Daily Papers

The field of protein folding research has been greatly advanced by deep learning methods, with AlphaFold2 (AF2) demonstrating exceptional performance and atomic-level precision. As co-evolution is integral to protein structure prediction, AF2's accuracy is significantly influenced by the depth of multiple sequence alignment (MSA), which requires extensive exploration of a large protein database for similar sequences. However, not all protein sequences possess abundant homologous families, and consequently, AF2's performance can degrade on such queries, at times failing to produce meaningful results. To address this, we introduce a novel generative language model, MSA-Augmenter, which leverages protein-specific attention mechanisms and large-scale MSAs to generate useful, novel protein sequences not currently found in databases. These sequences supplement shallow MSAs, enhancing the accuracy of structural property predictions. Our experiments on CASP14 demonstrate that MSA-Augmenter can generate de novo sequences that retain co-evolutionary information from inferior MSAs, thereby improving protein structure prediction quality on top of strong AF2.

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

Multiple sequence alignments (MSAs) of proteins encode rich biological information and have been workhorses in bioinformatic methods for tasks like protein design and protein structure prediction for decades. Recent breakthroughs like AlphaFold2 that use transformers to attend directly over large quantities of raw MSAs have reaffirmed their importance. Generation of MSAs is highly computationally intensive, however, and no datasets comparable to those used to train AlphaFold2 have been made available to the research community, hindering progress in machine learning for proteins. To remedy this problem, we introduce OpenProteinSet, an open-source corpus of more than 16 million MSAs, associated structural homologs from the Protein Data Bank, and AlphaFold2 protein structure predictions. We have previously demonstrated the utility of OpenProteinSet by successfully retraining AlphaFold2 on it. We expect OpenProteinSet to be broadly useful as training and validation data for 1) diverse tasks focused on protein structure, function, and design and 2) large-scale multimodal machine learning research.

The ability to accurately model the fitness landscape of protein sequences is critical to a wide range of applications, from quantifying the effects of human variants on disease likelihood, to predicting immune-escape mutations in viruses and designing novel biotherapeutic proteins. Deep generative models of protein sequences trained on multiple sequence alignments have been the most successful approaches so far to address these tasks. The performance of these methods is however contingent on the availability of sufficiently deep and diverse alignments for reliable training. Their potential scope is thus limited by the fact many protein families are hard, if not impossible, to align. Large language models trained on massive quantities of non-aligned protein sequences from diverse families address these problems and show potential to eventually bridge the performance gap. We introduce Tranception, a novel transformer architecture leveraging autoregressive predictions and retrieval of homologous sequences at inference to achieve state-of-the-art fitness prediction performance. Given its markedly higher performance on multiple mutants, robustness to shallow alignments and ability to score indels, our approach offers significant gain of scope over existing approaches. To enable more rigorous model testing across a broader range of protein families, we develop ProteinGym -- an extensive set of multiplexed assays of variant effects, substantially increasing both the number and diversity of assays compared to existing benchmarks.

Predicting which proteins interact together from amino-acid sequences is an important task. We develop a method to pair interacting protein sequences which leverages the power of protein language models trained on multiple sequence alignments, such as MSA Transformer and the EvoFormer module of AlphaFold. We formulate the problem of pairing interacting partners among the paralogs of two protein families in a differentiable way. We introduce a method called DiffPALM that solves it by exploiting the ability of MSA Transformer to fill in masked amino acids in multiple sequence alignments using the surrounding context. MSA Transformer encodes coevolution between functionally or structurally coupled amino acids. We show that it captures inter-chain coevolution, while it was trained on single-chain data, which means that it can be used out-of-distribution. Relying on MSA Transformer without fine-tuning, DiffPALM outperforms existing coevolution-based pairing methods on difficult benchmarks of shallow multiple sequence alignments extracted from ubiquitous prokaryotic protein datasets. It also outperforms an alternative method based on a state-of-the-art protein language model trained on single sequences. Paired alignments of interacting protein sequences are a crucial ingredient of supervised deep learning methods to predict the three-dimensional structure of protein complexes. DiffPALM substantially improves the structure prediction of some eukaryotic protein complexes by AlphaFold-Multimer, without significantly deteriorating any of those we tested. It also achieves competitive performance with using orthology-based pairing.

Powerful generative AI models of protein-ligand structure have recently been proposed, but few of these methods support both flexible protein-ligand docking and affinity estimation. Of those that do, none can directly model multiple binding ligands concurrently or have been rigorously benchmarked on pharmacologically relevant drug targets, hindering their widespread adoption in drug discovery efforts. In this work, we propose FlowDock, the first deep geometric generative model based on conditional flow matching that learns to directly map unbound (apo) structures to their bound (holo) counterparts for an arbitrary number of binding ligands. Furthermore, FlowDock provides predicted structural confidence scores and binding affinity values with each of its generated protein-ligand complex structures, enabling fast virtual screening of new (multi-ligand) drug targets. For the well-known PoseBusters Benchmark dataset, FlowDock outperforms single-sequence AlphaFold 3 with a 51% blind docking success rate using unbound (apo) protein input structures and without any information derived from multiple sequence alignments, and for the challenging new DockGen-E dataset, FlowDock outperforms single-sequence AlphaFold 3 and matches single-sequence Chai-1 for binding pocket generalization. Additionally, in the ligand category of the 16th community-wide Critical Assessment of Techniques for Structure Prediction (CASP16), FlowDock ranked among the top-5 methods for pharmacological binding affinity estimation across 140 protein-ligand complexes, demonstrating the efficacy of its learned representations in virtual screening. Source code, data, and pre-trained models are available at https://github.com/BioinfoMachineLearning/FlowDock.

In the field of antibody engineering, an essential task is to design a novel antibody whose paratopes bind to a specific antigen with correct epitopes. Understanding antibody structure and its paratope can facilitate a mechanistic understanding of its function. Therefore, antibody structure prediction from its sequence alone has always been a highly valuable problem for de novo antibody design. AlphaFold2, a breakthrough in the field of structural biology, provides a solution to predict protein structure based on protein sequences and computationally expensive coevolutionary multiple sequence alignments (MSAs). However, the computational efficiency and undesirable prediction accuracy of antibodies, especially on the complementarity-determining regions (CDRs) of antibodies limit their applications in the industrially high-throughput drug design. To learn an informative representation of antibodies, we employed a deep antibody language model (ALM) on curated sequences from the observed antibody space database via a transformer model. We also developed a novel model named xTrimoABFold to predict antibody structure from antibody sequence based on the pretrained ALM as well as efficient evoformers and structural modules. The model was trained end-to-end on the antibody structures in PDB by minimizing the ensemble loss of domain-specific focal loss on CDR and the frame-aligned point loss. xTrimoABFold outperforms AlphaFold2 and other protein language model based SOTAs, e.g., OmegaFold, HelixFold-Single, and IgFold with a large significant margin (30+\% improvement on RMSD) while performing 151 times faster than AlphaFold2. To the best of our knowledge, xTrimoABFold achieved state-of-the-art antibody structure prediction. Its improvement in both accuracy and efficiency makes it a valuable tool for de novo antibody design and could make further improvements in immuno-theory.

The effects of ligand binding on protein structures and their in vivo functions carry numerous implications for modern biomedical research and biotechnology development efforts such as drug discovery. Although several deep learning (DL) methods and benchmarks designed for protein-ligand docking have recently been introduced, to date no prior works have systematically studied the behavior of the latest docking and structure prediction methods within the broadly applicable context of (1) using predicted (apo) protein structures for docking (e.g., for applicability to new proteins); (2) binding multiple (cofactor) ligands concurrently to a given target protein (e.g., for enzyme design); and (3) having no prior knowledge of binding pockets (e.g., for generalization to unknown pockets). To enable a deeper understanding of docking methods' real-world utility, we introduce PoseBench, the first comprehensive benchmark for broadly applicable protein-ligand docking. PoseBench enables researchers to rigorously and systematically evaluate DL methods for apo-to-holo protein-ligand docking and protein-ligand structure prediction using both primary ligand and multi-ligand benchmark datasets, the latter of which we introduce for the first time to the DL community. Empirically, using PoseBench, we find that (1) DL co-folding methods generally outperform comparable conventional and DL docking baselines, yet popular methods such as AlphaFold 3 are still challenged by prediction targets with novel protein sequences; (2) certain DL co-folding methods are highly sensitive to their input multiple sequence alignments, while others are not; and (3) DL methods struggle to strike a balance between structural accuracy and chemical specificity when predicting novel or multi-ligand protein targets. Code, data, tutorials, and benchmark results are available at https://github.com/BioinfoMachineLearning/PoseBench.

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.

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

We introduce AMix-1, a powerful protein foundation model built on Bayesian Flow Networks and empowered by a systematic training methodology, encompassing pretraining scaling laws, emergent capability analysis, in-context learning mechanism, and test-time scaling algorithm. To guarantee robust scalability, we establish a predictive scaling law and reveal the progressive emergence of structural understanding via loss perspective, culminating in a strong 1.7-billion model. Building on this foundation, we devise a multiple sequence alignment (MSA)-based in-context learning strategy to unify protein design into a general framework, where AMix-1 recognizes deep evolutionary signals among MSAs and consistently generates structurally and functionally coherent proteins. This framework enables the successful design of a dramatically improved AmeR variant with an up to 50times activity increase over its wild type. Pushing the boundaries of protein engineering, we further empower AMix-1 with an evolutionary test-time scaling algorithm for in silico directed evolution that delivers substantial, scalable performance gains as verification budgets are intensified, laying the groundwork for next-generation lab-in-the-loop protein design.

Large-scale Protein Language Models (PLMs) have improved performance in protein prediction tasks, ranging from 3D structure prediction to various function predictions. In particular, AlphaFold, a ground-breaking AI system, could potentially reshape structural biology. However, the utility of the PLM module in AlphaFold, Evoformer, has not been explored beyond structure prediction. In this paper, we investigate the representation ability of three popular PLMs: ESM-1b (single sequence), MSA-Transformer (multiple sequence alignment) and Evoformer (structural), with a special focus on Evoformer. Specifically, we aim to answer the following key questions: (i) Does the Evoformer trained as part of AlphaFold produce representations amenable to predicting protein function? (ii) If yes, can Evoformer replace ESM-1b and MSA-Transformer? (ii) How much do these PLMs rely on evolution-related protein data? In this regard, are they complementary to each other? We compare these models by empirical study along with new insights and conclusions. All code and datasets for reproducibility are available at https://github.com/elttaes/Revisiting-PLMs.

Generative protein language models are a natural way to design new proteins with desired functions. However, current models are either difficult to direct to produce a protein from a specific family of interest, or must be trained on a large multiple sequence alignment (MSA) from the specific family of interest, making them unable to benefit from transfer learning across families. To address this, we propose Protein Evolutionary Transformer (PoET), an autoregressive generative model of whole protein families that learns to generate sets of related proteins as sequences-of-sequences across tens of millions of natural protein sequence clusters. PoET can be used as a retrieval-augmented language model to generate and score arbitrary modifications conditioned on any protein family of interest, and can extrapolate from short context lengths to generalize well even for small families. This is enabled by a unique Transformer layer; we model tokens sequentially within sequences while attending between sequences order invariantly, allowing PoET to scale to context lengths beyond those used during training. In extensive experiments on deep mutational scanning datasets, we show that PoET outperforms existing protein language models and evolutionary sequence models for variant function prediction across proteins of all MSA depths. We also demonstrate PoET's ability to controllably generate new protein sequences.

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.

Alignment is the most critical step in building large language models (LLMs) that meet human needs. With the rapid development of LLMs gradually surpassing human capabilities, traditional alignment methods based on human-annotation are increasingly unable to meet the scalability demands. Therefore, there is an urgent need to explore new sources of automated alignment signals and technical approaches. In this paper, we systematically review the recently emerging methods of automated alignment, attempting to explore how to achieve effective, scalable, automated alignment once the capabilities of LLMs exceed those of humans. Specifically, we categorize existing automated alignment methods into 4 major categories based on the sources of alignment signals and discuss the current status and potential development of each category. Additionally, we explore the underlying mechanisms that enable automated alignment and discuss the essential factors that make automated alignment technologies feasible and effective from the fundamental role of alignment.

AI alignment aims to make AI systems behave in line with human intentions and values. As AI systems grow more capable, so do risks from misalignment. To provide a comprehensive and up-to-date overview of the alignment field, in this survey, we delve into the core concepts, methodology, and practice of alignment. First, we identify four principles as the key objectives of AI alignment: Robustness, Interpretability, Controllability, and Ethicality (RICE). Guided by these four principles, we outline the landscape of current alignment research and decompose them into two key components: forward alignment and backward alignment. The former aims to make AI systems aligned via alignment training, while the latter aims to gain evidence about the systems' alignment and govern them appropriately to avoid exacerbating misalignment risks. On forward alignment, we discuss techniques for learning from feedback and learning under distribution shift. On backward alignment, we discuss assurance techniques and governance practices. We also release and continually update the website (www.alignmentsurvey.com) which features tutorials, collections of papers, blog posts, and other resources.

DNA sequence alignment involves assigning short DNA reads to the most probable locations on an extensive reference genome. This process is crucial for various genomic analyses, including variant calling, transcriptomics, and epigenomics. Conventional methods, refined over decades, tackle this challenge in 2 steps: genome indexing followed by efficient search to locate likely positions for given reads. Building on the success of Large Language Models in encoding text into embeddings, where the distance metric captures semantic similarity, recent efforts have explored whether the same Transformer architecture can produce embeddings for DNA sequences. Such models have shown early promise in classifying short DNA sequences, such as detecting coding/non-coding regions, and enhancer, promoter sequences. However, performance at sequence classification tasks does not translate to sequence alignment, where it is necessary to search across the genome to align each read, a significantly longer-range task. We bridge this gap by framing the Sequence Alignment task for Transformer models as an "Embed-Search-Align" task. In this framework, a novel Reference-Free DNA Embedding model generates embeddings of reads and reference fragments, which are projected into a shared vector space where the read-fragment distance is used as a surrogate for alignment. Technical contributions include: (1) Contrastive loss for self-supervised training of DNA sequence representations, facilitating rich reference-free, sequence-level embeddings, and (2) a DNA vector store to enable search across fragments on a global scale. DNA-ESA is 99% accurate when aligning 250-length reads onto a human genome (3gb), rivaling conventional methods such as Bowtie and BWA-Mem. DNA-ESA exceeds the performance of 6 Transformer model baselines such as Nucleotide Transformer, Hyena-DNA, and shows task transfer across chromosomes and species.

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.

The field of bioinformatics has seen significant progress, making the cross-modal text-molecule retrieval task increasingly vital. This task focuses on accurately retrieving molecule structures based on textual descriptions, by effectively aligning textual descriptions and molecules to assist researchers in identifying suitable molecular candidates. However, many existing approaches overlook the details inherent in molecule sub-structures. In this work, we introduce the Optimal TRansport-based Multi-grained Alignments model (ORMA), a novel approach that facilitates multi-grained alignments between textual descriptions and molecules. Our model features a text encoder and a molecule encoder. The text encoder processes textual descriptions to generate both token-level and sentence-level representations, while molecules are modeled as hierarchical heterogeneous graphs, encompassing atom, motif, and molecule nodes to extract representations at these three levels. A key innovation in ORMA is the application of Optimal Transport (OT) to align tokens with motifs, creating multi-token representations that integrate multiple token alignments with their corresponding motifs. Additionally, we employ contrastive learning to refine cross-modal alignments at three distinct scales: token-atom, multitoken-motif, and sentence-molecule, ensuring that the similarities between correctly matched text-molecule pairs are maximized while those of unmatched pairs are minimized. To our knowledge, this is the first attempt to explore alignments at both the motif and multi-token levels. Experimental results on the ChEBI-20 and PCdes datasets demonstrate that ORMA significantly outperforms existing state-of-the-art (SOTA) models.

Large language models (LLMs) can handle a wide variety of general tasks with simple prompts, without the need for task-specific training. Multimodal Large Language Models (MLLMs), built upon LLMs, have demonstrated impressive potential in tackling complex tasks involving visual, auditory, and textual data. However, critical issues related to truthfulness, safety, o1-like reasoning, and alignment with human preference remain insufficiently addressed. This gap has spurred the emergence of various alignment algorithms, each targeting different application scenarios and optimization goals. Recent studies have shown that alignment algorithms are a powerful approach to resolving the aforementioned challenges. In this paper, we aim to provide a comprehensive and systematic review of alignment algorithms for MLLMs. Specifically, we explore four key aspects: (1) the application scenarios covered by alignment algorithms, including general image understanding, multi-image, video, and audio, and extended multimodal applications; (2) the core factors in constructing alignment datasets, including data sources, model responses, and preference annotations; (3) the benchmarks used to evaluate alignment algorithms; and (4) a discussion of potential future directions for the development of alignment algorithms. This work seeks to help researchers organize current advancements in the field and inspire better alignment methods. The project page of this paper is available at https://github.com/BradyFU/Awesome-Multimodal-Large-Language-Models/tree/Alignment.

In this paper, we present a novel framework designed to reconstruct long-sequence 3D human motion in the world coordinates from in-the-wild videos with multiple shot transitions. Such long-sequence in-the-wild motions are highly valuable to applications such as motion generation and motion understanding, but are of great challenge to be recovered due to abrupt shot transitions, partial occlusions, and dynamic backgrounds presented in such videos. Existing methods primarily focus on single-shot videos, where continuity is maintained within a single camera view, or simplify multi-shot alignment in camera space only. In this work, we tackle the challenges by integrating an enhanced camera pose estimation with Human Motion Recovery (HMR) by incorporating a shot transition detector and a robust alignment module for accurate pose and orientation continuity across shots. By leveraging a custom motion integrator, we effectively mitigate the problem of foot sliding and ensure temporal consistency in human pose. Extensive evaluations on our created multi-shot dataset from public 3D human datasets demonstrate the robustness of our method in reconstructing realistic human motion in world coordinates.

As Large Language Models (LLMs) become increasingly integrated into real-world applications, ensuring their outputs align with human values and safety standards has become critical. The field has developed diverse alignment approaches including traditional fine-tuning methods (RLHF, instruction tuning), post-hoc correction systems, and inference-time interventions, each with distinct advantages and limitations. However, the lack of unified evaluation frameworks makes it difficult to systematically compare these paradigms and guide deployment decisions. This paper introduces a multi-dimensional evaluation of alignment techniques for LLMs, a comprehensive evaluation framework that provides a systematic comparison across all major alignment paradigms. Our framework assesses methods along four key dimensions: alignment detection, alignment quality, computational efficiency, and robustness. Through experiments across diverse base models and alignment strategies, we demonstrate the utility of our framework in identifying strengths and limitations of current state-of-the-art models, providing valuable insights for future research directions.

Large Language Models (LLMs) exhibit remarkably powerful capabilities. One of the crucial factors to achieve success is aligning the LLM's output with human preferences. This alignment process often requires only a small amount of data to efficiently enhance the LLM's performance. While effective, research in this area spans multiple domains, and the methods involved are relatively complex to understand. The relationships between different methods have been under-explored, limiting the development of the preference alignment. In light of this, we break down the existing popular alignment strategies into different components and provide a unified framework to study the current alignment strategies, thereby establishing connections among them. In this survey, we decompose all the strategies in preference learning into four components: model, data, feedback, and algorithm. This unified view offers an in-depth understanding of existing alignment algorithms and also opens up possibilities to synergize the strengths of different strategies. Furthermore, we present detailed working examples of prevalent existing algorithms to facilitate a comprehensive understanding for the readers. Finally, based on our unified perspective, we explore the challenges and future research directions for aligning large language models with human preferences.

In recent years, large language models (LLMs) have achieved state-of-the-art results in various biological sequence analysis tasks, such as sequence classification, structure prediction, and function prediction. Similar to advancements in AI for other scientific fields, deeper research into biological LLMs has begun to focus on using these models to rediscover important existing biological laws or uncover entirely new patterns in biological sequences.This study leverages GPT-like LLMs to utilize language transfer capabilities to rediscover the genetic code rules of the central dogma. In our experimental design, we transformed the central dogma into a binary classification problem of aligning DNA sequences with protein sequences, where positive examples are matching DNA and protein sequences, and negative examples are non-matching pairs.We first trained a GPT-2 model from scratch using a dataset comprising protein sequences, DNA sequences, and sequences from languages such as English and Chinese. Subsequently, we fine-tuned the model using the English similarity judgment dataset from PAWS-X. When tested on a dataset for DNA and protein sequence alignment judgment, the fine-tuned model achieved a classification accuracy of 76%. The study also analyzed factors contributing to this zero-shot capability, including model training stability and types of training data.This research demonstrates that LLMs can, through the transfer of natural language capabilities and solely relying on the analysis of sequences themselves, rediscover the central dogma without prior knowledge of it. This study opens a new door for AI-driven biological research.

Large language models have already demonstrated their formidable capabilities in general domains, ushering in a revolutionary transformation. However, exploring and exploiting the extensive knowledge of these models to comprehend multi-omics biology remains underexplored. To fill this research gap, we first introduce Biology-Instructions, the first large-scale multi-omics biological sequences-related instruction-tuning dataset including DNA, RNA, proteins, and multi-molecules, designed to bridge the gap between large language models (LLMs) and complex biological sequences-related tasks. This dataset can enhance the versatility of LLMs by integrating diverse biological sequenced-based prediction tasks with advanced reasoning capabilities, while maintaining conversational fluency. Additionally, we reveal significant performance limitations in even state-of-the-art LLMs on biological sequence-related multi-omics tasks without specialized pre-training and instruction-tuning. We further develop a strong baseline called ChatMultiOmics with a novel three-stage training pipeline, demonstrating the powerful ability to understand biology by using Biology-Instructions. Biology-Instructions and ChatMultiOmics are publicly available and crucial resources for enabling more effective integration of LLMs with multi-omics sequence analysis.

Cross-lingual alignment, the meaningful similarity of representations across languages in multilingual language models, has been an active field of research in recent years. We survey the literature of techniques to improve cross-lingual alignment, providing a taxonomy of methods and summarising insights from throughout the field. We present different understandings of cross-lingual alignment and their limitations. We provide a qualitative summary of results from a large number of surveyed papers. Finally, we discuss how these insights may be applied not only to encoder models, where this topic has been heavily studied, but also to encoder-decoder or even decoder-only models, and argue that an effective trade-off between language-neutral and language-specific information is key.

Word alignments are useful for tasks like statistical and neural machine translation (NMT) and cross-lingual annotation projection. Statistical word aligners perform well, as do methods that extract alignments jointly with translations in NMT. However, most approaches require parallel training data, and quality decreases as less training data is available. We propose word alignment methods that require no parallel data. The key idea is to leverage multilingual word embeddings, both static and contextualized, for word alignment. Our multilingual embeddings are created from monolingual data only without relying on any parallel data or dictionaries. We find that alignments created from embeddings are superior for four and comparable for two language pairs compared to those produced by traditional statistical aligners, even with abundant parallel data; e.g., contextualized embeddings achieve a word alignment F1 for English-German that is 5 percentage points higher than eflomal, a high-quality statistical aligner, trained on 100k parallel sentences.

The most common tools for word-alignment rely on a large amount of parallel sentences, which are then usually processed according to one of the IBM model algorithms. The training data is, however, the same as for machine translation (MT) systems, especially for neural MT (NMT), which itself is able to produce word-alignments using the trained attention heads. This is convenient because word-alignment is theoretically a viable byproduct of any attention-based NMT, which is also able to provide decoder scores for a translated sentence pair. We summarize different approaches on how word-alignment can be extracted from alignment scores and then explore ways in which scores can be extracted from NMT, focusing on inferring the word-alignment scores based on output sentence and token probabilities. We compare this to the extraction of alignment scores from attention. We conclude with aggregating all of the sources of alignment scores into a simple feed-forward network which achieves the best results when combined alignment extractors are used.

Due to the remarkable capabilities and growing impact of large language models (LLMs), they have been deeply integrated into many aspects of society. Thus, ensuring their alignment with human values and intentions has emerged as a critical challenge. This survey provides a comprehensive overview of practical alignment techniques, training protocols, and empirical findings in LLM alignment. We analyze the development of alignment methods across diverse paradigms, characterizing the fundamental trade-offs between core alignment objectives. Our analysis shows that while supervised fine-tuning enables basic instruction-following, preference-based methods offer more flexibility for aligning with nuanced human intent. We discuss state-of-the-art techniques, including Direct Preference Optimization (DPO), Constitutional AI, brain-inspired methods, and alignment uncertainty quantification (AUQ), highlighting their approaches to balancing quality and efficiency. We review existing evaluation frameworks and benchmarking datasets, emphasizing limitations such as reward misspecification, distributional robustness, and scalable oversight. We summarize strategies adopted by leading AI labs to illustrate the current state of practice. We conclude by outlining open problems in oversight, value pluralism, robustness, and continuous alignment. This survey aims to inform both researchers and practitioners navigating the evolving landscape of LLM alignment.

Recent approaches to large language model (LLM) alignment typically require millions of human annotations or rely on external aligned models for synthetic data generation. This paper introduces ALMA: Alignment with Minimal Annotation, demonstrating that effective alignment can be achieved using only 9,000 labeled examples -- less than 1% of conventional approaches. ALMA generates large amounts of high-quality synthetic alignment data through new techniques: diverse prompt synthesis via few-shot learning, diverse response generation with multiple model checkpoints, and judge (reward model) enhancement through score aggregation and self-distillation. Using only a pretrained Llama3 base model, 5,000 SFT examples, and 4,000 judge annotations, ALMA achieves performance close to Llama3-Instruct across diverse alignment benchmarks (e.g., 0.1% difference on AlpacaEval 2.0 score). These results are achieved with a multi-round, self-bootstrapped data synthesis and training recipe that continues to improve for 10 rounds, surpassing the typical 3-round ceiling of previous methods. These results suggest that base models already possess sufficient knowledge for effective alignment, and that synthetic data generation methods can expose it.

Recent studies have shown that post-aligning multilingual pretrained language models (mPLMs) using alignment objectives on both original and transliterated data can improve crosslingual alignment. This improvement further leads to better crosslingual transfer performance. However, it remains unclear how and why a better crosslingual alignment is achieved, as this technique only involves transliterations, and does not use any parallel data. This paper attempts to explicitly evaluate the crosslingual alignment and identify the key elements in transliteration-based approaches that contribute to better performance. For this, we train multiple models under varying setups for two pairs of related languages: (1) Polish and Ukrainian and (2) Hindi and Urdu. To assess alignment, we define four types of similarities based on sentence representations. Our experiments show that adding transliterations alone improves the overall similarities, even for random sentence pairs. With the help of auxiliary alignment objectives, especially the contrastive objective, the model learns to distinguish matched from random pairs, leading to better alignments. However, we also show that better alignment does not always yield better downstream performance, suggesting that further research is needed to clarify the connection between alignment and performance.

Real world deployments of word alignment are almost certain to cover both high and low resource languages. However, the state-of-the-art for this task recommends a different model class depending on the availability of gold alignment training data for a particular language pair. We propose BinaryAlign, a novel word alignment technique based on binary sequence labeling that outperforms existing approaches in both scenarios, offering a unifying approach to the task. Additionally, we vary the specific choice of multilingual foundation model, perform stratified error analysis over alignment error type, and explore the performance of BinaryAlign on non-English language pairs. We make our source code publicly available.

The transformer architecture has revolutionized bioinformatics and driven progress in the understanding and prediction of the properties of biomolecules. Almost all research on large-scale biosequence transformers has focused on one domain at a time (single-omic), usually nucleotides or peptides. These models have seen incredible success in downstream tasks in each domain and have achieved particularly noteworthy breakthroughs in sequences of peptides and structural modeling. However, these single-omic models are naturally incapable of modeling multi-omic tasks, one of the most biologically critical being nucleotide-peptide interactions. We present our work training the first multi-omic nucleotide-peptide foundation models. We show that these multi-omic models (MOMs) can learn joint representations between various single-omic distributions that are emergently consistent with the Central Dogma of molecular biology, despite only being trained on unlabeled biosequences. We further demonstrate that MOMs can be fine-tuned to achieve state-of-the-art results on peptide-nucleotide interaction tasks, namely predicting the change in Gibbs free energy ({\Delta}G) of the binding interaction between a given oligonucleotide and peptide, as well as the effect on this binding interaction due to mutations in the oligonucleotide sequence ({\Delta}{\Delta}G). Remarkably, we show that multi-omic biosequence transformers emergently learn useful structural information without any prior structural training, allowing us to predict which peptide residues are most involved in the peptide-nucleotide binding interaction. Lastly, we provide evidence that multi-omic biosequence models are non-inferior to foundation models trained on single-omics distributions, suggesting a more generalized or foundational approach to building these models.

In recent years, protein-text models have gained significant attention for their potential in protein generation and understanding. Current approaches focus on integrating protein-related knowledge into large language models through continued pretraining and multi-modal alignment, enabling simultaneous comprehension of textual descriptions and protein sequences. Through a thorough analysis of existing model architectures and text-based protein understanding benchmarks, we identify significant data leakage issues present in current benchmarks. Moreover, conventional metrics derived from natural language processing fail to accurately assess the model's performance in this domain. To address these limitations, we reorganize existing datasets and introduce a novel evaluation framework based on biological entities. Motivated by our observation, we propose a retrieval-enhanced method, which significantly outperforms fine-tuned LLMs for protein-to-text generation and shows accuracy and efficiency in training-free scenarios. Our code and data can be seen at https://github.com/IDEA-XL/RAPM.

Scientific Large Language Models (Sci-LLMs) have emerged as a promising frontier for accelerating biological discovery. However, these models face a fundamental challenge when processing raw biomolecular sequences: the tokenization dilemma. Whether treating sequences as a specialized language, risking the loss of functional motif information, or as a separate modality, introducing formidable alignment challenges, current strategies fundamentally limit their reasoning capacity. We challenge this sequence-centric paradigm by positing that a more effective strategy is to provide Sci-LLMs with high-level structured context derived from established bioinformatics tools, thereby bypassing the need to interpret low-level noisy sequence data directly. Through a systematic comparison of leading Sci-LLMs on biological reasoning tasks, we tested three input modes: sequence-only, context-only, and a combination of both. Our findings are striking: the context-only approach consistently and substantially outperforms all other modes. Even more revealing, the inclusion of the raw sequence alongside its high-level context consistently degrades performance, indicating that raw sequences act as informational noise, even for models with specialized tokenization schemes. These results suggest that the primary strength of existing Sci-LLMs lies not in their nascent ability to interpret biomolecular syntax from scratch, but in their profound capacity for reasoning over structured, human-readable knowledge. Therefore, we argue for reframing Sci-LLMs not as sequence decoders, but as powerful reasoning engines over expert knowledge. This work lays the foundation for a new class of hybrid scientific AI agents, repositioning the developmental focus from direct sequence interpretation towards high-level knowledge synthesis. The code is available at https://github.com/opendatalab-raiser/CoKE.

We introduce Aligner, a novel Parameter-Efficient Fine-Tuning (PEFT) method for aligning multi-billion-parameter-sized Large Language Models (LLMs). Aligner employs a unique design that constructs a globally shared set of tunable tokens that modify the attention of every layer. Remarkably with this method, even when using one token accounting for a mere 5,000 parameters, Aligner can still perform comparably well to state-of-the-art LLM adaptation methods like LoRA that require millions of parameters. This capacity is substantiated in both instruction following and value alignment tasks. Besides the multiple order-of-magnitude improvement in parameter efficiency, the insight Aligner provides into the internal mechanisms of LLMs is also valuable. The architectural features and efficacy of our method, in addition to our experiments demonstrate that an LLM separates its internal handling of "form" and "knowledge" in a somewhat orthogonal manner. This finding promises to motivate new research into LLM mechanism understanding and value alignment.

Recent AI advances have enabled multi-modal systems to model and translate diverse information spaces. Extending beyond text and vision, we introduce OneProt, a multi-modal AI for proteins that integrates structural, sequence, alignment, and binding site data. Using the ImageBind framework, OneProt aligns the latent spaces of modality encoders along protein sequences. It demonstrates strong performance in retrieval tasks and surpasses state-of-the-art methods in various downstream tasks, including metal ion binding classification, gene-ontology annotation, and enzyme function prediction. This work expands multi-modal capabilities in protein models, paving the way for applications in drug discovery, biocatalytic reaction planning, and protein engineering.

Aligning large language models with human objectives is paramount, yet common approaches including RLHF suffer from unstable and resource-intensive training. In response to this challenge, we introduce ARGS, Alignment as Reward-Guided Search, a novel framework that integrates alignment into the decoding process, eliminating the need for expensive RL training. By adjusting the model's probabilistic predictions using a reward signal, ARGS generates texts with semantic diversity while being aligned with human preferences, offering a promising and flexible solution for aligning language models. Notably, ARGS demonstrates consistent enhancements in average reward compared to baselines across diverse alignment tasks and various model dimensions. For example, under the same greedy-based decoding strategy, our method improves the average reward by 19.56% relative to the baseline and secures a preference or tie score of 64.33% in GPT-4 evaluation. We believe that our framework, emphasizing decoding-time alignment, paves the way for more responsive language models in the future. Code is publicly available at: https://github.com/deeplearning-wisc/args.

Predicting protein function from sequence is a central challenge in computational biology. While existing methods rely heavily on structured ontologies or similarity-based techniques, they often lack the flexibility to express structure-free functional descriptions and novel biological functions. In this work, we introduce Prot2Text-V2, a novel multimodal sequence-to-text model that generates free-form natural language descriptions of protein function directly from amino acid sequences. Our method combines a protein language model as a sequence encoder (ESM-3B) and a decoder-only language model (LLaMA-3.1-8B-Instruct) through a lightweight nonlinear modality projector. A key innovation is our Hybrid Sequence-level Contrastive Alignment Learning (H-SCALE), which improves cross-modal learning by matching mean- and std-pooled protein embeddings with text representations via contrastive loss. After the alignment phase, we apply instruction-based fine-tuning using LoRA on the decoder to teach the model how to generate accurate protein function descriptions conditioned on the protein sequence. We train Prot2Text-V2 on about 250K curated entries from SwissProt and evaluate it under low-homology conditions, where test sequences have low similarity with training samples. Prot2Text-V2 consistently outperforms traditional and LLM-based baselines across various metrics.

Recent work discovered Emergent Misalignment (EM): fine-tuning large language models on narrowly harmful datasets can lead them to become broadly misaligned. A survey of experts prior to publication revealed this was highly unexpected, demonstrating critical gaps in our understanding of model alignment. In this work, we both advance understanding and provide tools for future research. Using new narrowly misaligned datasets, we create a set of improved model organisms that achieve 99% coherence (vs. 67% prior), work with smaller 0.5B parameter models (vs. 32B), and that induce misalignment using a single rank-1 LoRA adapter. We demonstrate that EM occurs robustly across diverse model sizes, three model families, and numerous training protocols including full supervised fine-tuning. Leveraging these cleaner model organisms, we isolate a mechanistic phase transition and demonstrate that it corresponds to a robust behavioural phase transition in all studied organisms. Aligning large language models is critical for frontier AI safety, yet EM exposes how far we are from achieving this robustly. By distilling clean model organisms that isolate a minimal alignment-compromising change, and where this is learnt, we establish a foundation for future research into understanding and mitigating alignment risks in LLMs.

Recent studies in DNA sequence classification have leveraged sophisticated machine learning techniques, achieving notable accuracy in categorizing complex genomic data. Among these, methods such as k-mer counting have proven effective in distinguishing sequences from varied species like chimpanzees, dogs, and humans, becoming a staple in contemporary genomic research. However, these approaches often demand extensive computational resources, posing a challenge in terms of scalability and efficiency. Addressing this issue, our study introduces a novel adaptation of Jiang et al.'s compressor-based, parameter-free classification method, specifically tailored for DNA sequence analysis. This innovative approach utilizes a variety of compression algorithms, such as Gzip, Brotli, and LZMA, to efficiently process and classify genomic sequences. Not only does this method align with the current state-of-the-art in terms of accuracy, but it also offers a more resource-efficient alternative to traditional machine learning methods. Our comprehensive evaluation demonstrates the proposed method's effectiveness in accurately classifying DNA sequences from multiple species. We present a detailed analysis of the performance of each algorithm used, highlighting the strengths and limitations of our approach in various genomic contexts. Furthermore, we discuss the broader implications of our findings for bioinformatics, particularly in genomic data processing and analysis. The results of our study pave the way for more efficient and scalable DNA sequence classification methods, offering significant potential for advancements in genomic research and applications.

Big models, exemplified by Large Language Models (LLMs), are models typically pre-trained on massive data and comprised of enormous parameters, which not only obtain significantly improved performance across diverse tasks but also present emergent capabilities absent in smaller models. However, the growing intertwining of big models with everyday human lives poses potential risks and might cause serious social harm. Therefore, many efforts have been made to align LLMs with humans to make them better follow user instructions and satisfy human preferences. Nevertheless, `what to align with' has not been fully discussed, and inappropriate alignment goals might even backfire. In this paper, we conduct a comprehensive survey of different alignment goals in existing work and trace their evolution paths to help identify the most essential goal. Particularly, we investigate related works from two perspectives: the definition of alignment goals and alignment evaluation. Our analysis encompasses three distinct levels of alignment goals and reveals a goal transformation from fundamental abilities to value orientation, indicating the potential of intrinsic human values as the alignment goal for enhanced LLMs. Based on such results, we further discuss the challenges of achieving such intrinsic value alignment and provide a collection of available resources for future research on the alignment of big models.

The Scielo database is an important source of scientific information in Latin America, containing articles from several research domains. A striking characteristic of Scielo is that many of its full-text contents are presented in more than one language, thus being a potential source of parallel corpora. In this article, we present the development of a parallel corpus from Scielo in three languages: English, Portuguese, and Spanish. Sentences were automatically aligned using the Hunalign algorithm for all language pairs, and for a subset of trilingual articles also. We demonstrate the capabilities of our corpus by training a Statistical Machine Translation system (Moses) for each language pair, which outperformed related works on scientific articles. Sentence alignment was also manually evaluated, presenting an average of 98.8% correctly aligned sentences across all languages. Our parallel corpus is freely available in the TMX format, with complementary information regarding article metadata.

We introduce Baichuan Alignment, a detailed analysis of the alignment techniques employed in the Baichuan series of models. This represents the industry's first comprehensive account of alignment methodologies, offering valuable insights for advancing AI research. We investigate the critical components that enhance model performance during the alignment process, including optimization methods, data strategies, capability enhancements, and evaluation processes. The process spans three key stages: Prompt Augmentation System (PAS), Supervised Fine-Tuning (SFT), and Preference Alignment. The problems encountered, the solutions applied, and the improvements made are thoroughly recorded. Through comparisons across well-established benchmarks, we highlight the technological advancements enabled by Baichuan Alignment. Baichuan-Instruct is an internal model, while Qwen2-Nova-72B and Llama3-PBM-Nova-70B are instruct versions of the Qwen2-72B and Llama-3-70B base models, optimized through Baichuan Alignment. Baichuan-Instruct demonstrates significant improvements in core capabilities, with user experience gains ranging from 17% to 28%, and performs exceptionally well on specialized benchmarks. In open-source benchmark evaluations, both Qwen2-Nova-72B and Llama3-PBM-Nova-70B consistently outperform their respective official instruct versions across nearly all datasets. This report aims to clarify the key technologies behind the alignment process, fostering a deeper understanding within the community. Llama3-PBM-Nova-70B model is available at https://huggingface.co/PKU-Baichuan-MLSystemLab/Llama3-PBM-Nova-70B.

Neural sequence models are widely used to model time-series data. Equally ubiquitous is the usage of beam search (BS) as an approximate inference algorithm to decode output sequences from these models. BS explores the search space in a greedy left-right fashion retaining only the top-B candidates - resulting in sequences that differ only slightly from each other. Producing lists of nearly identical sequences is not only computationally wasteful but also typically fails to capture the inherent ambiguity of complex AI tasks. To overcome this problem, we propose Diverse Beam Search (DBS), an alternative to BS that decodes a list of diverse outputs by optimizing for a diversity-augmented objective. We observe that our method finds better top-1 solutions by controlling for the exploration and exploitation of the search space - implying that DBS is a better search algorithm. Moreover, these gains are achieved with minimal computational or memory over- head as compared to beam search. To demonstrate the broad applicability of our method, we present results on image captioning, machine translation and visual question generation using both standard quantitative metrics and qualitative human studies. Further, we study the role of diversity for image-grounded language generation tasks as the complexity of the image changes. We observe that our method consistently outperforms BS and previously proposed techniques for diverse decoding from neural sequence models.

Many machine learning tasks can be expressed as the transformation---or transduction---of input sequences into output sequences: speech recognition, machine translation, protein secondary structure prediction and text-to-speech to name but a few. One of the key challenges in sequence transduction is learning to represent both the input and output sequences in a way that is invariant to sequential distortions such as shrinking, stretching and translating. Recurrent neural networks (RNNs) are a powerful sequence learning architecture that has proven capable of learning such representations. However RNNs traditionally require a pre-defined alignment between the input and output sequences to perform transduction. This is a severe limitation since finding the alignment is the most difficult aspect of many sequence transduction problems. Indeed, even determining the length of the output sequence is often challenging. This paper introduces an end-to-end, probabilistic sequence transduction system, based entirely on RNNs, that is in principle able to transform any input sequence into any finite, discrete output sequence. Experimental results for phoneme recognition are provided on the TIMIT speech corpus.

During times of increasing antibiotic resistance and the spread of infectious diseases like COVID-19, it is important to classify genes related to antibiotic resistance. As natural language processing has advanced with transformer-based language models, many language models that learn characteristics of nucleotide sequences have also emerged. These models show good performance in classifying various features of nucleotide sequences. When classifying nucleotide sequences, not only the sequence itself, but also various background knowledge is utilized. In this study, we use not only a nucleotide sequence-based language model but also a text language model based on PubMed articles to reflect more biological background knowledge in the model. We propose a method to fine-tune the nucleotide sequence language model and the text language model based on various databases of antibiotic resistance genes. We also propose an LLM-based augmentation technique to supplement the data and an ensemble method to effectively combine the two models. We also propose a benchmark for evaluating the model. Our method achieved better performance than the nucleotide sequence language model in the drug resistance class prediction.

Word alignment over parallel corpora has a wide variety of applications, including learning translation lexicons, cross-lingual transfer of language processing tools, and automatic evaluation or analysis of translation outputs. The great majority of past work on word alignment has worked by performing unsupervised learning on parallel texts. Recently, however, other work has demonstrated that pre-trained contextualized word embeddings derived from multilingually trained language models (LMs) prove an attractive alternative, achieving competitive results on the word alignment task even in the absence of explicit training on parallel data. In this paper, we examine methods to marry the two approaches: leveraging pre-trained LMs but fine-tuning them on parallel text with objectives designed to improve alignment quality, and proposing methods to effectively extract alignments from these fine-tuned models. We perform experiments on five language pairs and demonstrate that our model can consistently outperform previous state-of-the-art models of all varieties. In addition, we demonstrate that we are able to train multilingual word aligners that can obtain robust performance on different language pairs. Our aligner, AWESOME (Aligning Word Embedding Spaces of Multilingual Encoders), with pre-trained models is available at https://github.com/neulab/awesome-align

Non-autoregressive translation (NAT) models are typically trained with the cross-entropy loss, which forces the model outputs to be aligned verbatim with the target sentence and will highly penalize small shifts in word positions. Latent alignment models relax the explicit alignment by marginalizing out all monotonic latent alignments with the CTC loss. However, they cannot handle non-monotonic alignments, which is non-negligible as there is typically global word reordering in machine translation. In this work, we explore non-monotonic latent alignments for NAT. We extend the alignment space to non-monotonic alignments to allow for the global word reordering and further consider all alignments that overlap with the target sentence. We non-monotonically match the alignments to the target sentence and train the latent alignment model to maximize the F1 score of non-monotonic matching. Extensive experiments on major WMT benchmarks show that our method substantially improves the translation performance of CTC-based models. Our best model achieves 30.06 BLEU on WMT14 En-De with only one-iteration decoding, closing the gap between non-autoregressive and autoregressive models.

Individual neurons participate in the representation of multiple high-level concepts. To what extent can different interpretability methods successfully disentangle these roles? To help address this question, we introduce RAVEL (Resolving Attribute-Value Entanglements in Language Models), a dataset that enables tightly controlled, quantitative comparisons between a variety of existing interpretability methods. We use the resulting conceptual framework to define the new method of Multi-task Distributed Alignment Search (MDAS), which allows us to find distributed representations satisfying multiple causal criteria. With Llama2-7B as the target language model, MDAS achieves state-of-the-art results on RAVEL, demonstrating the importance of going beyond neuron-level analyses to identify features distributed across activations. We release our benchmark at https://github.com/explanare/ravel.

Data of sequential nature arise in many application domains in forms of, e.g. textual data, DNA sequences, and software execution traces. Different research disciplines have developed methods to learn sequence models from such datasets: (i) in the machine learning field methods such as (hidden) Markov models and recurrent neural networks have been developed and successfully applied to a wide-range of tasks, (ii) in process mining process discovery techniques aim to generate human-interpretable descriptive models, and (iii) in the grammar inference field the focus is on finding descriptive models in the form of formal grammars. Despite their different focuses, these fields share a common goal - learning a model that accurately describes the behavior in the underlying data. Those sequence models are generative, i.e, they can predict what elements are likely to occur after a given unfinished sequence. So far, these fields have developed mainly in isolation from each other and no comparison exists. This paper presents an interdisciplinary experimental evaluation that compares sequence modeling techniques on the task of next-element prediction on four real-life sequence datasets. The results indicate that machine learning techniques that generally have no aim at interpretability in terms of accuracy outperform techniques from the process mining and grammar inference fields that aim to yield interpretable models.

Monolingual word alignment is crucial to model semantic interactions between sentences. In particular, null alignment, a phenomenon in which words have no corresponding counterparts, is pervasive and critical in handling semantically divergent sentences. Identification of null alignment is useful on its own to reason about the semantic similarity of sentences by indicating there exists information inequality. To achieve unbalanced word alignment that values both alignment and null alignment, this study shows that the family of optimal transport (OT), i.e., balanced, partial, and unbalanced OT, are natural and powerful approaches even without tailor-made techniques. Our extensive experiments covering unsupervised and supervised settings indicate that our generic OT-based alignment methods are competitive against the state-of-the-arts specially designed for word alignment, remarkably on challenging datasets with high null alignment frequencies.

Genomic language models (gLMs) have shown mostly modest success in identifying evolutionarily constrained elements in mammalian genomes. To address this issue, we introduce a novel framework for training gLMs that explicitly models nucleotide evolution on phylogenetic trees using multispecies whole-genome alignments. Our approach integrates an alignment into the loss function during training but does not require it for making predictions, thereby enhancing the model's applicability. We applied this framework to train PhyloGPN, a model that excels at predicting functionally disruptive variants from a single sequence alone and demonstrates strong transfer learning capabilities.

The rapid expansion of genomic sequence data calls for new methods to achieve robust sequence representations. Existing techniques often neglect intricate structural details, emphasizing mainly contextual information. To address this, we developed k-mer embeddings that merge contextual and structural string information by enhancing De Bruijn graphs with structural similarity connections. Subsequently, we crafted a self-supervised method based on Contrastive Learning that employs a heterogeneous Graph Convolutional Network encoder and constructs positive pairs based on node similarities. Our embeddings consistently outperform prior techniques for Edit Distance Approximation and Closest String Retrieval tasks.

LLM alignment ensures that large language models behave safely and effectively by aligning their outputs with human values, goals, and intentions. Aligning LLMs employ huge amounts of data, computation, and time. Moreover, curating data with human feedback is expensive and takes time. Recent research depicts the benefit of data engineering in the fine-tuning and pre-training paradigms to bring down such costs. However, alignment differs from the afore-mentioned paradigms and it is unclear if data efficient alignment is feasible. In this work, we first aim to understand how the performance of LLM alignment scales with data. We find out that LLM alignment performance follows an exponential plateau pattern which tapers off post a rapid initial increase. Based on this, we identify data subsampling as a viable method to reduce resources required for alignment. Further, we propose an information theory-based methodology for efficient alignment by identifying a small high quality subset thereby reducing the computation and time required by alignment. We evaluate the proposed methodology over multiple datasets and compare the results. We find that the model aligned using our proposed methodology outperforms other sampling methods and performs comparable to the model aligned with the full dataset while using less than 10% data, leading to greater than 90% savings in costs, resources, and faster LLM alignment.

Direct alignment methods are increasingly used for aligning large language models (LLMs) with human preferences. However, these methods suffer from the issues of verbosity and likelihood displacement, which can be driven by the noisy preference pairs that induce similar likelihood for preferred and dispreferred responses. The contributions of this paper are two-fold. First, we propose a new preference alignment method based on comparison oracles and provide the convergence guarantee for its basic scheme. Second, we improve our method using some heuristics and conduct the experiments to demonstrate the flexibility and compatibility of practical scheme in improving the performance of LLMs using noisy preference pairs. Evaluations are conducted across multiple base and instruction-tuned models (Mistral-7B, Llama-3-8B and Gemma-2-9B) with benchmarks (AlpacaEval 2, MT-Bench and Arena-Hard). Experimental results show the effectiveness of our method as an alternative to addressing the limitations of existing direct alignment methods. A highlight of our work is that we evidence the importance of designing specialized methods for preference pairs with distinct likelihood margin, which complements the recent findings in Razin-2025-Unintentional.

Causal abstraction is a promising theoretical framework for explainable artificial intelligence that defines when an interpretable high-level causal model is a faithful simplification of a low-level deep learning system. However, existing causal abstraction methods have two major limitations: they require a brute-force search over alignments between the high-level model and the low-level one, and they presuppose that variables in the high-level model will align with disjoint sets of neurons in the low-level one. In this paper, we present distributed alignment search (DAS), which overcomes these limitations. In DAS, we find the alignment between high-level and low-level models using gradient descent rather than conducting a brute-force search, and we allow individual neurons to play multiple distinct roles by analyzing representations in non-standard bases-distributed representations. Our experiments show that DAS can discover internal structure that prior approaches miss. Overall, DAS removes previous obstacles to conducting causal abstraction analyses and allows us to find conceptual structure in trained neural nets.

Large Language Models (LLMs) have achieved significant advancements, however, the common learning paradigm treats LLMs as passive information repositories, neglecting their potential for active learning and alignment. Some approaches train LLMs using their own generated synthetic data, exploring the possibility of active alignment. However, there is still a huge gap between these one-time alignment methods and the continuous automatic alignment of humans. In this paper, we introduce I-SHEEP, an Iterative Self-EnHancEmEnt Paradigm.This human-like paradigm enables LLMs to continuously self-align from scratch with nothing. Compared to the one-time alignment method Dromedary sun2023principledriven, which refers to the first iteration in this paper, I-SHEEP can significantly enhance capacities on both Qwen and Llama models. I-SHEEP achieves a maximum relative improvement of 78.2\% in the Alpaca Eval, 24.0\% in the MT Bench, and an absolute increase of 8.88\% in the IFEval accuracy over subsequent iterations in Qwen-1.5 72B model. Additionally, I-SHEEP surpasses the base model in various standard benchmark generation tasks, achieving an average improvement of 24.77\% in code generation tasks, 12.04\% in TrivialQA, and 20.29\% in SQuAD. We also provide new insights based on the experiment results. Our codes, datasets, and models are available at https://anonymous.4open.science/r/I-SHEEP.

We test similarity-based word alignment models (SimAlign and awesome-align) in combination with word embeddings from mBERT and XLM-R on parallel sentences in German and Romansh. Since Romansh is an unseen language, we are dealing with a zero-shot setting. Using embeddings from mBERT, both models reach an alignment error rate of 0.22, which outperforms fast_align, a statistical model, and is on par with similarity-based word alignment for seen languages. We interpret these results as evidence that mBERT contains information that can be meaningful and applicable to Romansh. To evaluate performance, we also present a new trilingual corpus, which we call the DERMIT (DE-RM-IT) corpus, containing press releases made by the Canton of Grisons in German, Romansh and Italian in the past 25 years. The corpus contains 4 547 parallel documents and approximately 100 000 sentence pairs in each language combination. We additionally present a gold standard for German-Romansh word alignment. The data is available at https://github.com/eyldlv/DERMIT-Corpus.

Offline preference optimization allows fine-tuning large models directly from offline data, and has proved effective in recent alignment practices. We propose generalized preference optimization (GPO), a family of offline losses parameterized by a general class of convex functions. GPO enables a unified view over preference optimization, encompassing existing algorithms such as DPO, IPO and SLiC as special cases, while naturally introducing new variants. The GPO framework also sheds light on how offline algorithms enforce regularization, through the design of the convex function that defines the loss. Our analysis and experiments reveal the connections and subtle differences between the offline regularization and the KL divergence regularization intended by the canonical RLHF formulation. In a controlled setting akin to Gao et al 2023, we also show that different GPO variants achieve similar trade-offs between regularization and performance, though the optimal values of hyper-parameter might differ as predicted by theory. In all, our results present new algorithmic toolkits and empirical insights to alignment practitioners.

By compressing diverse narratives, LLMs go beyond memorization, achieving intelligence by capturing generalizable causal relationships. However, they suffer from local 'representation gaps' due to insufficient training data diversity, limiting their real-world utility, especially in tasks requiring strict alignment to rules. Traditional alignment methods relying on heavy human annotations are inefficient and unscalable. Recent self-alignment techniques also fall short, as they often depend on self-selection based prompting and memorization-based learning. To address these issues, we introduce Iterative Graph Alignment (IGA), an annotation-free rule-based alignment algorithm. A teacher model (VLM) employs Iterative Graph Prompting (IGP) to create logical graphs and reference answers. The student model (LLM) identifies local knowledge gaps by attempting to align its responses with these references, collaborating with helper models to generate diverse answers. These aligned responses are then used for iterative supervised fine-tuning (SFT). Our evaluations across five rule-based scenarios demonstrate IGP's effectiveness, with a 73.12\% alignment improvement in Claude Sonnet 3.5, and Llama3-8B-Instruct achieving an 86.20\% improvement, outperforming Claude Sonnet 3.5 in rule-based alignment.

Recent years have witnessed remarkable progress made in large language models (LLMs). Such advancements, while garnering significant attention, have concurrently elicited various concerns. The potential of these models is undeniably vast; however, they may yield texts that are imprecise, misleading, or even detrimental. Consequently, it becomes paramount to employ alignment techniques to ensure these models to exhibit behaviors consistent with human values. This survey endeavors to furnish an extensive exploration of alignment methodologies designed for LLMs, in conjunction with the extant capability research in this domain. Adopting the lens of AI alignment, we categorize the prevailing methods and emergent proposals for the alignment of LLMs into outer and inner alignment. We also probe into salient issues including the models' interpretability, and potential vulnerabilities to adversarial attacks. To assess LLM alignment, we present a wide variety of benchmarks and evaluation methodologies. After discussing the state of alignment research for LLMs, we finally cast a vision toward the future, contemplating the promising avenues of research that lie ahead. Our aspiration for this survey extends beyond merely spurring research interests in this realm. We also envision bridging the gap between the AI alignment research community and the researchers engrossed in the capability exploration of LLMs for both capable and safe LLMs.

Inference-time alignment provides an efficient alternative for aligning LLMs with humans. However, these approaches still face challenges, such as limited scalability due to policy-specific value functions and latency during the inference phase. In this paper, we propose a novel approach, Diffusion-styled Preference Optimization (\model), which provides an efficient and policy-agnostic solution for aligning LLMs with humans. By directly performing alignment at sentence level, \model~avoids the time latency associated with token-level generation. Designed as a plug-and-play module, \model~can be seamlessly integrated with various base models to enhance their alignment. Extensive experiments on AlpacaEval 2, MT-bench, and HH-RLHF demonstrate that \model~achieves superior alignment performance across various settings, achieving a favorable trade-off between alignment quality and inference-time latency. Furthermore, \model~demonstrates model-agnostic scalability, significantly improving the performance of large models such as Llama-3-70B.

Classifying genome sequences based on metadata has been an active area of research in comparative genomics for decades with many important applications across the life sciences. Established methods for classifying genomes can be broadly grouped into sequence alignment-based and alignment-free models. Conventional alignment-based models rely on genome similarity measures calculated based on local sequence alignments or consistent ordering among sequences. However, such methods are computationally expensive when dealing with large ensembles of even moderately sized genomes. In contrast, alignment-free (AF) approaches measure genome similarity based on summary statistics in an unsupervised setting and are efficient enough to analyze large datasets. However, both alignment-based and AF methods typically assume fixed scoring rubrics that lack the flexibility to assign varying importance to different parts of the sequences based on prior knowledge. In this study, we integrate AI and network science approaches to develop a comparative genomic analysis framework that addresses these limitations. Our approach, termed the Genome Misclassification Network Analysis (GMNA), simultaneously leverages misclassified instances, a learned scoring rubric, and label information to classify genomes based on associated metadata and better understand potential drivers of misclassification. We evaluate the utility of the GMNA using Naive Bayes and convolutional neural network models, supplemented by additional experiments with transformer-based models, to construct SARS-CoV-2 sampling location classifiers using over 500,000 viral genome sequences and study the resulting network of misclassifications. We demonstrate the global health potential of the GMNA by leveraging the SARS-CoV-2 genome misclassification networks to investigate the role human mobility played in structuring geographic clustering of SARS-CoV-2.

We study methods for efficiently aligning large language models (LLMs) with human preferences given budgeted online feedback. We first formulate the LLM alignment problem in the frame of contextual dueling bandits. This formulation, subsuming recent paradigms such as online RLHF and online DPO, inherently quests for sample-efficient algorithms that incorporate online active exploration. Leveraging insights from bandit theory, we introduce a unified algorithm based on Thompson sampling and highlight its applications in two distinct LLM alignment scenarios. The practical agent that efficiently implements this algorithm, named SEA (Sample-Efficient Alignment), is empirically validated through extensive experiments across three model scales (1B, 2.8B, 6.9B) and three preference learning algorithms (DPO, IPO, SLiC). The results demonstrate that SEA achieves highly sample-efficient alignment with oracle's preferences, outperforming recent active exploration methods for LLMs. Additionally, we release the implementation of SEA together with an efficient codebase designed for online alignment of LLMs, aiming to accelerate future research in this field.

AI alignment research is the field of study dedicated to ensuring that artificial intelligence (AI) benefits humans. As machine intelligence gets more advanced, this research is becoming increasingly important. Researchers in the field share ideas across different media to speed up the exchange of information. However, this focus on speed means that the research landscape is opaque, making it difficult for young researchers to enter the field. In this project, we collected and analyzed existing AI alignment research. We found that the field is growing quickly, with several subfields emerging in parallel. We looked at the subfields and identified the prominent researchers, recurring topics, and different modes of communication in each. Furthermore, we found that a classifier trained on AI alignment research articles can detect relevant articles that we did not originally include in the dataset. We are sharing the dataset with the research community and hope to develop tools in the future that will help both established researchers and young researchers get more involved in the field.

We study unsupervised multilingual alignment, the problem of finding word-to-word translations between multiple languages without using any parallel data. One popular strategy is to reduce multilingual alignment to the much simplified bilingual setting, by picking one of the input languages as the pivot language that we transit through. However, it is well-known that transiting through a poorly chosen pivot language (such as English) may severely degrade the translation quality, since the assumed transitive relations among all pairs of languages may not be enforced in the training process. Instead of going through a rather arbitrarily chosen pivot language, we propose to use the Wasserstein barycenter as a more informative "mean" language: it encapsulates information from all languages and minimizes all pairwise transportation costs. We evaluate our method on standard benchmarks and demonstrate state-of-the-art performances.

The advancement of transformer neural networks has significantly elevated the capabilities of sentence similarity models, particularly in creating effective vector representations of natural language inputs. However, these models face notable challenges in domain-specific contexts, especially in highly specialized scientific sub-fields. Traditional methods often struggle in this regime, either overgeneralizing similarities within a niche or being overly sensitive to minor differences, resulting in inaccurate text classification and subpar vector representation. In an era where retrieval augmentation and search are increasingly crucial, precise and concise numerical representations are essential. In this paper, we target this issue by assembling niche datasets using co-citations as a similarity metric, focusing on biomedical domains. We employ two key strategies for fine-tuning state-of-the-art models: 1. Domain-specific Fine-Tuning, which tailors pretrained models to a single domain, and 2. Universal Applicability with Mixture of Experts (MoE), adapting pretrained models with enforced routing for multiple domains simultaneously. Our training approach emphasizes the use of abstracts for faster training, incorporating Multiple Negative Rankings loss for efficient contrastive learning. Notably, our MoE variants, equipped with N experts, achieve the efficacy of N individual models, heralding a new era of versatile, One-Size-Fits-All transformer networks for various tasks. This methodology marks significant advancements in scientific text classification metrics and holds promise for enhancing vector database search and compilation.

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.

We introduce a protein language model for determining the complete sequence of a peptide based on measurement of a limited set of amino acids. To date, protein sequencing relies on mass spectrometry, with some novel edman degregation based platforms able to sequence non-native peptides. Current protein sequencing techniques face limitations in accurately identifying all amino acids, hindering comprehensive proteome analysis. Our method simulates partial sequencing data by selectively masking amino acids that are experimentally difficult to identify in protein sequences from the UniRef database. This targeted masking mimics real-world sequencing limitations. We then modify and finetune a ProtBert derived transformer-based model, for a new downstream task predicting these masked residues, providing an approximation of the complete sequence. Evaluating on three bacterial Escherichia species, we achieve per-amino-acid accuracy up to 90.5% when only four amino acids ([KCYM]) are known. Structural assessment using AlphaFold and TM-score validates the biological relevance of our predictions. The model also demonstrates potential for evolutionary analysis through cross-species performance. This integration of simulated experimental constraints with computational predictions offers a promising avenue for enhancing protein sequence analysis, potentially accelerating advancements in proteomics and structural biology by providing a probabilistic reconstruction of the complete protein sequence from limited experimental data.

Drug discovery typically consists of multiple steps, including identifying a target protein key to a disease's etiology, validating that interacting with this target could prevent symptoms or cure the disease, discovering a small molecule or biologic therapeutic to interact with it, and optimizing the candidate molecule through a complex landscape of required properties. Drug discovery related tasks often involve prediction and generation while considering multiple entities that potentially interact, which poses a challenge for typical AI models. For this purpose we present MAMMAL - Molecular Aligned Multi-Modal Architecture and Language - a method that we applied to create a versatile multi-task foundation model ibm/biomed.omics.bl.sm.ma-ted-458m that learns from large-scale biological datasets (2 billion samples) across diverse modalities, including proteins, small molecules, and genes. We introduce a prompt syntax that supports a wide range of classification, regression, and generation tasks. It allows combining different modalities and entity types as inputs and/or outputs. Our model handles combinations of tokens and scalars and enables the generation of small molecules and proteins, property prediction, and transcriptomic lab test predictions. We evaluated the model on 11 diverse downstream tasks spanning different steps within a typical drug discovery pipeline, where it reaches new SOTA in 9 tasks and is comparable to SOTA in 2 tasks. This performance is achieved while using a unified architecture serving all tasks, in contrast to the original SOTA performance achieved using tailored architectures. The model code and pretrained weights are publicly available at https://github.com/BiomedSciAI/biomed-multi-alignment and https://huggingface.co/ibm/biomed.omics.bl.sm.ma-ted-458m.

Large Language Models (LLMs) need to be aligned with human expectations to ensure their safety and utility in most applications. Alignment is challenging, costly, and needs to be repeated for every LLM and alignment criterion. We propose to decouple LLMs and alignment by training aligner models that can be used to align any LLM for a given criteria on an as-needed basis, thus also reducing the potential negative impacts of alignment on performance. Our recipe for training the aligner models solely relies on synthetic data generated with a (prompted) LLM and can be easily adjusted for a variety of alignment criteria. We illustrate our method by training an "ethical" aligner and verify its efficacy empirically.

We introduce the Efficient Monotonic Multihead Attention (EMMA), a state-of-the-art simultaneous translation model with numerically-stable and unbiased monotonic alignment estimation. In addition, we present improved training and inference strategies, including simultaneous fine-tuning from an offline translation model and reduction of monotonic alignment variance. The experimental results demonstrate that the proposed model attains state-of-the-art performance in simultaneous speech-to-text translation on the Spanish and English translation task.

With the proliferation of large language models (LLMs), the comprehensive alignment of such models across multiple tasks has emerged as a critical area of research. Existing alignment methodologies primarily address single task, such as multi-turn dialogue, coding, mathematical problem-solving, and tool usage. However, AI-driven products that leverage language models usually necessitate a fusion of these abilities to function effectively in real-world scenarios. Moreover, the considerable computational resources required for proper alignment of LLMs underscore the need for a more robust, efficient, and encompassing approach to multi-task alignment, ensuring improved generative performance. In response to these challenges, we introduce a novel technique termed Mixture-of-Instructions (MoI), which employs a strategy of instruction concatenation combined with diverse system prompts to boost the alignment efficiency of language models. We have also compiled a diverse set of seven benchmark datasets to rigorously evaluate the alignment efficacy of the MoI-enhanced language model. Our methodology was applied to the open-source Qwen-7B-chat model, culminating in the development of Qwen-SFT-MoI. This enhanced model demonstrates significant advancements in generative capabilities across coding, mathematics, and tool use tasks.

The transcriptional response to genetic perturbation reveals fundamental insights into complex cellular systems. While current approaches have made progress in predicting genetic perturbation responses, they provide limited biological understanding and cannot systematically refine existing knowledge. Overcoming these limitations requires an end-to-end integration of data-driven learning and existing knowledge. However, this integration is challenging due to inconsistencies between data and knowledge bases, such as noise, misannotation, and incompleteness. To address this challenge, we propose ALIGNED (Adaptive aLignment for Inconsistent Genetic kNowledgE and Data), a neuro-symbolic framework based on the Abductive Learning (ABL) paradigm. This end-to-end framework aligns neural and symbolic components and performs systematic knowledge refinement. We introduce a balanced consistency metric to evaluate the predictions' consistency against both data and knowledge. Our results show that ALIGNED outperforms state-of-the-art methods by achieving the highest balanced consistency, while also re-discovering biologically meaningful knowledge. Our work advances beyond existing methods to enable both the transparency and the evolution of mechanistic biological understanding.

The widespread applicability and increasing omnipresence of LLMs have instigated a need to align LLM responses to user and stakeholder preferences. Many preference optimization approaches have been proposed that fine-tune LLM parameters to achieve good alignment. However, such parameter tuning is known to interfere with model performance on many tasks. Moreover, keeping up with shifting user preferences is tricky in such a situation. Decoding-time alignment with reward model guidance solves these issues at the cost of increased inference time. However, most of such methods fail to strike the right balance between exploration and exploitation of reward -- often due to the conflated formulation of these two aspects - to give well-aligned responses. To remedy this we decouple these two aspects and implement them in an evolutionary fashion: exploration is enforced by decoding from mutated instructions and exploitation is represented as the periodic replacement of poorly-rewarded generations with well-rewarded ones. Empirical evidences indicate that this strategy outperforms many preference optimization and decode-time alignment approaches on two widely accepted alignment benchmarks AlpacaEval 2 and MT-Bench. Our implementation will be available at: https://darwin-alignment.github.io.

The alignment of large language models (LLMs) aims to ensure their outputs adhere to human values, ethical standards, and legal norms. Traditional alignment methods often rely on resource-intensive fine-tuning (FT), which may suffer from knowledge degradation and face challenges in scenarios where the model accessibility or computational resources are constrained. In contrast, training-free (TF) alignment techniques--leveraging in-context learning, decoding-time adjustments, and post-generation corrections--offer a promising alternative by enabling alignment without heavily retraining LLMs, making them adaptable to both open-source and closed-source environments. This paper presents the first systematic review of TF alignment methods, categorizing them by stages of pre-decoding, in-decoding, and post-decoding. For each stage, we provide a detailed examination from the viewpoint of LLMs and multimodal LLMs (MLLMs), highlighting their mechanisms and limitations. Furthermore, we identify key challenges and future directions, paving the way for more inclusive and effective TF alignment techniques. By synthesizing and organizing the rapidly growing body of research, this survey offers a guidance for practitioners and advances the development of safer and more reliable LLMs.

Self-supervised representation learning of biological sequence embeddings alleviates computational resource constraints on downstream tasks while circumventing expensive experimental label acquisition. However, existing methods mostly borrow directly from large language models designed for NLP, rather than with bioinformatics philosophies in mind. Recently, contrastive mutual information maximization methods have achieved state-of-the-art representations for ImageNet. In this perspective piece, we discuss how viewing evolution as natural sequence augmentation and maximizing information across phylogenetic "noisy channels" is a biologically and theoretically desirable objective for pretraining encoders. We first provide a review of current contrastive learning literature, then provide an illustrative example where we show that contrastive learning using evolutionary augmentation can be used as a representation learning objective which maximizes the mutual information between biological sequences and their conserved function, and finally outline rationale for this approach.

Connectionist Temporal Classification (CTC) is a widely used criterion for training supervised sequence-to-sequence (seq2seq) models. It enables learning the relations between input and output sequences, termed alignments, by marginalizing over perfect alignments (that yield the ground truth), at the expense of imperfect alignments. This binary differentiation of perfect and imperfect alignments falls short of capturing other essential alignment properties that hold significance in other real-world applications. Here we propose Align With Purpose, a general Plug-and-Play framework for enhancing a desired property in models trained with the CTC criterion. We do that by complementing the CTC with an additional loss term that prioritizes alignments according to a desired property. Our method does not require any intervention in the CTC loss function, enables easy optimization of a variety of properties, and allows differentiation between both perfect and imperfect alignments. We apply our framework in the domain of Automatic Speech Recognition (ASR) and show its generality in terms of property selection, architectural choice, and scale of training dataset (up to 280,000 hours). To demonstrate the effectiveness of our framework, we apply it to two unrelated properties: emission time and word error rate (WER). For the former, we report an improvement of up to 570ms in latency optimization with a minor reduction in WER, and for the latter, we report a relative improvement of 4.5% WER over the baseline models. To the best of our knowledge, these applications have never been demonstrated to work on a scale of data as large as ours. Notably, our method can be implemented using only a few lines of code, and can be extended to other alignment-free loss functions and to domains other than ASR.

Large Language Models (LLMs) are expected to produce safe, helpful, and honest content during interaction with human users, but they frequently fail to align with such values when given flawed instructions, e.g., missing context, ambiguous directives, or inappropriate tone, leaving substantial room for improvement along multiple dimensions. A cost-effective yet high-impact way is to pre-align instructions before the model begins decoding. Existing approaches either rely on prohibitive test-time search costs or end-to-end model rewrite, which is powered by a customized training corpus with unclear objectives. In this work, we demonstrate that the goal of efficient and effective preference alignment can be achieved by P-Aligner, a lightweight module generating instructions that preserve the original intents while being expressed in a more human-preferred form. P-Aligner is trained on UltraPrompt, a new dataset synthesized via a proposed principle-guided pipeline using Monte-Carlo Tree Search, which systematically explores the space of candidate instructions that are closely tied to human preference. Experiments across different methods show that P-Aligner generally outperforms strong baselines across various models and benchmarks, including average win-rate gains of 28.35% and 8.69% on GPT-4-turbo and Gemma-2-SimPO, respectively. Further analyses validate its effectiveness and efficiency through multiple perspectives, including data quality, search strategies, iterative deployment, and time overhead.

Recent research trends in computational biology have increasingly focused on integrating text and bio-entity modeling, especially in the context of molecules and proteins. However, previous efforts like BioT5 faced challenges in generalizing across diverse tasks and lacked a nuanced understanding of molecular structures, particularly in their textual representations (e.g., IUPAC). This paper introduces BioT5+, an extension of the BioT5 framework, tailored to enhance biological research and drug discovery. BioT5+ incorporates several novel features: integration of IUPAC names for molecular understanding, inclusion of extensive bio-text and molecule data from sources like bioRxiv and PubChem, the multi-task instruction tuning for generality across tasks, and a novel numerical tokenization technique for improved processing of numerical data. These enhancements allow BioT5+ to bridge the gap between molecular representations and their textual descriptions, providing a more holistic understanding of biological entities, and largely improving the grounded reasoning of bio-text and bio-sequences. The model is pre-trained and fine-tuned with a large number of experiments, including 3 types of problems (classification, regression, generation), 15 kinds of tasks, and 21 total benchmark datasets, demonstrating the remarkable performance and state-of-the-art results in most cases. BioT5+ stands out for its ability to capture intricate relationships in biological data, thereby contributing significantly to bioinformatics and computational biology. Our code is available at https://github.com/QizhiPei/BioT5.

Pre-trained LLMs have demonstrated substantial capabilities across a range of conventional natural language processing (NLP) tasks, such as summarization and entity recognition. In this paper, we explore the application of LLMs in the generation of high-quality protein sequences. Specifically, we adopt a suite of pre-trained LLMs, including Mistral-7B1, Llama-2-7B2, Llama-3-8B3, and gemma-7B4, to produce valid protein sequences. All of these models are publicly available.5 Unlike previous work in this field, our approach utilizes a relatively small dataset comprising 42,000 distinct human protein sequences. We retrain these models to process protein-related data, ensuring the generation of biologically feasible protein structures. Our findings demonstrate that even with limited data, the adapted models exhibit efficiency comparable to established protein-focused models such as ProGen varieties, ProtGPT2, and ProLLaMA, which were trained on millions of protein sequences. To validate and quantify the performance of our models, we conduct comparative analyses employing standard metrics such as pLDDT, RMSD, TM-score, and REU. Furthermore, we commit to making the trained versions of all four models publicly available, fostering greater transparency and collaboration in the field of computational biology.

Building a general-purpose task model similar to ChatGPT has been an important research direction for gene large language models. Instruction fine-tuning is a key component in building ChatGPT, but existing instructions are primarily based on natural language. Natural language and gene sequences have significant differences in tokenization and encoding. Therefore, constructing a multilingual model that can handle both natural language and gene sequences is crucial for solving this problem.In this paper, we expand the capabilities of the LLaMA large language model to include gene language. This involves expanding the vocabulary using the Byte Pair Encoding (BPE) method, specifically tailored for DNA and protein sequences, and conducting further pre-training on these sequences. We then convert various downstream gene task data into a unified format for instruction fine-tuning and further fine-tune the model on this data.Our study demonstrates that a mixed model of gene and natural language, fine-tuned with instructions, achieves results comparable to the current state-of-the-art (SOTA) in tasks such as gene classification and gene sequence interaction. This provides a promising direction for building a unified large language model for gene tasks.

Large Language Models (LLMs) trained on extensive textual corpora have emerged as leading solutions for a broad array of Natural Language Processing (NLP) tasks. Despite their notable performance, these models are prone to certain limitations such as misunderstanding human instructions, generating potentially biased content, or factually incorrect (hallucinated) information. Hence, aligning LLMs with human expectations has become an active area of interest within the research community. This survey presents a comprehensive overview of these alignment technologies, including the following aspects. (1) Data collection: the methods for effectively collecting high-quality instructions for LLM alignment, including the use of NLP benchmarks, human annotations, and leveraging strong LLMs. (2) Training methodologies: a detailed review of the prevailing training methods employed for LLM alignment. Our exploration encompasses Supervised Fine-tuning, both Online and Offline human preference training, along with parameter-efficient training mechanisms. (3) Model Evaluation: the methods for evaluating the effectiveness of these human-aligned LLMs, presenting a multifaceted approach towards their assessment. In conclusion, we collate and distill our findings, shedding light on several promising future research avenues in the field. This survey, therefore, serves as a valuable resource for anyone invested in understanding and advancing the alignment of LLMs to better suit human-oriented tasks and expectations. An associated GitHub link collecting the latest papers is available at https://github.com/GaryYufei/AlignLLMHumanSurvey.

The alignment problem in Large Language Models (LLMs) involves adapting them to the broad spectrum of human values. This requirement challenges existing alignment methods due to diversity of preferences and regulatory standards. This paper introduces a novel alignment paradigm, priority rule following, which defines rules as the primary control mechanism in each dialog, prioritizing them over user instructions. Our preliminary analysis reveals that even the advanced LLMs, such as GPT-4, exhibit shortcomings in understanding and prioritizing the rules. Therefore, we present PriorityDistill, a semi-automated approach for distilling priority following signals from LLM simulations to ensure robust rule integration and adherence. Our experiments show that this method not only effectively minimizes misalignments utilizing only one general rule but also adapts smoothly to various unseen rules, ensuring they are shielded from hijacking and that the model responds appropriately.

Protein language models (PLMs) have emerged as powerful tools to detect complex patterns of protein sequences. However, the capability of PLMs to fully capture information on protein sequences might be limited by focusing on single pre-training tasks. Although adding data modalities or supervised objectives can improve the performance of PLMs, pre-training often remains focused on denoising corrupted sequences. To push the boundaries of PLMs, our research investigated a multi-task pre-training strategy. We developed Ankh3, a model jointly optimized on two objectives: masked language modeling with multiple masking probabilities and protein sequence completion relying only on protein sequences as input. This multi-task pre-training demonstrated that PLMs can learn richer and more generalizable representations solely from protein sequences. The results demonstrated improved performance in downstream tasks, such as secondary structure prediction, fluorescence, GB1 fitness, and contact prediction. The integration of multiple tasks gave the model a more comprehensive understanding of protein properties, leading to more robust and accurate predictions.

Text-to-image generation has advanced rapidly, yet aligning complex textual prompts with generated visuals remains challenging, especially with intricate object relationships and fine-grained details. This paper introduces Fast Prompt Alignment (FPA), a prompt optimization framework that leverages a one-pass approach, enhancing text-to-image alignment efficiency without the iterative overhead typical of current methods like OPT2I. FPA uses large language models (LLMs) for single-iteration prompt paraphrasing, followed by fine-tuning or in-context learning with optimized prompts to enable real-time inference, reducing computational demands while preserving alignment fidelity. Extensive evaluations on the COCO Captions and PartiPrompts datasets demonstrate that FPA achieves competitive text-image alignment scores at a fraction of the processing time, as validated through both automated metrics (TIFA, VQA) and human evaluation. A human study with expert annotators further reveals a strong correlation between human alignment judgments and automated scores, underscoring the robustness of FPA's improvements. The proposed method showcases a scalable, efficient alternative to iterative prompt optimization, enabling broader applicability in real-time, high-demand settings. The codebase is provided to facilitate further research: https://github.com/tiktok/fast_prompt_alignment

Large Language Models (LLMs), including GPT-x and LLaMA2, have achieved remarkable performance in multiple Natural Language Processing (NLP) tasks. Under the premise that protein sequences constitute the protein language, Protein Large Language Models (ProLLMs) trained on protein corpora excel at de novo protein sequence generation. However, as of now, unlike LLMs in NLP, no ProLLM is capable of multiple tasks in the Protein Language Processing (PLP) field. This prompts us to delineate the inherent limitations in current ProLLMs: (i) the lack of natural language capabilities, (ii) insufficient instruction understanding, and (iii) high training resource demands. To address these challenges, we introduce a training framework to transform any general LLM into a ProLLM capable of handling multiple PLP tasks. Specifically, our framework utilizes low-rank adaptation and employs a two-stage training approach, and it is distinguished by its universality, low overhead, and scalability. Through training under this framework, we propose the ProLLaMA model, the first known ProLLM to handle multiple PLP tasks simultaneously. Experiments show that ProLLaMA achieves state-of-the-art results in the unconditional protein sequence generation task. In the controllable protein sequence generation task, ProLLaMA can design novel proteins with desired functionalities. In the protein property prediction task, ProLLaMA achieves nearly 100\% accuracy across many categories. The latter two tasks are beyond the reach of other ProLLMs. Code is available at https://github.com/Lyu6PosHao/ProLLaMA.

We present a new scientific document similarity model based on matching fine-grained aspects of texts. To train our model, we exploit a naturally-occurring source of supervision: sentences in the full-text of papers that cite multiple papers together (co-citations). Such co-citations not only reflect close paper relatedness, but also provide textual descriptions of how the co-cited papers are related. This novel form of textual supervision is used for learning to match aspects across papers. We develop multi-vector representations where vectors correspond to sentence-level aspects of documents, and present two methods for aspect matching: (1) A fast method that only matches single aspects, and (2) a method that makes sparse multiple matches with an Optimal Transport mechanism that computes an Earth Mover's Distance between aspects. Our approach improves performance on document similarity tasks in four datasets. Further, our fast single-match method achieves competitive results, paving the way for applying fine-grained similarity to large scientific corpora. Code, data, and models available at: https://github.com/allenai/aspire

The parallels between protein sequences and natural language in their sequential structures have inspired the application of large language models (LLMs) to protein understanding. Despite the success of LLMs in NLP, their effectiveness in comprehending protein sequences remains an open question, largely due to the absence of datasets linking protein sequences to descriptive text. Researchers have then attempted to adapt LLMs for protein understanding by integrating a protein sequence encoder with a pre-trained LLM. However, this adaptation raises a fundamental question: "Can LLMs, originally designed for NLP, effectively comprehend protein sequences as a form of language?" Current datasets fall short in addressing this question due to the lack of a direct correlation between protein sequences and corresponding text descriptions, limiting the ability to train and evaluate LLMs for protein understanding effectively. To bridge this gap, we introduce ProteinLMDataset, a dataset specifically designed for further self-supervised pretraining and supervised fine-tuning (SFT) of LLMs to enhance their capability for protein sequence comprehension. Specifically, ProteinLMDataset includes 17.46 billion tokens for pretraining and 893,000 instructions for SFT. Additionally, we present ProteinLMBench, the first benchmark dataset consisting of 944 manually verified multiple-choice questions for assessing the protein understanding capabilities of LLMs. ProteinLMBench incorporates protein-related details and sequences in multiple languages, establishing a new standard for evaluating LLMs' abilities in protein comprehension. The large language model InternLM2-7B, pretrained and fine-tuned on the ProteinLMDataset, outperforms GPT-4 on ProteinLMBench, achieving the highest accuracy score. The dataset and the benchmark are available at https://huggingface.co/datasets/tsynbio/ProteinLMBench.

We show that margin-based bitext mining in a multilingual sentence space can be applied to monolingual corpora of billions of sentences. We are using ten snapshots of a curated common crawl corpus (Wenzek et al., 2019) totalling 32.7 billion unique sentences. Using one unified approach for 38 languages, we were able to mine 4.5 billions parallel sentences, out of which 661 million are aligned with English. 20 language pairs have more then 30 million parallel sentences, 112 more then 10 million, and most more than one million, including direct alignments between many European or Asian languages. To evaluate the quality of the mined bitexts, we train NMT systems for most of the language pairs and evaluate them on TED, WMT and WAT test sets. Using our mined bitexts only and no human translated parallel data, we achieve a new state-of-the-art for a single system on the WMT'19 test set for translation between English and German, Russian and Chinese, as well as German/French. In particular, our English/German system outperforms the best single one by close to 4 BLEU points and is almost on pair with best WMT'19 evaluation system which uses system combination and back-translation. We also achieve excellent results for distant languages pairs like Russian/Japanese, outperforming the best submission at the 2019 workshop on Asian Translation (WAT).

High-quality instruction data is critical for aligning large language models (LLMs). Although some models, such as Llama-3-Instruct, have open weights, their alignment data remain private, which hinders the democratization of AI. High human labor costs and a limited, predefined scope for prompting prevent existing open-source data creation methods from scaling effectively, potentially limiting the diversity and quality of public alignment datasets. Is it possible to synthesize high-quality instruction data at scale by extracting it directly from an aligned LLM? We present a self-synthesis method for generating large-scale alignment data named Magpie. Our key observation is that aligned LLMs like Llama-3-Instruct can generate a user query when we input only the left-side templates up to the position reserved for user messages, thanks to their auto-regressive nature. We use this method to prompt Llama-3-Instruct and generate 4 million instructions along with their corresponding responses. We perform a comprehensive analysis of the extracted data and select 300K high-quality instances. To compare Magpie data with other public instruction datasets, we fine-tune Llama-3-8B-Base with each dataset and evaluate the performance of the fine-tuned models. Our results indicate that in some tasks, models fine-tuned with Magpie perform comparably to the official Llama-3-8B-Instruct, despite the latter being enhanced with 10 million data points through supervised fine-tuning (SFT) and subsequent feedback learning. We also show that using Magpie solely for SFT can surpass the performance of previous public datasets utilized for both SFT and preference optimization, such as direct preference optimization with UltraFeedback. This advantage is evident on alignment benchmarks such as AlpacaEval, ArenaHard, and WildBench.

The alignment of large language models (LLMs) often assumes that using more clean data yields better outcomes, overlooking the match between model capacity and example difficulty. Challenging this, we propose a new principle: Preference data vary in difficulty, and overly difficult examples hinder alignment, by exceeding the model's capacity. Through systematic experimentation, we validate this principle with three key findings: (1) preference examples vary in difficulty, as evidenced by consistent learning orders across alignment runs; (2) overly difficult examples significantly degrade performance across four LLMs and two datasets; and (3) the capacity of a model dictates its threshold for handling difficult examples, underscoring a critical relationship between data selection and model capacity. Building on this principle, we introduce Selective DPO, which filters out overly difficult examples. This simple adjustment improves alignment performance by 9-16% in win rates on the AlpacaEval 2 benchmark compared to the DPO baseline, suppressing a series of DPO variants with different algorithmic adjustments. Together, these results illuminate the importance of aligning data difficulty with model capacity, offering a transformative perspective for improving alignment strategies in LLMs. Code is available at https://github.com/glorgao/SelectiveDPO.

Vector representations of natural language are ubiquitous in search applications. Recently, various methods based on contrastive learning have been proposed to learn textual representations from unlabelled data; by maximizing alignment between minimally-perturbed embeddings of the same text, and encouraging a uniform distribution of embeddings across a broader corpus. Differently, we propose maximizing alignment between texts and a composition of their phrasal constituents. We consider several realizations of this objective and elaborate the impact on representations in each case. Experimental results on semantic textual similarity tasks show improvements over baselines that are comparable with state-of-the-art approaches. Moreover, this work is the first to do so without incurring costs in auxiliary training objectives or additional network parameters.

With the rapid development of Large Language Models (LLMs), aligning these models with human preferences and values is critical to ensuring ethical and safe applications. However, existing alignment techniques such as RLHF or DPO often require direct fine-tuning on LLMs with billions of parameters, resulting in substantial computational costs and inefficiencies. To address this, we propose Micro token-level Accept-Reject Aligning (MARA) approach designed to operate independently of the language models. MARA simplifies the alignment process by decomposing sentence-level preference learning into token-level binary classification, where a compact three-layer fully-connected network determines whether candidate tokens are "Accepted" or "Rejected" as part of the response. Extensive experiments across seven different LLMs and three open-source datasets show that MARA achieves significant improvements in alignment performance while reducing computational costs.

Multilingual speech translation (ST) in the medical domain enhances patient care by enabling efficient communication across language barriers, alleviating specialized workforce shortages, and facilitating improved diagnosis and treatment, particularly during pandemics. In this work, we present the first systematic study on medical ST, to our best knowledge, by releasing MultiMed-ST, a large-scale ST dataset for the medical domain, spanning all translation directions in five languages: Vietnamese, English, German, French, Traditional Chinese and Simplified Chinese, together with the models. With 290,000 samples, our dataset is the largest medical machine translation (MT) dataset and the largest many-to-many multilingual ST among all domains. Secondly, we present the most extensive analysis study in ST research to date, including: empirical baselines, bilingual-multilingual comparative study, end-to-end vs. cascaded comparative study, task-specific vs. multi-task sequence-to-sequence (seq2seq) comparative study, code-switch analysis, and quantitative-qualitative error analysis. All code, data, and models are available online: https://github.com/leduckhai/MultiMed-ST.

The importance of qualitative parallel data in machine translation has long been determined but it has always been very difficult to obtain such in sufficient quantity for the majority of world languages, mainly because of the associated cost and also the lack of accessibility to these languages. Despite the potential for obtaining parallel datasets from online articles using automatic approaches, forensic investigations have found a lot of quality-related issues such as misalignment, and wrong language codes. In this work, we present a simple but qualitative parallel sentence aligner that carefully leveraged the closed-access Cohere multilingual embedding, a solution that ranked second in the just concluded #CoHereAIHack 2023 Challenge (see https://ai6lagos.devpost.com). The proposed approach achieved 94.96 and 54.83 f1 scores on FLORES and MAFAND-MT, compared to 3.64 and 0.64 of LASER respectively. Our method also achieved an improvement of more than 5 BLEU scores over LASER, when the resulting datasets were used with MAFAND-MT dataset to train translation models. Our code and data are available for research purposes here (https://github.com/abumafrim/Cohere-Align).

In AI alignment, extensive latitude must be granted to annotators, either human or algorithmic, to judge which model outputs are `better' or `safer.' We refer to this latitude as alignment discretion. Such discretion remains largely unexamined, posing two risks: (i) annotators may use their power of discretion arbitrarily, and (ii) models may fail to mimic this discretion. To study this phenomenon, we draw on legal concepts of discretion that structure how decision-making authority is conferred and exercised, particularly in cases where principles conflict or their application is unclear or irrelevant. Extended to AI alignment, discretion is required when alignment principles and rules are (inevitably) conflicting or indecisive. We present a set of metrics to systematically analyze when and how discretion in AI alignment is exercised, such that both risks (i) and (ii) can be observed. Moreover, we distinguish between human and algorithmic discretion and analyze the discrepancy between them. By measuring both human and algorithmic discretion over safety alignment datasets, we reveal layers of discretion in the alignment process that were previously unaccounted for. Furthermore, we demonstrate how algorithms trained on these datasets develop their own forms of discretion in interpreting and applying these principles, which challenges the purpose of having any principles at all. Our paper presents the first step towards formalizing this core gap in current alignment processes, and we call on the community to further scrutinize and control alignment discretion.

The connection between music and lyrics is far beyond semantic bonds. Conceptual pairs in the two modalities such as rhythm and rhyme, note duration and syllabic stress, and structure correspondence, raise a compelling yet seldom-explored direction in the field of music information retrieval. In this paper, we present melody-lyrics matching (MLM), a new task which retrieves potential lyrics for a given symbolic melody from text sources. Rather than generating lyrics from scratch, MLM essentially exploits the relationships between melody and lyrics. We propose a self-supervised representation learning framework with contrastive alignment loss for melody and lyrics. This has the potential to leverage the abundance of existing songs with paired melody and lyrics. No alignment annotations are required. Additionally, we introduce sylphone, a novel representation for lyrics at syllable-level activated by phoneme identity and vowel stress. We demonstrate that our method can match melody with coherent and singable lyrics with empirical results and intuitive examples. We open source code and provide matching examples on the companion webpage: https://github.com/changhongw/mlm.

Multilingual Large Language Models are capable of using powerful Large Language Models to handle and respond to queries in multiple languages, which achieves remarkable success in multilingual natural language processing tasks. Despite these breakthroughs, there still remains a lack of a comprehensive survey to summarize existing approaches and recent developments in this field. To this end, in this paper, we present a thorough review and provide a unified perspective to summarize the recent progress as well as emerging trends in multilingual large language models (MLLMs) literature. The contributions of this paper can be summarized: (1) First survey: to our knowledge, we take the first step and present a thorough review in MLLMs research field according to multi-lingual alignment; (2) New taxonomy: we offer a new and unified perspective to summarize the current progress of MLLMs; (3) New frontiers: we highlight several emerging frontiers and discuss the corresponding challenges; (4) Abundant resources: we collect abundant open-source resources, including relevant papers, data corpora, and leaderboards. We hope our work can provide the community with quick access and spur breakthrough research in MLLMs.

This paper introduces PhyloLM, a method adapting phylogenetic algorithms to Large Language Models (LLMs) to explore whether and how they relate to each other and to predict their performance characteristics. Our method calculates a phylogenetic distance metrics based on the similarity of LLMs' output. The resulting metric is then used to construct dendrograms, which satisfactorily capture known relationships across a set of 111 open-source and 45 closed models. Furthermore, our phylogenetic distance predicts performance in standard benchmarks, thus demonstrating its functional validity and paving the way for a time and cost-effective estimation of LLM capabilities. To sum up, by translating population genetic concepts to machine learning, we propose and validate a tool to evaluate LLM development, relationships and capabilities, even in the absence of transparent training information.

During a virus's evolution,various regions of the genome are subjected to distinct levels of functional constraints.Combined with factors like codon bias and DNA repair efficiency,these constraints contribute to unique mutation patterns within the genome or a specific gene. In this project, we harnessed the power of Large Language Models(LLMs) to predict the evolution of SARS-CoV-2. By treating the mutation process from one generation to the next as a translation task, we trained a transformer model, called VirusT5, to capture the mutation patterns underlying SARS-CoV-2 evolution. We evaluated the VirusT5's ability to detect these mutation patterns including its ability to identify mutation hotspots and explored the potential of using VirusT5 to predict future virus variants. Our findings demonstrate the feasibility of using a large language model to model viral evolution as a translation process. This study establishes the groundbreaking concept of "mutation-as-translation," paving the way for new methodologies and tools for combating virus threats

Pathogen identification is pivotal in diagnosing, treating, and preventing diseases, crucial for controlling infections and safeguarding public health. Traditional alignment-based methods, though widely used, are computationally intense and reliant on extensive reference databases, often failing to detect novel pathogens due to their low sensitivity and specificity. Similarly, conventional machine learning techniques, while promising, require large annotated datasets and extensive feature engineering and are prone to overfitting. Addressing these challenges, we introduce PathoLM, a cutting-edge pathogen language model optimized for the identification of pathogenicity in bacterial and viral sequences. Leveraging the strengths of pre-trained DNA models such as the Nucleotide Transformer, PathoLM requires minimal data for fine-tuning, thereby enhancing pathogen detection capabilities. It effectively captures a broader genomic context, significantly improving the identification of novel and divergent pathogens. We developed a comprehensive data set comprising approximately 30 species of viruses and bacteria, including ESKAPEE pathogens, seven notably virulent bacterial strains resistant to antibiotics. Additionally, we curated a species classification dataset centered specifically on the ESKAPEE group. In comparative assessments, PathoLM dramatically outperforms existing models like DciPatho, demonstrating robust zero-shot and few-shot capabilities. Furthermore, we expanded PathoLM-Sp for ESKAPEE species classification, where it showed superior performance compared to other advanced deep learning methods, despite the complexities of the task.

The integration of biomolecular modeling with natural language (BL) has emerged as a promising interdisciplinary area at the intersection of artificial intelligence, chemistry and biology. This approach leverages the rich, multifaceted descriptions of biomolecules contained within textual data sources to enhance our fundamental understanding and enable downstream computational tasks such as biomolecule property prediction. The fusion of the nuanced narratives expressed through natural language with the structural and functional specifics of biomolecules described via various molecular modeling techniques opens new avenues for comprehensively representing and analyzing biomolecules. By incorporating the contextual language data that surrounds biomolecules into their modeling, BL aims to capture a holistic view encompassing both the symbolic qualities conveyed through language as well as quantitative structural characteristics. In this review, we provide an extensive analysis of recent advancements achieved through cross modeling of biomolecules and natural language. (1) We begin by outlining the technical representations of biomolecules employed, including sequences, 2D graphs, and 3D structures. (2) We then examine in depth the rationale and key objectives underlying effective multi-modal integration of language and molecular data sources. (3) We subsequently survey the practical applications enabled to date in this developing research area. (4) We also compile and summarize the available resources and datasets to facilitate future work. (5) Looking ahead, we identify several promising research directions worthy of further exploration and investment to continue advancing the field. The related resources and contents are updating in https://github.com/QizhiPei/Awesome-Biomolecule-Language-Cross-Modeling.

Inspired by the success of unsupervised pre-training paradigms, researchers have applied these approaches to DNA pre-training. However, we argue that these approaches alone yield suboptimal results because pure DNA sequences lack sufficient information, since their functions are regulated by genomic profiles like chromatin accessibility. Here, we demonstrate that supervised training for genomic profile prediction serves as a more effective alternative to pure sequence pre-training. Furthermore, considering the multi-species and multi-profile nature of genomic profile prediction, we introduce our Species-Profile Adaptive Collaborative Experts (SPACE) that leverages Mixture of Experts (MoE) to better capture the relationships between DNA sequences across different species and genomic profiles, thereby learning more effective DNA representations. Through extensive experiments across various tasks, our model achieves state-of-the-art performance, establishing that DNA models trained with supervised genomic profiles serve as powerful DNA representation learners. The code is available at https://github.com/ZhuJiwei111/SPACE.

Alignment with human preference is a desired property of large language models (LLMs). Currently, the main alignment approach is based on reinforcement learning from human feedback (RLHF). Despite the effectiveness of RLHF, it is intricate to implement and train, thus recent studies explore how to develop alternative alignment approaches based on supervised fine-tuning (SFT). A major limitation of SFT is that it essentially does imitation learning, which cannot fully understand what are the expected behaviors. To address this issue, we propose an improved alignment approach named FIGA. Different from prior methods, we incorporate fine-grained (i.e., token or phrase level) quality signals that are derived by contrasting good and bad responses. Our approach has made two major contributions. Firstly, we curate a refined alignment dataset that pairs initial responses and the corresponding revised ones. Secondly, we devise a new loss function can leverage fine-grained quality signals to instruct the learning of LLMs for alignment. Extensive experiments have demonstrated the effectiveness of our approaches by comparing a number of competitive baselines.

We build upon vec2vec, a procedure designed to align text embedding spaces without parallel data. vec2vec finds a near-perfect alignment, but it is expensive and unstable. We present mini-vec2vec, a simple and efficient alternative that requires substantially lower computational cost and is highly robust. Moreover, the learned mapping is a linear transformation. Our method consists of three main stages: a tentative matching of pseudo-parallel embedding vectors, transformation fitting, and iterative refinement. Our linear alternative exceeds the original instantiation of vec2vec by orders of magnitude in efficiency, while matching or exceeding their results. The method's stability and interpretable algorithmic steps facilitate scaling and unlock new opportunities for adoption in new domains and fields.

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.

Let p denote a generative language model. Let r denote a reward model that returns a scalar that captures the degree at which a draw from p is preferred. The goal of language model alignment is to alter p to a new distribution phi that results in a higher expected reward while keeping phi close to p. A popular alignment method is the KL-constrained reinforcement learning (RL), which chooses a distribution phi_Delta that maximizes E_{phi_{Delta}} r(y) subject to a relative entropy constraint KL(phi_Delta || p) leq Delta. Another simple alignment method is best-of-N, where N samples are drawn from p and one with highest reward is selected. In this paper, we offer a closed-form characterization of the optimal KL-constrained RL solution. We demonstrate that any alignment method that achieves a comparable trade-off between KL divergence and reward must approximate the optimal KL-constrained RL solution in terms of relative entropy. To further analyze the properties of alignment methods, we introduce two simplifying assumptions: we let the language model be memoryless, and the reward model be linear. Although these assumptions may not reflect complex real-world scenarios, they enable a precise characterization of the asymptotic behavior of both the best-of-N alignment, and the KL-constrained RL method, in terms of information-theoretic quantities. We prove that the reward of the optimal KL-constrained RL solution satisfies a large deviation principle, and we fully characterize its rate function. We also show that the rate of growth of the scaled cumulants of the reward is characterized by a proper Renyi cross entropy. Finally, we show that best-of-N is asymptotically equivalent to KL-constrained RL solution by proving that their expected rewards are asymptotically equal, and concluding that the two distributions must be close in KL divergence.

Conditional neural text generation models generate high-quality outputs, but often concentrate around a mode when what we really want is a diverse set of options. We present a search algorithm to construct lattices encoding a massive number of generation options. First, we restructure decoding as a best-first search, which explores the space differently than beam search and improves efficiency by avoiding pruning paths. Second, we revisit the idea of hypothesis recombination: we can identify pairs of similar generation candidates during search and merge them as an approximation. On both summarization and machine translation, we show that our algorithm encodes thousands of diverse options that remain grammatical and high-quality into one lattice. This algorithm provides a foundation for building downstream generation applications on top of massive-scale diverse outputs.

As the size of Large Multi-Modal Models (LMMs) increases consistently, the adaptation of these pre-trained models to specialized tasks has become a computationally and memory-intensive challenge. Traditional fine-tuning methods require isolated, exhaustive retuning for each new task, limiting the models' versatility. Moreover, current efficient adaptation techniques often overlook modality alignment, focusing only on the knowledge extraction of new tasks. To tackle these issues, we introduce Multiway-Adapter, an innovative framework incorporating an 'Alignment Enhancer' to deepen modality alignment, enabling high transferability without tuning pre-trained parameters. Our method adds fewer than 1.25\% of additional parameters to LMMs, exemplified by the BEiT-3 model in our study. This leads to superior zero-shot image-text retrieval performance compared to fully fine-tuned models, while achieving up to a 57\% reduction in fine-tuning time. Our approach offers a resource-efficient and effective adaptation pathway for LMMs, broadening their applicability. The source code is publicly available at: https://github.com/longkukuhi/MultiWay-Adapter.

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.

Large language models (LLMs) trained on text demonstrated remarkable results on natural language processing (NLP) tasks. These models have been adapted to decipher the language of DNA, where sequences of nucleotides act as "words" that encode genomic functions. However, the genome differs fundamentally from natural language, as it lacks clearly defined words or a consistent grammar. Although DNA language models (DNALMs) such as DNABERT, GENA-LM have achieved high level of performance on genome-related biological tasks, these models do not encode biological functions in the presence of sequence variations. To address this problem, we pre-train foundation models that effectively integrate sequence variations, in particular Single Nucleotide Polymorphisms (SNPs), as they underlie important biological functions. Specifically, we use ModernBERT to pre-train two different Biomedical Foundation Models (BMFM), namely, BMFM-DNA-REF in which the model is trained with sequences of varying lengths along with their reverse complements derived from the reference genome and BMFM-DNA-SNP in which the model is trained with sequences created using a novel representation scheme that encodes sequence variations. Our findings indicate that integrating sequence variations into DNALMs helps capture the biological functions as seen in improvements on all fine-tuning tasks. To explore the model's practical utility, we experimented with various strategies for SNP imputation on promoter detection task introduced in DNABERT-2. However, we acknowledge that the current benchmarks are limited in their ability to fully evaluate these models. To enable more comprehensive assessment in the future and encourage community contributions, we release our models through HuggingFace and the code to reproduce the results at https://github.com/BiomedSciAI/biomed-multi-omic

Effective DNA embedding remains crucial in genomic analysis, particularly in scenarios lacking labeled data for model fine-tuning, despite the significant advancements in genome foundation models. A prime example is metagenomics binning, a critical process in microbiome research that aims to group DNA sequences by their species from a complex mixture of DNA sequences derived from potentially thousands of distinct, often uncharacterized species. To fill the lack of effective DNA embedding models, we introduce DNABERT-S, a genome foundation model that specializes in creating species-aware DNA embeddings. To encourage effective embeddings to error-prone long-read DNA sequences, we introduce Manifold Instance Mixup (MI-Mix), a contrastive objective that mixes the hidden representations of DNA sequences at randomly selected layers and trains the model to recognize and differentiate these mixed proportions at the output layer. We further enhance it with the proposed Curriculum Contrastive Learning (C^2LR) strategy. Empirical results on 18 diverse datasets showed DNABERT-S's remarkable performance. It outperforms the top baseline's performance in 10-shot species classification with just a 2-shot training while doubling the Adjusted Rand Index (ARI) in species clustering and substantially increasing the number of correctly identified species in metagenomics binning. The code, data, and pre-trained model are publicly available at https://github.com/Zhihan1996/DNABERT_S.

Recently, there has been a significant upsurge of interest in leveraging large language models (LLMs) to assist scientific discovery. However, most LLMs only focus on general science, while they lack domain-specific knowledge, such as chemical molecules and amino acid sequences. To bridge these gaps, we introduce SciDFM, a mixture-of-experts LLM, which is trained from scratch and is able to conduct college-level scientific reasoning and understand molecules and amino acid sequences. We collect a large-scale training corpus containing numerous scientific papers and books from different disciplines as well as data from domain-specific databases. We further fine-tune the pre-trained model on lots of instruction data to improve performances on downstream benchmarks. From experiment results, we show that SciDFM achieves strong performance on general scientific benchmarks such as SciEval and SciQ, and it reaches a SOTA performance on domain-specific benchmarks among models of similar size. We further analyze the expert layers and show that the results of expert selection vary with data from different disciplines. To benefit the broader research community, we open-source SciDFM at https://huggingface.co/OpenDFM/SciDFM-MoE-A5.6B-v1.0.

Alignment in artificial intelligence pursues the consistency between model responses and human preferences as well as values. In practice, the multifaceted nature of human preferences inadvertently introduces what is known as the "alignment tax" -a compromise where enhancements in alignment within one objective (e.g.,harmlessness) can diminish performance in others (e.g.,helpfulness). However, existing alignment techniques are mostly unidirectional, leading to suboptimal trade-offs and poor flexibility over various objectives. To navigate this challenge, we argue the prominence of grounding LLMs with evident preferences. We introduce controllable preference optimization (CPO), which explicitly specifies preference scores for different objectives, thereby guiding the model to generate responses that meet the requirements. Our experimental analysis reveals that the aligned models can provide responses that match various preferences among the "3H" (helpfulness, honesty, harmlessness) desiderata. Furthermore, by introducing diverse data and alignment goals, we surpass baseline methods in aligning with single objectives, hence mitigating the impact of the alignment tax and achieving improvements in multi-objective alignment.

Alignment with human preference prevents large language models (LLMs) from generating misleading or toxic content while requiring high-cost human feedback. Assuming resources of human annotation are limited, there are two different ways of allocating considered: more diverse PROMPTS or more diverse RESPONSES to be labeled. Nonetheless, a straightforward comparison between their impact is absent. In this work, we first control the diversity of both sides according to the number of samples for fine-tuning, which can directly reflect their influence. We find that instead of numerous prompts, more responses but fewer prompts better trigger LLMs for human alignment. Additionally, the concept of diversity for prompts can be more complex than responses that are typically quantified by single digits. Consequently, a new formulation of prompt diversity is proposed, further implying a linear correlation with the final performance of LLMs after fine-tuning. We also leverage it on data augmentation and conduct experiments to show its effect on different algorithms.

The five idioms (i.e., varieties) of the Romansh language are largely standardized and are taught in the schools of the respective communities in Switzerland. In this paper, we present the first parallel corpus of Romansh idioms. The corpus is based on 291 schoolbook volumes, which are comparable in content for the five idioms. We use automatic alignment methods to extract 207k multi-parallel segments from the books, with more than 2M tokens in total. A small-scale human evaluation confirms that the segments are highly parallel, making the dataset suitable for NLP applications such as machine translation between Romansh idioms. We release the parallel and unaligned versions of the dataset under a CC-BY-NC-SA license and demonstrate its utility for machine translation by training and evaluating an LLM on a sample of the dataset.

Recent studies have demonstrated the cross-lingual alignment ability of multilingual pretrained language models. In this work, we found that the cross-lingual alignment can be further improved by training seq2seq models on sentence pairs mined using their own encoder outputs. We utilized these findings to develop a new approach -- cross-lingual retrieval for iterative self-supervised training (CRISS), where mining and training processes are applied iteratively, improving cross-lingual alignment and translation ability at the same time. Using this method, we achieved state-of-the-art unsupervised machine translation results on 9 language directions with an average improvement of 2.4 BLEU, and on the Tatoeba sentence retrieval task in the XTREME benchmark on 16 languages with an average improvement of 21.5% in absolute accuracy. Furthermore, CRISS also brings an additional 1.8 BLEU improvement on average compared to mBART, when finetuned on supervised machine translation downstream tasks.

The word alignment task, despite its prominence in the era of statistical machine translation (SMT), is niche and under-explored today. In this two-part tutorial, we argue for the continued relevance for word alignment. The first part provides a historical background to word alignment as a core component of the traditional SMT pipeline. We zero-in on GIZA++, an unsupervised, statistical word aligner with surprising longevity. Jumping forward to the era of neural machine translation (NMT), we show how insights from word alignment inspired the attention mechanism fundamental to present-day NMT. The second part shifts to a survey approach. We cover neural word aligners, showing the slow but steady progress towards surpassing GIZA++ performance. Finally, we cover the present-day applications of word alignment, from cross-lingual annotation projection, to improving translation.