoration is defined as a task of predicting undistorted audio from damaged input, often trained using a GAN framework to balance perception and distortion. Since audio degradation is primarily concentrated in mid- and high-frequency ranges, especially due to codecs, a key challenge lies in designing a generator capable of preserving low-frequency information while accurately reconstructing high-quality mid- and high-frequency content. Inspired by recent advancements in high-sample-rate music separation, speech enhancement, and audio codec models, we propose Apollo, a generative model designed for high-sample-rate audio restoration. Apollo employs an explicit frequency band split module to model the relationships between different frequency bands, allowing for more coherent and higher-quality restored audio. Evaluated on the MUSDB18-HQ and MoisesDB datasets, Apollo consistently outperforms existing SR-GAN models across various bit rates and music genres, particularly excelling in complex scenarios involving mixtures of multiple instruments and vocals. Apollo significantly improves music restoration quality while maintaining computational efficiency. The source code for Apollo is publicly available at https://github.com/JusperLee/Apollo.

Linear attention mechanisms deliver significant advantages for Large Language Models (LLMs) by providing linear computational complexity, enabling efficient processing of ultra-long sequences (e.g., 1M context). However, existing Sequence Parallelism (SP) methods, essential for distributing these workloads across devices, become the primary bottleneck due to substantial communication overhead. In this paper, we introduce ZeCO (Zero Communication Overhead) sequence parallelism for linear attention models, a new SP method designed to overcome these limitations and achieve end-to-end near-linear scalability for long sequence training. For example, training a model with a 1M sequence length across 64 devices using ZeCO takes roughly the same time as training with an 16k sequence on a single device. At the heart of ZeCO lies All-Scan, a new collective communication primitive. All-Scan provides each SP rank with precisely the initial operator state it requires while maintaining a minimal communication footprint, effectively eliminating communication overhead. Theoretically, we prove the optimaity of ZeCO, showing that it introduces only negligible time and space overhead. Empirically, we compare the communication costs of different sequence parallelism strategies and demonstrate that All-Scan achieves the fastest communication in SP scenarios. Specifically, on 256 GPUs with an 8M sequence length, ZeCO achieves a 60\% speedup compared to the current state-of-the-art (SOTA) SP method. We believe ZeCO establishes a clear path toward efficiently training next-generation LLMs on previously intractable sequence lengths.

Sequence parallelism (SP), which divides the sequence dimension of input tensors across multiple computational devices, is becoming key to unlocking the long-context capabilities of generative AI models. This paper investigates the state-of-the-art SP approaches, i.e. DeepSpeed-Ulysses and Ring-Attention, and proposes a unified SP approach, which is more robust to transformer model architectures and network hardware topology. This paper compares the communication and memory cost of SP and existing parallelism, including data/tensor/zero/expert/pipeline parallelism, and discusses the best practices for designing hybrid 4D parallelism involving SP. We achieved 86% MFU on two 8xA800 nodes using SP for sequence length 208K for the LLAMA3-8B model. Our code is publicly available on https://github.com/feifeibear/long-context-attention.

Reinforcement Learning (RL) is increasingly utilized to enhance the reasoning capabilities of Large Language Models (LLMs). However, effectively scaling these RL methods presents significant challenges, primarily due to the difficulty in maintaining high AI accelerator utilization without generating stale, off-policy data that harms common RL algorithms. This paper introduces PipelineRL, an approach designed to achieve a superior trade-off between hardware efficiency and data on-policyness for LLM training. PipelineRL employs concurrent asynchronous data generation and model training, distinguished by the novel in-flight weight updates. This mechanism allows the LLM generation engine to receive updated model weights with minimal interruption during the generation of token sequences, thereby maximizing both the accelerator utilization and the freshness of training data. Experiments conducted on long-form reasoning tasks using 128 H100 GPUs demonstrate that PipelineRL achieves approximately sim 2x faster learning compared to conventional RL baselines while maintaining highly on-policy training data. A scalable and modular open-source implementation of PipelineRL is also released as a key contribution.

The increasing sophistication of large vision-language models (LVLMs) has been accompanied by advances in safety alignment mechanisms designed to prevent harmful content generation. However, these defenses remain vulnerable to sophisticated adversarial attacks. Existing jailbreak methods typically rely on direct and semantically explicit prompts, overlooking subtle vulnerabilities in how LVLMs compose information over multiple reasoning steps. In this paper, we propose a novel and effective jailbreak framework inspired by Return-Oriented Programming (ROP) techniques from software security. Our approach decomposes a harmful instruction into a sequence of individually benign visual gadgets. A carefully engineered textual prompt directs the sequence of inputs, prompting the model to integrate the benign visual gadgets through its reasoning process to produce a coherent and harmful output. This makes the malicious intent emergent and difficult to detect from any single component. We validate our method through extensive experiments on established benchmarks including SafeBench and MM-SafetyBench, targeting popular LVLMs. Results show that our approach consistently and substantially outperforms existing baselines on state-of-the-art models, achieving near-perfect attack success rates (over 0.90 on SafeBench) and improving ASR by up to 0.39. Our findings reveal a critical and underexplored vulnerability that exploits the compositional reasoning abilities of LVLMs, highlighting the urgent need for defenses that secure the entire reasoning process.

Recent advancements in multi-view scene reconstruction have been significant, yet existing methods face limitations when processing streams of input images. These methods either rely on time-consuming offline optimization or are restricted to shorter sequences, hindering their applicability in real-time scenarios. In this work, we propose LONG3R (LOng sequence streaming 3D Reconstruction), a novel model designed for streaming multi-view 3D scene reconstruction over longer sequences. Our model achieves real-time processing by operating recurrently, maintaining and updating memory with each new observation. We first employ a memory gating mechanism to filter relevant memory, which, together with a new observation, is fed into a dual-source refined decoder for coarse-to-fine interaction. To effectively capture long-sequence memory, we propose a 3D spatio-temporal memory that dynamically prunes redundant spatial information while adaptively adjusting resolution along the scene. To enhance our model's performance on long sequences while maintaining training efficiency, we employ a two-stage curriculum training strategy, each stage targeting specific capabilities. Experiments demonstrate that LONG3R outperforms state-of-the-art streaming methods, particularly for longer sequences, while maintaining real-time inference speed. Project page: https://zgchen33.github.io/LONG3R/.

In this paper, we present a novel sequence generation-based framework for lane detection, called Lane2Seq. It unifies various lane detection formats by casting lane detection as a sequence generation task. This is different from previous lane detection methods, which depend on well-designed task-specific head networks and corresponding loss functions. Lane2Seq only adopts a plain transformer-based encoder-decoder architecture with a simple cross-entropy loss. Additionally, we propose a new multi-format model tuning based on reinforcement learning to incorporate the task-specific knowledge into Lane2Seq. Experimental results demonstrate that such a simple sequence generation paradigm not only unifies lane detection but also achieves competitive performance on benchmarks. For example, Lane2Seq gets 97.95\% and 97.42\% F1 score on Tusimple and LLAMAS datasets, establishing a new state-of-the-art result for two benchmarks.

Despite significant progress of generative models in the natural sciences, their controllability remains challenging. One fundamentally missing aspect of molecular or protein generative models is an inductive bias that can reflect continuous properties of interest. To that end, we propose the Regression Transformer (RT), a novel method that abstracts regression as a conditional sequence modeling problem. This introduces a new paradigm of multitask language models which seamlessly bridge sequence regression and conditional sequence generation. We thoroughly demonstrate that, despite using a nominal-scale training objective, the RT matches or surpasses the performance of conventional regression models in property prediction tasks of small molecules, proteins and chemical reactions. Critically, priming the same model with continuous properties yields a highly competitive conditional generative model that outperforms specialized approaches in a substructure-constrained, property-driven molecule generation benchmark. Our dichotomous approach is facilitated by a novel, alternating training scheme that enables the model to decorate seed sequences by desired properties, e.g., to optimize reaction yield. In sum, the RT is the first report of a multitask model that concurrently excels at predictive and generative tasks in biochemistry. This finds particular application in property-driven, local exploration of the chemical or protein space and could pave the road toward foundation models in material design. The code to reproduce all experiments of the paper is available at: https://github.com/IBM/regression-transformer

Spider silks are remarkable materials characterized by superb mechanical properties such as strength, extensibility and lightweightedness. Yet, to date, limited models are available to fully explore sequence-property relationships for analysis and design. Here we propose a custom generative large-language model to enable design of novel spider silk protein sequences to meet complex combinations of target mechanical properties. The model, pretrained on a large set of protein sequences, is fine-tuned on ~1,000 major ampullate spidroin (MaSp) sequences for which associated fiber-level mechanical properties exist, to yield an end-to-end forward and inverse generative strategy. Performance is assessed through: (1), a novelty analysis and protein type classification for generated spidroin sequences through BLAST searches, (2) property evaluation and comparison with similar sequences, (3) comparison of molecular structures, as well as, and (4) a detailed sequence motif analyses. We generate silk sequences with property combinations that do not exist in nature, and develop a deep understanding the mechanistic roles of sequence patterns in achieving overarching key mechanical properties (elastic modulus, strength, toughness, failure strain). The model provides an efficient approach to expand the silkome dataset, facilitating further sequence-structure analyses of silks, and establishes a foundation for synthetic silk design and optimization.

Antibody design is an essential yet challenging task in various domains like therapeutics and biology. There are two major defects in current learning-based methods: 1) tackling only a certain subtask of the whole antibody design pipeline, making them suboptimal or resource-intensive. 2) omitting either the framework regions or side chains, thus incapable of capturing the full-atom geometry. To address these pitfalls, we propose dynamic Multi-channel Equivariant grAph Network (dyMEAN), an end-to-end full-atom model for E(3)-equivariant antibody design given the epitope and the incomplete sequence of the antibody. Specifically, we first explore structural initialization as a knowledgeable guess of the antibody structure and then propose shadow paratope to bridge the epitope-antibody connections. Both 1D sequences and 3D structures are updated via an adaptive multi-channel equivariant encoder that is able to process protein residues of variable sizes when considering full atoms. Finally, the updated antibody is docked to the epitope via the alignment of the shadow paratope. Experiments on epitope-binding CDR-H3 design, complex structure prediction, and affinity optimization demonstrate the superiority of our end-to-end framework and full-atom modeling.

Attention for transformers is a critical workload that has recently received significant "attention" as a target for custom acceleration. Yet, while prior work succeeds in reducing attention's memory-bandwidth requirements, it creates load imbalance between attention operators (resulting in severe compute under-utilization) and requires on-chip memory that scales with sequence length (which is expected to grow over time). This paper ameliorates these issues, enabling attention with nearly 100% compute utilization, no off-chip memory traffic bottlenecks, and on-chip buffer size requirements that are independent of sequence length. The main conceptual contribution is to use a recently proposed abstraction -- the cascade of Einsums -- to describe, formalize and taxonomize the space of attention algorithms that appear in the literature. In particular, we show how Einsum cascades can be used to infer non-trivial lower bounds on the number of passes a kernel must take through its input data, which has implications for either required on-chip buffer capacity or memory traffic. We show how this notion can be used to meaningfully divide the space of attention algorithms into several categories and use these categories to inform our design process. Based on the above characterization, we propose FuseMax -- a novel mapping of attention onto a spatial array-style architecture. On attention, in an iso-area comparison, FuseMax achieves an average 6.7times speedup over the prior state-of-the-art FLAT while using 79% of the energy. Similarly, on the full end-to-end transformer inference, FuseMax achieves an average 5.3times speedup over FLAT using 83% of the energy.

Generative models have demonstrated substantial promise in Natural Language Processing (NLP) and have found application in designing molecules, as seen in General Pretrained Transformer (GPT) models. In our efforts to develop such a tool for exploring the organic chemical space in search of potentially electro-active compounds, we present "LLamol", a single novel generative transformer model based on the LLama 2 architecture, which was trained on a 13M superset of organic compounds drawn from diverse public sources. To allow for a maximum flexibility in usage and robustness in view of potentially incomplete data, we introduce "Stochastic Context Learning" as a new training procedure. We demonstrate that the resulting model adeptly handles single- and multi-conditional organic molecule generation with up to four conditions, yet more are possible. The model generates valid molecular structures in SMILES notation while flexibly incorporating three numerical and/or one token sequence into the generative process, just as requested. The generated compounds are very satisfactory in all scenarios tested. In detail, we showcase the model's capability to utilize token sequences for conditioning, either individually or in combination with numerical properties, making LLamol a potent tool for de novo molecule design, easily expandable with new properties.