Daily Papers

Vision-language model (VLM) agents increasingly rely on memory-augmented reinforcement learning to reuse experience across long-horizon tasks, yet most existing frameworks store memory as text and depend on proprietary teacher models to summarize or refine it. This design is poorly matched to spatial decision making: geometric priors are compressed into lossy language, and sparse interaction is often supervised through delayed textual feedback rather than dense visually grounded signals. We argue that reusable experience for VLM agents should remain visually grounded. Based on this insight, we propose AtlasVA, a teacher-free visual skill memory framework that organizes memory into three complementary layers: spatial heatmaps, visual exemplars, and symbolic text skills. AtlasVA further evolves danger and affinity atlases directly from trajectory statistics and lightweight grid heuristics, and reuses these self-evolving atlases as potential-based shaping rewards for reinforcement learning. This unifies perception, memory, and optimization without external LLM supervision. Experiments on Sokoban, FrozenLake, 3D embodied navigation, and 3D robotic manipulation benchmarks show that AtlasVA consistently outperforms text-centric memory baselines and competitive VLM agents, with especially strong gains on spatially intensive tasks. Homepage: https://wangpan-ustc.github.io/AtlasvaWeb

Protein-ligand binding affinity prediction is essential for drug discovery and toxicity assessment. While machine learning (ML) promises fast and accurate predictions, its progress is constrained by the availability of reliable data. In contrast, physics-based methods such as absolute binding free energy perturbation (AB-FEP) deliver high accuracy but are computationally prohibitive for high-throughput applications. To bridge this gap, we introduce ToxBench, the first large-scale AB-FEP dataset designed for ML development and focused on a single pharmaceutically critical target, Human Estrogen Receptor Alpha (ERalpha). ToxBench contains 8,770 ERalpha-ligand complex structures with binding free energies computed via AB-FEP with a subset validated against experimental affinities at 1.75 kcal/mol RMSE, along with non-overlapping ligand splits to assess model generalizability. Using ToxBench, we further benchmark state-of-the-art ML methods, and notably, our proposed DualBind model, which employs a dual-loss framework to effectively learn the binding energy function. The benchmark results demonstrate the superior performance of DualBind and the potential of ML to approximate AB-FEP at a fraction of the computational cost.

Predicting peptide--major histocompatibility complex I (pMHC-I) binding affinity remains challenging due to extreme allelic diversity (sim30,000 HLA alleles), severe data scarcity for most alleles, and noisy experimental measurements. Current methods particularly struggle with underrepresented alleles and quantitative binding prediction. We test whether domain-specific continued pre-training of protein language models is beneficial for their application to pMHC-I binding affinity prediction. Starting from ESM Cambrian (300M parameters), we perform masked-language modeling (MLM)-based continued pre-training on HLA-associated peptides (epitopes), testing two input formats: epitope sequences alone versus epitopes concatenated with HLA heavy chain sequences. We then fine-tune for functional IC_{50} binding affinity prediction using only high-quality quantitative data, avoiding mass spectrometry biases that are inherited by existing methods.

Identifying drug-target interactions is essential for developing effective therapeutics. Binding affinity quantifies these interactions, and traditional approaches rely on computationally intensive 3D structural data. In contrast, language models can efficiently process sequential data, offering an alternative approach to molecular representation. In the current study, we introduce BAPULM, an innovative sequence-based framework that leverages the chemical latent representations of proteins via ProtT5-XL-U50 and ligands through MolFormer, eliminating reliance on complex 3D configurations. Our approach was validated extensively on benchmark datasets, achieving scoring power (R) values of 0.925 pm 0.043, 0.914 pm 0.004, and 0.8132 pm 0.001 on benchmark1k2101, Test2016_290, and CSAR-HiQ_36, respectively. These findings indicate the robustness and accuracy of BAPULM across diverse datasets and underscore the potential of sequence-based models in-silico drug discovery, offering a scalable alternative to 3D-centric methods for screening potential ligands.

Machine learning-based antibody design is emerging as one of the most promising approaches to combat infectious diseases, due to significant advancements in the field of artificial intelligence and an exponential surge in experimental antibody data (in particular related to COVID-19). The ability of an antibody to bind to an antigens (called binding affinity) is one of the the most critical properties in designing neutralizing antibodies. In this study we introduce Ab-Affinity, a new large language model that can accurately predict the binding affinity of antibodies against a target peptide, e.g., the SARS-CoV-2 spike protein. Code and model are available at https://github.com/ucrbioinfo/AbAffinity.

Accurate prediction of Drug-Target Affinity (DTA) is of vital importance in early-stage drug discovery, facilitating the identification of drugs that can effectively interact with specific targets and regulate their activities. While wet experiments remain the most reliable method, they are time-consuming and resource-intensive, resulting in limited data availability that poses challenges for deep learning approaches. Existing methods have primarily focused on developing techniques based on the available DTA data, without adequately addressing the data scarcity issue. To overcome this challenge, we present the SSM-DTA framework, which incorporates three simple yet highly effective strategies: (1) A multi-task training approach that combines DTA prediction with masked language modeling (MLM) using paired drug-target data. (2) A semi-supervised training method that leverages large-scale unpaired molecules and proteins to enhance drug and target representations. This approach differs from previous methods that only employed molecules or proteins in pre-training. (3) The integration of a lightweight cross-attention module to improve the interaction between drugs and targets, further enhancing prediction accuracy. Through extensive experiments on benchmark datasets such as BindingDB, DAVIS, and KIBA, we demonstrate the superior performance of our framework. Additionally, we conduct case studies on specific drug-target binding activities, virtual screening experiments, drug feature visualizations, and real-world applications, all of which showcase the significant potential of our work. In conclusion, our proposed SSM-DTA framework addresses the data limitation challenge in DTA prediction and yields promising results, paving the way for more efficient and accurate drug discovery processes. Our code is available at https://github.com/QizhiPei/SSM-DTA{Github}.

Prediction of protein-ligand (PL) binding affinity remains the key to drug discovery. Popular approaches in recent years involve graph neural networks (GNNs), which are used to learn the topology and geometry of PL complexes. However, GNNs are computationally heavy and have poor scalability to graph sizes. On the other hand, traditional machine learning (ML) approaches, such as gradient-boosted decision trees (GBDTs), are lightweight yet extremely efficient for tabular data. We propose to use PL interaction features along with PL graph-level features in GBDT. We show that this combination outperforms the existing solutions.

We present HistoAtlas, a pan-cancer computational atlas that extracts 38 interpretable histomic features from 6,745 diagnostic H&E slides across 21 TCGA cancer types and systematically links every feature to survival, gene expression, somatic mutations, and immune subtypes. All associations are covariate-adjusted, multiple-testing corrected, and classified into evidence-strength tiers. The atlas recovers known biology, from immune infiltration and prognosis to proliferation and kinase signaling, while uncovering compartment-specific immune signals and morphological subtypes with divergent outcomes. Every result is spatially traceable to tissue compartments and individual cells, statistically calibrated, and openly queryable. HistoAtlas enables systematic, large-scale biomarker discovery from routine H&E without specialized staining or sequencing. Data and an interactive web atlas are freely available at https://histoatlas.com .

In an era where accumulating data is easy and storing it inexpensive, feature selection plays a central role in helping to reduce the high-dimensionality of huge amounts of otherwise meaningless data. In this paper, we propose a graph-based method for feature selection that ranks features by identifying the most important ones into arbitrary set of cues. Mapping the problem on an affinity graph-where features are the nodes-the solution is given by assessing the importance of nodes through some indicators of centrality, in particular, the Eigen-vector Centrality (EC). The gist of EC is to estimate the importance of a feature as a function of the importance of its neighbors. Ranking central nodes individuates candidate features, which turn out to be effective from a classification point of view, as proved by a thoroughly experimental section. Our approach has been tested on 7 diverse datasets from recent literature (e.g., biological data and object recognition, among others), and compared against filter, embedded and wrappers methods. The results are remarkable in terms of accuracy, stability and low execution time.

We describe the accurate prediction of ligand-protein interaction (LPI) affinities, also known as drug-target interactions (DTI), with instruction fine-tuned pretrained generative small language models (SLMs). We achieved accurate predictions for a range of affinity values associated with ligand-protein interactions on out-of-sample data in a zero-shot setting. Only the SMILES string of the ligand and the amino acid sequence of the protein were used as the model inputs. Our results demonstrate a clear improvement over machine learning (ML) and free-energy perturbation (FEP+) based methods in accurately predicting a range of ligand-protein interaction affinities, which can be leveraged to further accelerate drug discovery campaigns against challenging therapeutic targets.

The rapid advancement of Large Language Models (LLMs) has led to performance saturation on many established benchmarks, questioning their ability to distinguish frontier models. Concurrently, existing high-difficulty benchmarks often suffer from narrow disciplinary focus, oversimplified answer formats, and vulnerability to data contamination, creating a fidelity gap with real-world scientific inquiry. To address these challenges, we introduce ATLAS (AGI-Oriented Testbed for Logical Application in Science), a large-scale, high-difficulty, and cross-disciplinary evaluation suite composed of approximately 800 original problems. Developed by domain experts (PhD-level and above), ATLAS spans seven core scientific fields: mathematics, physics, chemistry, biology, computer science, earth science, and materials science. Its key features include: (1) High Originality and Contamination Resistance, with all questions newly created or substantially adapted to prevent test data leakage; (2) Cross-Disciplinary Focus, designed to assess models' ability to integrate knowledge and reason across scientific domains; (3) High-Fidelity Answers, prioritizing complex, open-ended answers involving multi-step reasoning and LaTeX-formatted expressions over simple multiple-choice questions; and (4) Rigorous Quality Control, employing a multi-stage process of expert peer review and adversarial testing to ensure question difficulty, scientific value, and correctness. We also propose a robust evaluation paradigm using a panel of LLM judges for automated, nuanced assessment of complex answers. Preliminary results on leading models demonstrate ATLAS's effectiveness in differentiating their advanced scientific reasoning capabilities. We plan to develop ATLAS into a long-term, open, community-driven platform to provide a reliable "ruler" for progress toward Artificial General Intelligence.

We introduce AbBiBench (Antibody Binding Benchmarking), a benchmarking framework for antibody binding affinity maturation and design. Unlike previous strategies that evaluate antibodies in isolation, typically by comparing them to natural sequences with metrics such as amino acid recovery rate or structural RMSD, AbBiBench instead treats the antibody-antigen (Ab-Ag) complex as the fundamental unit. It evaluates an antibody design's binding potential by measuring how well a protein model scores the full Ab-Ag complex. We first curate, standardize, and share more than 184,500 experimental measurements of antibody mutants across 14 antibodies and 9 antigens-including influenza, lysozyme, HER2, VEGF, integrin, Ang2, and SARS-CoV-2-covering both heavy-chain and light-chain mutations. Using these datasets, we systematically compare 15 protein models including masked language models, autoregressive language models, inverse folding models, diffusion-based generative models, and geometric graph models by comparing the correlation between model likelihood and experimental affinity values. Additionally, to demonstrate AbBiBench's generative utility, we apply it to antibody F045-092 in order to introduce binding to influenza H1N1. We sample new antibody variants with the top-performing models, rank them by the structural integrity and biophysical properties of the Ab-Ag complex, and assess them with in vitro ELISA binding assays. Our findings show that structure-conditioned inverse folding models outperform others in both affinity correlation and generation tasks. Overall, AbBiBench provides a unified, biologically grounded evaluation framework to facilitate the development of more effective, function-aware antibody design models.

Protein-protein interactions (PPIs) are fundamental to numerous cellular processes, and their characterization is vital for understanding disease mechanisms and guiding drug discovery. While protein language models (PLMs) have demonstrated remarkable success in predicting protein structure and function, their application to sequence-based PPI binding affinity prediction remains relatively underexplored. This gap is often attributed to the scarcity of high-quality, rigorously refined datasets and the reliance on simple strategies for concatenating protein representations. In this work, we address these limitations. First, we introduce a meticulously curated version of the PPB-Affinity dataset of a total of 8,207 unique protein-protein interaction entries, by resolving annotation inconsistencies and duplicate entries for multi-chain protein interactions. This dataset incorporates a stringent, less than or equal to 30%, sequence identity threshold to ensure robust splitting into training, validation, and test sets, minimizing data leakage. Second, we propose and systematically evaluate four architectures for adapting PLMs to PPI binding affinity prediction: embeddings concatenation (EC), sequences concatenation (SC), hierarchical pooling (HP), and pooled attention addition (PAD). These architectures were assessed using two training methods: full fine-tuning and a lightweight approach employing ConvBERT heads over frozen PLM features. Our comprehensive experiments across multiple leading PLMs (ProtT5, ESM2, Ankh, Ankh2, and ESM3) demonstrated that the HP and PAD architectures consistently outperform conventional concatenation methods, achieving up to 12% increase in terms of Spearman correlation. These results highlight the necessity of sophisticated architectural designs to fully exploit the capabilities of PLMs for nuanced PPI binding affinity prediction.

Antibodies have become an important class of therapeutic agents to treat human diseases. To accelerate therapeutic antibody discovery, computational methods, especially machine learning, have attracted considerable interest for predicting specific interactions between antibody candidates and target antigens such as viruses and bacteria. However, the publicly available datasets in existing works have notable limitations, such as small sizes and the lack of non-binding samples and exact amino acid sequences. To overcome these limitations, we have developed AVIDa-hIL6, a large-scale dataset for predicting antigen-antibody interactions in the variable domain of heavy chain of heavy chain antibodies (VHHs), produced from an alpaca immunized with the human interleukin-6 (IL-6) protein, as antigens. By leveraging the simple structure of VHHs, which facilitates identification of full-length amino acid sequences by DNA sequencing technology, AVIDa-hIL6 contains 573,891 antigen-VHH pairs with amino acid sequences. All the antigen-VHH pairs have reliable labels for binding or non-binding, as generated by a novel labeling method. Furthermore, via introduction of artificial mutations, AVIDa-hIL6 contains 30 different mutants in addition to wild-type IL-6 protein. This characteristic provides opportunities to develop machine learning models for predicting changes in antibody binding by antigen mutations. We report experimental benchmark results on AVIDa-hIL6 by using neural network-based baseline models. The results indicate that the existing models have potential, but further research is needed to generalize them to predict effective antibodies against unknown mutants. The dataset is available at https://avida-hil6.cognanous.com.

Foundation models applied to bio-molecular space hold promise to accelerate drug discovery. Molecular representation is key to building such models. Previous works have typically focused on a single representation or view of the molecules. Here, we develop a multi-view foundation model approach, that integrates molecular views of graph, image and text. Single-view foundation models are each pre-trained on a dataset of up to 200M molecules and then aggregated into combined representations. Our multi-view model is validated on a diverse set of 18 tasks, encompassing ligand-protein binding, molecular solubility, metabolism and toxicity. We show that the multi-view models perform robustly and are able to balance the strengths and weaknesses of specific views. We then apply this model to screen compounds against a large (>100 targets) set of G Protein-Coupled receptors (GPCRs). From this library of targets, we identify 33 that are related to Alzheimer's disease. On this subset, we employ our model to identify strong binders, which are validated through structure-based modeling and identification of key binding motifs.

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.

The complementarity-determining regions of antibodies are loop structures that are key to their interactions with antigens, and of high importance to the design of novel biologics. Since the 1980s, categorizing the diversity of CDR structures into canonical clusters has enabled the identification of key structural motifs of antibodies. However, existing approaches have limited coverage and cannot be readily incorporated into protein foundation models. Here we introduce ImmunoGlobulin LOOp Tokenizer, Igloo, a multimodal antibody loop tokenizer that encodes backbone dihedral angles and sequence. Igloo is trained using a contrastive learning objective to map loops with similar backbone dihedral angles closer together in latent space. Igloo can efficiently retrieve the closest matching loop structures from a structural antibody database, outperforming existing methods on identifying similar H3 loops by 5.9\%. Igloo assigns tokens to all loops, addressing the limited coverage issue of canonical clusters, while retaining the ability to recover canonical loop conformations. To demonstrate the versatility of Igloo tokens, we show that they can be incorporated into protein language models with IglooLM and IglooALM. On predicting binding affinity of heavy chain variants, IglooLM outperforms the base protein language model on 8 out of 10 antibody-antigen targets. Additionally, it is on par with existing state-of-the-art sequence-based and multimodal protein language models, performing comparably to models with 7times more parameters. IglooALM samples antibody loops which are diverse in sequence and more consistent in structure than state-of-the-art antibody inverse folding models. Igloo demonstrates the benefit of introducing multimodal tokens for antibody loops for encoding the diverse landscape of antibody loops, improving protein foundation models, and for antibody CDR design.

Recent research in representation learning utilizes large databases of proteins or molecules to acquire knowledge of drug and protein structures through unsupervised learning techniques. These pre-trained representations have proven to significantly enhance the accuracy of subsequent tasks, such as predicting the affinity between drugs and target proteins. In this study, we demonstrate that by incorporating knowledge graphs from diverse sources and modalities into the sequences or SMILES representation, we can further enrich the representation and achieve state-of-the-art results on established benchmark datasets. We provide preprocessed and integrated data obtained from 7 public sources, which encompass over 30M triples. Additionally, we make available the pre-trained models based on this data, along with the reported outcomes of their performance on three widely-used benchmark datasets for drug-target binding affinity prediction found in the Therapeutic Data Commons (TDC) benchmarks. Additionally, we make the source code for training models on benchmark datasets publicly available. Our objective in releasing these pre-trained models, accompanied by clean data for model pretraining and benchmark results, is to encourage research in knowledge-enhanced representation learning.

Accurate medical image segmentation is essential for clinical diagnosis and treatment planning. While recent interactive foundation models (e.g., nnInteractive) enhance generalization through large-scale multimodal pretraining, they still depend on precise prompts and often perform below expectations in contexts that are underrepresented in their training data. We present AtlasSegFM, an atlas-guided framework that customizes available foundation models to clinical contexts with a single annotated example. The core innovations are: 1) a pipeline that provides context-aware prompts for foundation models via registration between a context atlas and query images, and 2) a test-time adapter to fuse predictions from both atlas registration and the foundation model. Extensive experiments across public and in-house datasets spanning multiple modalities and organs demonstrate that AtlasSegFM consistently improves segmentation, particularly for small, delicate structures. AtlasSegFM provides a lightweight, deployable solution one-shot customization of foundation models in real-world clinical workflows. The code will be made publicly available.

The detection of ligand binding sites for proteins is a fundamental step in Structure-Based Drug Design. Despite notable advances in recent years, existing methods, datasets, and evaluation metrics are confronted with several key challenges: (1) current datasets and methods are centered on individual protein-ligand complexes and neglect that diverse binding sites may exist across multiple complexes of the same protein, introducing significant statistical bias; (2) ligand binding site detection is typically modeled as a discontinuous workflow, employing binary segmentation and subsequent clustering algorithms; (3) traditional evaluation metrics do not adequately reflect the actual performance of different binding site prediction methods. To address these issues, we first introduce UniSite-DS, the first UniProt (Unique Protein)-centric ligand binding site dataset, which contains 4.81 times more multi-site data and 2.08 times more overall data compared to the previously most widely used datasets. We then propose UniSite, the first end-to-end ligand binding site detection framework supervised by set prediction loss with bijective matching. In addition, we introduce Average Precision based on Intersection over Union (IoU) as a more accurate evaluation metric for ligand binding site prediction. Extensive experiments on UniSite-DS and several representative benchmark datasets demonstrate that IoU-based Average Precision provides a more accurate reflection of prediction quality, and that UniSite outperforms current state-of-the-art methods in ligand binding site detection. The dataset and codes will be made publicly available at https://github.com/quanlin-wu/unisite.

As convolution has empowered many smart applications, dynamic convolution further equips it with the ability to adapt to diverse inputs. However, the static and dynamic convolutions are either layout-agnostic or computation-heavy, making it inappropriate for layout-specific applications, e.g., face recognition and medical image segmentation. We observe that these applications naturally exhibit the characteristics of large intra-image (spatial) variance and small cross-image variance. This observation motivates our efficient translation variant convolution (TVConv) for layout-aware visual processing. Technically, TVConv is composed of affinity maps and a weight-generating block. While affinity maps depict pixel-paired relationships gracefully, the weight-generating block can be explicitly overparameterized for better training while maintaining efficient inference. Although conceptually simple, TVConv significantly improves the efficiency of the convolution and can be readily plugged into various network architectures. Extensive experiments on face recognition show that TVConv reduces the computational cost by up to 3.1x and improves the corresponding throughput by 2.3x while maintaining a high accuracy compared to the depthwise convolution. Moreover, for the same computation cost, we boost the mean accuracy by up to 4.21%. We also conduct experiments on the optic disc/cup segmentation task and obtain better generalization performance, which helps mitigate the critical data scarcity issue. Code is available at https://github.com/JierunChen/TVConv.

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.

As there are now millions of publicly available neural networks, searching and analyzing large model repositories becomes increasingly important. Navigating so many models requires an atlas, but as most models are poorly documented charting such an atlas is challenging. To explore the hidden potential of model repositories, we chart a preliminary atlas representing the documented fraction of Hugging Face. It provides stunning visualizations of the model landscape and evolution. We demonstrate several applications of this atlas including predicting model attributes (e.g., accuracy), and analyzing trends in computer vision models. However, as the current atlas remains incomplete, we propose a method for charting undocumented regions. Specifically, we identify high-confidence structural priors based on dominant real-world model training practices. Leveraging these priors, our approach enables accurate mapping of previously undocumented areas of the atlas. We publicly release our datasets, code, and interactive atlas.

Structure-based drug design (SBDD) aims to efficiently discover high-affinity ligands within vast chemical spaces. However, current generative models struggle with objective misalignment and rigid sampling budgets. We present MolFORM, a fast multi-modal flow matching framework for discrete atom types and continuous coordinates. Crucially, to bridge the gap between generative capability and biochemical objectives, we introduce two distinct post-training strategies: (1) Direct Preference Optimization (DPO), which performs offline alignment using ranked preference pairs; and (2) an online reinforcement learning paradigm that optimizes the generative flow directly on the forward process. Both strategies effectively navigate the chemical space toward high-affinity regions. MolFORM achieves state-of-the-art results on the CrossDocked2020 benchmark (Vina Score -7.60, Diversity 0.75), demonstrating that incorporating preference alignment mechanisms-whether via offline optimization or online reinforcement-is crucial for steering generative models toward high-affinity binding regions. The source code for MolFORM is publicly available at https://github.com/daiheng-zhang/SBDD-MolFORM.

Few-Shot Semantic Segmentation (FSS) models achieve strong performance in segmenting novel classes with minimal labeled examples, yet their decision-making processes remain largely opaque. While explainable AI has advanced significantly in standard computer vision tasks, interpretability in FSS remains virtually unexplored despite its critical importance for understanding model behavior and guiding support set selection in data-scarce scenarios. This paper introduces the first dedicated method for interpreting matching-based FSS models by leveraging their inherent structural properties. Our Affinity Explainer approach extracts attribution maps that highlight which pixels in support images contribute most to query segmentation predictions, using matching scores computed between support and query features at multiple feature levels. We extend standard interpretability evaluation metrics to the FSS domain and propose additional metrics to better capture the practical utility of explanations in few-shot scenarios. Comprehensive experiments on FSS benchmark datasets, using different models, demonstrate that our Affinity Explainer significantly outperforms adapted standard attribution methods. Qualitative analysis reveals that our explanations provide structured, coherent attention patterns that align with model architectures and and enable effective model diagnosis. This work establishes the foundation for interpretable FSS research, enabling better model understanding and diagnostic for more reliable few-shot segmentation systems. The source code is publicly available at https://github.com/pasqualedem/AffinityExplainer.

Nanobodies, single-domain antibody fragments derived from camelid heavy-chain-only antibodies, exhibit unique advantages such as compact size, high stability, and strong binding affinity, making them valuable tools in therapeutics and diagnostics. While recent advances in pretrained protein and antibody language models (PPLMs and PALMs) have greatly enhanced biomolecular understanding, nanobody-specific modeling remains underexplored and lacks a unified benchmark. To address this gap, we introduce NbBench, the first comprehensive benchmark suite for nanobody representation learning. Spanning eight biologically meaningful tasks across nine curated datasets, NbBench encompasses structure annotation, binding prediction, and developability assessment. We systematically evaluate eleven representative models--including general-purpose protein LMs, antibody-specific LMs, and nanobody-specific LMs--in a frozen setting. Our analysis reveals that antibody language models excel in antigen-related tasks, while performance on regression tasks such as thermostability and affinity remains challenging across all models. Notably, no single model consistently outperforms others across all tasks. By standardizing datasets, task definitions, and evaluation protocols, NbBench offers a reproducible foundation for assessing and advancing nanobody modeling.

Recently, significant progress has been made in protein-ligand docking, especially in modern deep learning methods, and some benchmarks were proposed, e.g., PoseBench, Plinder. However, these benchmarks suffer from less practical evaluation setups (e.g., blind docking, self docking), or heavy framework that involves training, raising challenges to assess docking methods efficiently. To fill this gap, we proposed PoseX, an open-source benchmark focusing on self-docking and cross-docking, to evaluate the algorithmic advances practically and comprehensively. Specifically, first, we curate a new evaluation dataset with 718 entries for self docking and 1,312 for cross docking; second, we incorporate 22 docking methods across three methodological categories, including (1) traditional physics-based methods (e.g., Schr\"odinger Glide), (2) AI docking methods (e.g., DiffDock), (3) AI co-folding methods (e.g., AlphaFold3); third, we design a relaxation method as post-processing to minimize conformation energy and refine binding pose; fourth, we released a leaderboard to rank submitted models in real time. We draw some key insights via extensive experiments: (1) AI-based approaches have already surpassed traditional physics-based approaches in overall docking accuracy (RMSD). The longstanding generalization issues that have plagued AI molecular docking have been significantly alleviated in the latest models. (2) The stereochemical deficiencies of AI-based approaches can be greatly alleviated with post-processing relaxation. Combining AI docking methods with the enhanced relaxation method achieves the best performance to date. (3) AI co-folding methods commonly face ligand chirality issues, which cannot be resolved by relaxation. The code, curated dataset and leaderboard are released at https://github.com/CataAI/PoseX.

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

Deep learning models have driven significant progress in predicting protein function and interactions at the protein level. While these advancements have been invaluable for many biological applications such as enzyme engineering and function annotation, a more detailed perspective is essential for understanding protein functional mechanisms and evaluating the biological knowledge captured by models. To address this demand, we introduce VenusX, the first large-scale benchmark for fine-grained functional annotation and function-based protein pairing at the residue, fragment, and domain levels. VenusX comprises three major task categories across six types of annotations, including residue-level binary classification, fragment-level multi-class classification, and pairwise functional similarity scoring for identifying critical active sites, binding sites, conserved sites, motifs, domains, and epitopes. The benchmark features over 878,000 samples curated from major open-source databases such as InterPro, BioLiP, and SAbDab. By providing mixed-family and cross-family splits at three sequence identity thresholds, our benchmark enables a comprehensive assessment of model performance on both in-distribution and out-of-distribution scenarios. For baseline evaluation, we assess a diverse set of popular and open-source models, including pre-trained protein language models, sequence-structure hybrids, structure-based methods, and alignment-based techniques. Their performance is reported across all benchmark datasets and evaluation settings using multiple metrics, offering a thorough comparison and a strong foundation for future research. Code and data are publicly available at https://github.com/ai4protein/VenusX.

Accurate prediction of protein-ligand binding affinities is crucial in drug discovery, particularly during hit-to-lead and lead optimization phases, however, limitations in ligand force fields continue to impact prediction accuracy. In this work, we validate relative binding free energy (RBFE) accuracy using neural network potentials (NNPs) for the ligands. We utilize a novel NNP model, AceForce 1.0, based on the TensorNet architecture for small molecules that broadens the applicability to diverse drug-like compounds, including all important chemical elements and supporting charged molecules. Using established benchmarks, we show overall improved accuracy and correlation in binding affinity predictions compared with GAFF2 for molecular mechanics and ANI2-x for NNPs. Slightly less accuracy but comparable correlations with OPLS4. We also show that we can run the NNP simulations at 2 fs timestep, at least two times larger than previous NNP models, providing significant speed gains. The results show promise for further evolutions of free energy calculations using NNPs while demonstrating its practical use already with the current generation. The code and NNP model are publicly available for research use.

Modern AI technologies for drug discovery are distributed across heterogeneous platforms-including web applications, desktop environments, and code libraries-leading to fragmented workflows, inconsistent interfaces, and high integration overhead. We present an agentic end-to-end drug design framework that leverages a Large Language Model (LLM) in conjunction with the Model Context Protocol (MCP) to dynamically coordinate access to biochemical databases, modular toolchains, and task-specific AI models. The system integrates four state-of-the-art components: MaSIF (MaSIF-site and MaSIF-seed-search) for geometric deep learning-based identification of protein-protein interaction (PPI) sites, Rosetta for grafting protein fragments onto protein backbones to form mini proteins, ProteinMPNN for amino acid sequences redesign, and AlphaFold3 for near-experimental accuracy in complex structure prediction. Starting from a target structure, the framework supports de novo binder generation via surface analysis, scaffold grafting and pose construction, sequence optimization, and structure prediction. Additionally, by replacing rigid, script-based workflows with a protocol-driven, LLM-coordinated architecture, the framework improves reproducibility, reduces manual overhead, and ensures extensibility, portability, and auditability across the entire drug design process.

Generative models for structure-based drug design (SBDD) have shown promising results in recent years. Existing works mainly focus on how to generate molecules with higher binding affinity, ignoring the feasibility prerequisites for generated 3D poses and resulting in false positives. We conduct thorough studies on key factors of ill-conformational problems when applying autoregressive methods and diffusion to SBDD, including mode collapse and hybrid continuous-discrete space. In this paper, we introduce MolCRAFT, the first SBDD model that operates in the continuous parameter space, together with a novel noise reduced sampling strategy. Empirical results show that our model consistently achieves superior performance in binding affinity with more stable 3D structure, demonstrating our ability to accurately model interatomic interactions. To our best knowledge, MolCRAFT is the first to achieve reference-level Vina Scores (-6.59 kcal/mol) with comparable molecular size, outperforming other strong baselines by a wide margin (-0.84 kcal/mol). Code is available at https://github.com/AlgoMole/MolCRAFT.

Predicting drug-target interaction (DTI) is critical in the drug discovery process. Despite remarkable advances in recent DTI models through the integration of representations from diverse drug and target encoders, such models often struggle to capture the fine-grained interactions between drugs and protein, i.e. the binding of specific drug atoms (or substructures) and key amino acids of proteins, which is crucial for understanding the binding mechanisms and optimising drug design. To address this issue, this paper introduces a novel model, called FusionDTI, which uses a token-level Fusion module to effectively learn fine-grained information for Drug-Target Interaction. In particular, our FusionDTI model uses the SELFIES representation of drugs to mitigate sequence fragment invalidation and incorporates the structure-aware (SA) vocabulary of target proteins to address the limitation of amino acid sequences in structural information, additionally leveraging pre-trained language models extensively trained on large-scale biomedical datasets as encoders to capture the complex information of drugs and targets. Experiments on three well-known benchmark datasets show that our proposed FusionDTI model achieves the best performance in DTI prediction compared with seven existing state-of-the-art baselines. Furthermore, our case study indicates that FusionDTI could highlight the potential binding sites, enhancing the explainability of the DTI prediction.

In response to the global need for efficient early diagnosis of Autism Spectrum Disorder (ASD), this paper bridges the gap between traditional, time-consuming diagnostic methods and potential automated solutions. We propose a multi-atlas deep ensemble network, MADE-for-ASD, that integrates multiple atlases of the brain's functional magnetic resonance imaging (fMRI) data through a weighted deep ensemble network. Our approach integrates demographic information into the prediction workflow, which enhances ASD diagnosis performance and offers a more holistic perspective on patient profiling. We experiment with the well-known publicly available ABIDE (Autism Brain Imaging Data Exchange) I dataset, consisting of resting state fMRI data from 17 different laboratories around the globe. Our proposed system achieves 75.20% accuracy on the entire dataset and 96.40% on a specific subset - both surpassing reported ASD diagnosis accuracy in ABIDE I fMRI studies. Specifically, our model improves by 4.4 percentage points over prior works on the same amount of data. The model exhibits a sensitivity of 82.90% and a specificity of 69.70% on the entire dataset, and 91.00% and 99.50%, respectively, on the specific subset. We leverage the F-score to pinpoint the top 10 ROI in ASD diagnosis, such as precuneus and anterior cingulate/ventromedial. The proposed system can potentially pave the way for more cost-effective, efficient and scalable strategies in ASD diagnosis. Codes and evaluations are publicly available at https://github.com/hasan-rakibul/MADE-for-ASD.

Personalized vaccines and T-cell immunotherapies depend critically on identifying peptide-MHC class I (pMHC-I) interactions capable of eliciting potent immune responses. However, current benchmarks and models inherit biases present in mass-spectrometry and binding-assay datasets, limiting discovery of novel peptide ligands. To address this issue, we introduce a structure-guided benchmark of pMHC-I peptides designed using diffusion models conditioned on crystal structure interaction distances. Spanning twenty high-priority HLA alleles, this benchmark is independent of previously characterized peptides yet reproduces canonical anchor residue preferences, indicating structural generalization without experimental dataset bias. Using this resource, we demonstrate that state-of-the-art sequence-based predictors perform poorly at recognizing the binding potential of these structurally stable designs, indicating allele-specific limitations invisible in conventional evaluations. Our geometry-aware design pipeline yields peptides with high predicted structural integrity and higher residue diversity than existing datasets, representing a key resource for unbiased model training and evaluation. Our code, and data are available at: https://github.com/sermare/struct-mhc-dev.

Computational design of protein-binding proteins is a fundamental capability with broad utility in biomedical research and biotechnology. Recent methods have made strides against some target proteins, but on-demand creation of high-affinity binders without multiple rounds of experimental testing remains an unsolved challenge. This technical report introduces AlphaProteo, a family of machine learning models for protein design, and details its performance on the de novo binder design problem. With AlphaProteo, we achieve 3- to 300-fold better binding affinities and higher experimental success rates than the best existing methods on seven target proteins. Our results suggest that AlphaProteo can generate binders "ready-to-use" for many research applications using only one round of medium-throughput screening and no further optimization.

With the fast development of COVID-19 into a global pandemic, scientists around the globe are desperately searching for effective antiviral therapeutic agents. Bridging systems biology and drug discovery, we propose a deep learning framework for conditional de novo design of antiviral candidate drugs tailored against given protein targets. First, we train a multimodal ligand--protein binding affinity model on predicting affinities of antiviral compounds to target proteins and couple this model with pharmacological toxicity predictors. Exploiting this multi-objective as a reward function of a conditional molecular generator (consisting of two VAEs), we showcase a framework that navigates the chemical space toward regions with more antiviral molecules. Specifically, we explore a challenging setting of generating ligands against unseen protein targets by performing a leave-one-out-cross-validation on 41 SARS-CoV-2-related target proteins. Using deep RL, it is demonstrated that in 35 out of 41 cases, the generation is biased towards sampling more binding ligands, with an average increase of 83% comparing to an unbiased VAE. We present a case-study on a potential Envelope-protein inhibitor and perform a synthetic accessibility assessment of the best generated molecules is performed that resembles a viable roadmap towards a rapid in-vitro evaluation of potential SARS-CoV-2 inhibitors.

Chemical language models, combined with reinforcement learning (RL), have shown significant promise to efficiently traverse large chemical spaces for drug discovery. However, the performance of various RL algorithms and their best practices for practical drug discovery are still unclear. Here, starting from the principles of the REINFORCE algorithm, we investigate the effect of different components from RL theory including experience replay, hill-climbing, baselines to reduce variance, and alternative reward shaping. We propose a new regularization method more aligned to REINFORCE than current standard practices, and demonstrate how RL hyperparameters can be fine-tuned for effectiveness and efficiency. Lastly, we apply our learnings to practical drug discovery by demonstrating enhanced learning efficiency on frontier binding affinity models by using Boltz2 as a reward model. We share our RL models used in the ACEGEN repository, and hope the experiments here act as a guide to researchers applying RL to chemical language models for drug discovery.

The tumor microenvironment (TME) plays a central role in cancer progression, treatment response, and patient outcomes, yet large-scale, consistent, and quantitative TME characterization from routine hematoxylin and eosin (H&E)-stained histopathology remains scarce. We introduce OpenTME, an open-access dataset of pre-computed TME profiles derived from 3,634 H&E-stained whole-slide images across five cancer types (bladder, breast, colorectal, liver, and lung cancer) from The Cancer Genome Atlas (TCGA). All outputs were generated using Atlas H&E-TME, an AI-powered application built on the Atlas family of pathology foundation models, which performs tissue quality control, tissue segmentation, cell detection and classification, and spatial neighborhood analysis, yielding over 4,500 quantitative readouts per slide at cell-level resolution. OpenTME is available for non-commercial academic research on Hugging Face. We will continue to expand OpenTME over time and anticipate it will serve as a resource for biomarker discovery, spatial biology research, and the development of computational methods for TME analysis.

Existing efforts in building GUI agents heavily rely on the availability of robust commercial Vision-Language Models (VLMs) such as GPT-4o and GeminiProVision. Practitioners are often reluctant to use open-source VLMs due to their significant performance lag compared to their closed-source counterparts, particularly in GUI grounding and Out-Of-Distribution (OOD) scenarios. To facilitate future research in this area, we developed OS-Atlas - a foundational GUI action model that excels at GUI grounding and OOD agentic tasks through innovations in both data and modeling. We have invested significant engineering effort in developing an open-source toolkit for synthesizing GUI grounding data across multiple platforms, including Windows, Linux, MacOS, Android, and the web. Leveraging this toolkit, we are releasing the largest open-source cross-platform GUI grounding corpus to date, which contains over 13 million GUI elements. This dataset, combined with innovations in model training, provides a solid foundation for OS-Atlas to understand GUI screenshots and generalize to unseen interfaces. Through extensive evaluation across six benchmarks spanning three different platforms (mobile, desktop, and web), OS-Atlas demonstrates significant performance improvements over previous state-of-the-art models. Our evaluation also uncovers valuable insights into continuously improving and scaling the agentic capabilities of open-source VLMs.

We introduce FragAtlas-62M, a specialized foundation model trained on the largest fragment dataset to date. Built on the complete ZINC-22 fragment subset comprising over 62 million molecules, it achieves unprecedented coverage of fragment chemical space. Our GPT-2 based model (42.7M parameters) generates 99.90% chemically valid fragments. Validation across 12 descriptors and three fingerprint methods shows generated fragments closely match the training distribution (all effect sizes < 0.4). The model retains 53.6% of known ZINC fragments while producing 22% novel structures with practical relevance. We release FragAtlas-62M with training code, preprocessed data, documentation, and model weights to accelerate adoption.

We develop a learning framework for building deformable templates, which play a fundamental role in many image analysis and computational anatomy tasks. Conventional methods for template creation and image alignment to the template have undergone decades of rich technical development. In these frameworks, templates are constructed using an iterative process of template estimation and alignment, which is often computationally very expensive. Due in part to this shortcoming, most methods compute a single template for the entire population of images, or a few templates for specific sub-groups of the data. In this work, we present a probabilistic model and efficient learning strategy that yields either universal or conditional templates, jointly with a neural network that provides efficient alignment of the images to these templates. We demonstrate the usefulness of this method on a variety of domains, with a special focus on neuroimaging. This is particularly useful for clinical applications where a pre-existing template does not exist, or creating a new one with traditional methods can be prohibitively expensive. Our code and atlases are available online as part of the VoxelMorph library at http://voxelmorph.csail.mit.edu.

Recent years have witnessed a surge in the development of protein foundation models, significantly improving performance in protein prediction and generative tasks ranging from 3D structure prediction and protein design to conformational dynamics. However, the capabilities and limitations associated with these models remain poorly understood due to the absence of a unified evaluation framework. To fill this gap, we introduce ProteinBench, a holistic evaluation framework designed to enhance the transparency of protein foundation models. Our approach consists of three key components: (i) A taxonomic classification of tasks that broadly encompass the main challenges in the protein domain, based on the relationships between different protein modalities; (ii) A multi-metric evaluation approach that assesses performance across four key dimensions: quality, novelty, diversity, and robustness; and (iii) In-depth analyses from various user objectives, providing a holistic view of model performance. Our comprehensive evaluation of protein foundation models reveals several key findings that shed light on their current capabilities and limitations. To promote transparency and facilitate further research, we release the evaluation dataset, code, and a public leaderboard publicly for further analysis and a general modular toolkit. We intend for ProteinBench to be a living benchmark for establishing a standardized, in-depth evaluation framework for protein foundation models, driving their development and application while fostering collaboration within the field.

This article introduces idMotif, a visual analytics framework designed to aid domain experts in the identification of motifs within protein sequences. Motifs, short sequences of amino acids, are critical for understanding the distinct functions of proteins. Identifying these motifs is pivotal for predicting diseases or infections. idMotif employs a deep learning-based method for the categorization of protein sequences, enabling the discovery of potential motif candidates within protein groups through local explanations of deep learning model decisions. It offers multiple interactive views for the analysis of protein clusters or groups and their sequences. A case study, complemented by expert feedback, illustrates idMotif's utility in facilitating the analysis and identification of protein sequences and motifs.

Virtual Screening is an essential technique in the early phases of drug discovery, aimed at identifying promising drug candidates from vast molecular libraries. Recently, ligand-based virtual screening has garnered significant attention due to its efficacy in conducting extensive database screenings without relying on specific protein-binding site information. Obtaining binding affinity data for complexes is highly expensive, resulting in a limited amount of available data that covers a relatively small chemical space. Moreover, these datasets contain a significant amount of inconsistent noise. It is challenging to identify an inductive bias that consistently maintains the integrity of molecular activity during data augmentation. To tackle these challenges, we propose S-MolSearch, the first framework to our knowledge, that leverages molecular 3D information and affinity information in semi-supervised contrastive learning for ligand-based virtual screening. Drawing on the principles of inverse optimal transport, S-MolSearch efficiently processes both labeled and unlabeled data, training molecular structural encoders while generating soft labels for the unlabeled data. This design allows S-MolSearch to adaptively utilize unlabeled data within the learning process. Empirically, S-MolSearch demonstrates superior performance on widely-used benchmarks LIT-PCBA and DUD-E. It surpasses both structure-based and ligand-based virtual screening methods for AUROC, BEDROC and EF.

Immunohistochemistry (IHC) provides information on protein expression in tissue sections and is commonly used to support pathology diagnosis and disease triage. While AI models for H\&E-stained slides show promise, their applicability to IHC is limited due to domain-specific variations. Here we introduce HPA10M, a dataset that contains 10,495,672 IHC images from the Human Protein Atlas with comprehensive metadata included, and encompasses 45 normal tissue types and 20 major cancer types. Based on HPA10M, we trained iSight, a multi-task learning framework for automated IHC staining assessment. iSight combines visual features from whole-slide images with tissue metadata through a token-level attention mechanism, simultaneously predicting staining intensity, location, quantity, tissue type, and malignancy status. On held-out data, iSight achieved 85.5\% accuracy for location, 76.6\% for intensity, and 75.7\% for quantity, outperforming fine-tuned foundation models (PLIP, CONCH) by 2.5--10.2\%. In addition, iSight demonstrates well-calibrated predictions with expected calibration errors of 0.0150-0.0408. Furthermore, in a user study with eight pathologists evaluating 200 images from two datasets, iSight outperformed initial pathologist assessments on the held-out HPA dataset (79\% vs 68\% for location, 70\% vs 57\% for intensity, 68\% vs 52\% for quantity). Inter-pathologist agreement also improved after AI assistance in both held-out HPA (Cohen's κ increased from 0.63 to 0.70) and Stanford TMAD datasets (from 0.74 to 0.76), suggesting expert--AI co-assessment can improve IHC interpretation. This work establishes a foundation for AI systems that can improve IHC diagnostic accuracy and highlights the potential for integrating iSight into clinical workflows to enhance the consistency and reliability of IHC assessment.

Machine Learning Force Fields (MLFFs) are a promising alternative to expensive ab initio quantum mechanical molecular simulations. Given the diversity of chemical spaces that are of interest and the cost of generating new data, it is important to understand how MLFFs generalize beyond their training distributions. In order to characterize and better understand distribution shifts in MLFFs, we conduct diagnostic experiments on chemical datasets, revealing common shifts that pose significant challenges, even for large foundation models trained on extensive data. Based on these observations, we hypothesize that current supervised training methods inadequately regularize MLFFs, resulting in overfitting and learning poor representations of out-of-distribution systems. We then propose two new methods as initial steps for mitigating distribution shifts for MLFFs. Our methods focus on test-time refinement strategies that incur minimal computational cost and do not use expensive ab initio reference labels. The first strategy, based on spectral graph theory, modifies the edges of test graphs to align with graph structures seen during training. Our second strategy improves representations for out-of-distribution systems at test-time by taking gradient steps using an auxiliary objective, such as a cheap physical prior. Our test-time refinement strategies significantly reduce errors on out-of-distribution systems, suggesting that MLFFs are capable of and can move towards modeling diverse chemical spaces, but are not being effectively trained to do so. Our experiments establish clear benchmarks for evaluating the generalization capabilities of the next generation of MLFFs. Our code is available at https://tkreiman.github.io/projects/mlff_distribution_shifts/.

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

We resolve difficulties in training and sampling from a discrete generative model by learning a smoothed energy function, sampling from the smoothed data manifold with Langevin Markov chain Monte Carlo (MCMC), and projecting back to the true data manifold with one-step denoising. Our Discrete Walk-Jump Sampling formalism combines the contrastive divergence training of an energy-based model and improved sample quality of a score-based model, while simplifying training and sampling by requiring only a single noise level. We evaluate the robustness of our approach on generative modeling of antibody proteins and introduce the distributional conformity score to benchmark protein generative models. By optimizing and sampling from our models for the proposed distributional conformity score, 97-100% of generated samples are successfully expressed and purified and 70% of functional designs show equal or improved binding affinity compared to known functional antibodies on the first attempt in a single round of laboratory experiments. We also report the first demonstration of long-run fast-mixing MCMC chains where diverse antibody protein classes are visited in a single MCMC chain.

Pathology foundation models substantially advanced the possibilities in computational pathology -- yet tradeoffs in terms of performance, robustness, and computational requirements remained, which limited their clinical deployment. In this report, we present Atlas 2, Atlas 2-B, and Atlas 2-S, three pathology vision foundation models which bridge these shortcomings by showing state-of-the-art performance in prediction performance, robustness, and resource efficiency in a comprehensive evaluation across eighty public benchmarks. Our models were trained on the largest pathology foundation model dataset to date comprising 5.5 million histopathology whole slide images, collected from three medical institutions Charité - Universtätsmedizin Berlin, LMU Munich, and Mayo Clinic.

Large-scale chemical reaction datasets are crucial for AI research in chemistry. However, existing chemical reaction data often exist as images within papers, making them not machine-readable and unusable for training machine learning models. In response to this challenge, we propose the RxnCaption framework for the task of chemical Reaction Diagram Parsing (RxnDP). Our framework reformulates the traditional coordinate prediction driven parsing process into an image captioning problem, which Large Vision Language Models (LVLMs) handle naturally. We introduce a strategy termed BBox and Index as Visual Prompt (BIVP), which uses our state-of-the-art molecular detector, MolYOLO, to pre-draw molecular bounding boxes and indices directly onto the input image. This turns the downstream parsing into a natural-language description problem. Extensive experiments show that the BIVP strategy significantly improves structural extraction quality while simplifying model design. We further construct the RxnCaption-15k dataset, an order of magnitude larger than prior real-world literature benchmarks, with a balanced test subset across four layout archetypes. Experiments demonstrate that RxnCaption-VL achieves state-of-the-art performance on multiple metrics. We believe our method, dataset, and models will advance structured information extraction from chemical literature and catalyze broader AI applications in chemistry. We will release data, models, and code on GitHub.

Most human proteins remain undrugged, over 96% of human proteins remain unexploited by approved therapeutics. While structure-based virtual screening promises to expand the druggable proteome, existing methods lack atomic-level precision and fail to predict binding fitness, limiting translational impact. We present AuroBind, a scalable virtual screening framework that fine-tunes a custom atomic-level structural model on million-scale chemogenomic data. AuroBind integrates direct preference optimization, self-distillation from high-confidence complexes, and a teacher-student acceleration strategy to jointly predict ligand-bound structures and binding fitness. The proposed models outperform state-of-the-art models on structural and functional benchmarks while enabling 100,000-fold faster screening across ultra-large compound libraries. In a prospective screen across ten disease-relevant targets, AuroBind achieved experimental hit rates of 7-69%, with top compounds reaching sub-nanomolar to picomolar potency. For the orphan GPCRs GPR151 and GPR160, AuroBind identified both agonists and antagonists with success rates of 16-30%, and functional assays confirmed GPR160 modulation in liver and prostate cancer models. AuroBind offers a generalizable framework for structure-function learning and high-throughput molecular screening, bridging the gap between structure prediction and therapeutic discovery.

The binding between proteins and ligands plays a crucial role in the realm of drug discovery. Previous deep learning approaches have shown promising results over traditional computationally intensive methods, but resulting in poor generalization due to limited supervised data. In this paper, we propose to learn protein-ligand binding representation in a self-supervised learning manner. Different from existing pre-training approaches which treat proteins and ligands individually, we emphasize to discern the intricate binding patterns from fine-grained interactions. Specifically, this self-supervised learning problem is formulated as a prediction of the conclusive binding complex structure given a pocket and ligand with a Transformer based interaction module, which naturally emulates the binding process. To ensure the representation of rich binding information, we introduce two pre-training tasks, i.e.~atomic pairwise distance map prediction and mask ligand reconstruction, which comprehensively model the fine-grained interactions from both structure and feature space. Extensive experiments have demonstrated the superiority of our method across various binding tasks, including protein-ligand affinity prediction, virtual screening and protein-ligand docking.

Scientific posters play a vital role in academic communication by presenting ideas through visual summaries. Analyzing reading order and parent-child relations of posters is essential for building structure-aware interfaces that facilitate clear and accurate understanding of research content. Despite their prevalence in academic communication, posters remain underexplored in structural analysis research, which has primarily focused on papers. To address this gap, we constructed SciPostLayoutTree, a dataset of approximately 8,000 posters annotated with reading order and parent-child relations. Compared to an existing structural analysis dataset, SciPostLayoutTree contains more instances of spatially challenging relations, including upward, horizontal, and long-distance relations. As a solution to these challenges, we develop Layout Tree Decoder, which incorporates visual features as well as bounding box features including position and category information. The model also uses beam search to predict relations while capturing sequence-level plausibility. Experimental results demonstrate that our model improves the prediction accuracy for spatially challenging relations and establishes a solid baseline for poster structure analysis. The dataset is publicly available at https://huggingface.co/datasets/omron-sinicx/scipostlayouttree. The code is also publicly available at https://github.com/omron-sinicx/scipostlayouttree.

Motivation: The activity of the adaptive immune system is governed by T-cells and their specific T-cell receptors (TCR), which selectively recognize foreign antigens. Recent advances in experimental techniques have enabled sequencing of TCRs and their antigenic targets (epitopes), allowing to research the missing link between TCR sequence and epitope binding specificity. Scarcity of data and a large sequence space make this task challenging, and to date only models limited to a small set of epitopes have achieved good performance. Here, we establish a k-nearest-neighbor (K-NN) classifier as a strong baseline and then propose TITAN (Tcr epITope bimodal Attention Networks), a bimodal neural network that explicitly encodes both TCR sequences and epitopes to enable the independent study of generalization capabilities to unseen TCRs and/or epitopes. Results: By encoding epitopes at the atomic level with SMILES sequences, we leverage transfer learning and data augmentation to enrich the input data space and boost performance. TITAN achieves high performance in the prediction of specificity of unseen TCRs (ROC-AUC 0.87 in 10-fold CV) and surpasses the results of the current state-of-the-art (ImRex) by a large margin. Notably, our Levenshtein-distance-based K-NN classifier also exhibits competitive performance on unseen TCRs. While the generalization to unseen epitopes remains challenging, we report two major breakthroughs. First, by dissecting the attention heatmaps, we demonstrate that the sparsity of available epitope data favors an implicit treatment of epitopes as classes. This may be a general problem that limits unseen epitope performance for sufficiently complex models. Second, we show that TITAN nevertheless exhibits significantly improved performance on unseen epitopes and is capable of focusing attention on chemically meaningful molecular structures.

Deep generative models are rapidly advancing structure-based drug design, offering substantial promise for generating small molecule ligands that bind to specific protein targets. However, most current approaches assume a rigid protein binding pocket, neglecting the intrinsic flexibility of proteins and the conformational rearrangements induced by ligand binding, limiting their applicability in practical drug discovery. Here, we propose Apo2Mol, a diffusion-based generative framework for 3D molecule design that explicitly accounts for conformational flexibility in protein binding pockets. To support this, we curate a dataset of over 24,000 experimentally resolved apo-holo structure pairs from the Protein Data Bank, enabling the characterization of protein structure changes associated with ligand binding. Apo2Mol employs a full-atom hierarchical graph-based diffusion model that simultaneously generates 3D ligand molecules and their corresponding holo pocket conformations from input apo states. Empirical studies demonstrate that Apo2Mol can achieve state-of-the-art performance in generating high-affinity ligands and accurately capture realistic protein pocket conformational changes.

Large language models (LLMs) have shown growing promise in biomedical research, particularly for knowledge-driven interpretation tasks. However, their ability to reliably reason from gene-level knowledge to functional understanding, a core requirement for knowledge-enhanced cell atlas interpretation, remains largely underexplored. To address this gap, we introduce SciHorizon-GENE, a large-scale gene-centric benchmark constructed from authoritative biological databases. The benchmark integrates curated knowledge for over 190K human genes and comprises more than 540K questions covering diverse gene-to-function reasoning scenarios relevant to cell type annotation, functional interpretation, and mechanism-oriented analysis. Motivated by behavioral patterns observed in preliminary examinations, SciHorizon-GENE evaluates LLMs along four biologically critical perspectives: research attention sensitivity, hallucination tendency, answer completeness, and literature influence, explicitly targeting failure modes that limit the safe adoption of LLMs in biological interpretation pipelines. We systematically evaluate a wide range of state-of-the-art general-purpose and biomedical LLMs, revealing substantial heterogeneity in gene-level reasoning capabilities and persistent challenges in generating faithful, complete, and literature-grounded functional interpretations. Our benchmark establishes a systematic foundation for analyzing LLM behavior at the gene scale and offers insights for model selection and development, with direct relevance to knowledge-enhanced biological interpretation.

Pocket representations play a vital role in various biomedical applications, such as druggability estimation, ligand affinity prediction, and de novo drug design. While existing geometric features and pretrained representations have demonstrated promising results, they usually treat pockets independent of ligands, neglecting the fundamental interactions between them. However, the limited pocket-ligand complex structures available in the PDB database (less than 100 thousand non-redundant pairs) hampers large-scale pretraining endeavors for interaction modeling. To address this constraint, we propose a novel pocket pretraining approach that leverages knowledge from high-resolution atomic protein structures, assisted by highly effective pretrained small molecule representations. By segmenting protein structures into drug-like fragments and their corresponding pockets, we obtain a reasonable simulation of ligand-receptor interactions, resulting in the generation of over 5 million complexes. Subsequently, the pocket encoder is trained in a contrastive manner to align with the representation of pseudo-ligand furnished by some pretrained small molecule encoders. Our method, named ProFSA, achieves state-of-the-art performance across various tasks, including pocket druggability prediction, pocket matching, and ligand binding affinity prediction. Notably, ProFSA surpasses other pretraining methods by a substantial margin. Moreover, our work opens up a new avenue for mitigating the scarcity of protein-ligand complex data through the utilization of high-quality and diverse protein structure databases.

This paper proposes a simple but effective graph-based agglomerative algorithm, for clustering high-dimensional data. We explore the different roles of two fundamental concepts in graph theory, indegree and outdegree, in the context of clustering. The average indegree reflects the density near a sample, and the average outdegree characterizes the local geometry around a sample. Based on such insights, we define the affinity measure of clusters via the product of average indegree and average outdegree. The product-based affinity makes our algorithm robust to noise. The algorithm has three main advantages: good performance, easy implementation, and high computational efficiency. We test the algorithm on two fundamental computer vision problems: image clustering and object matching. Extensive experiments demonstrate that it outperforms the state-of-the-arts in both applications.

Modeling the interaction between proteins and ligands and accurately predicting their binding structures is a critical yet challenging task in drug discovery. Recent advancements in deep learning have shown promise in addressing this challenge, with sampling-based and regression-based methods emerging as two prominent approaches. However, these methods have notable limitations. Sampling-based methods often suffer from low efficiency due to the need for generating multiple candidate structures for selection. On the other hand, regression-based methods offer fast predictions but may experience decreased accuracy. Additionally, the variation in protein sizes often requires external modules for selecting suitable binding pockets, further impacting efficiency. In this work, we propose FABind, an end-to-end model that combines pocket prediction and docking to achieve accurate and fast protein-ligand binding. FABind incorporates a unique ligand-informed pocket prediction module, which is also leveraged for docking pose estimation. The model further enhances the docking process by incrementally integrating the predicted pocket to optimize protein-ligand binding, reducing discrepancies between training and inference. Through extensive experiments on benchmark datasets, our proposed FABind demonstrates strong advantages in terms of effectiveness and efficiency compared to existing methods. Our code is available at https://github.com/QizhiPei/FABind

Determining the binding pose of a ligand to a protein, known as molecular docking, is a fundamental task in drug discovery. Generative approaches promise faster, improved, and more diverse pose sampling than physics-based methods, but are often hindered by chemically implausible outputs, poor generalisability, and high computational cost. To address these challenges, we introduce a novel fragmentation scheme, leveraging inductive biases from structural chemistry, to decompose ligands into rigid-body fragments. Building on this decomposition, we present SigmaDock, an SE(3) Riemannian diffusion model that generates poses by learning to reassemble these rigid bodies within the binding pocket. By operating at the level of fragments in SE(3), SigmaDock exploits well-established geometric priors while avoiding overly complex diffusion processes and unstable training dynamics. Experimentally, we show SigmaDock achieves state-of-the-art performance, reaching Top-1 success rates (RMSD<2 & PB-valid) above 79.9% on the PoseBusters set, compared to 12.7-30.8% reported by recent deep learning approaches, whilst demonstrating consistent generalisation to unseen proteins. SigmaDock is the first deep learning approach to surpass classical physics-based docking under the PB train-test split, marking a significant leap forward in the reliability and feasibility of deep learning for molecular modelling.

High Content Screening (HCS) microscopy datasets have transformed the ability to profile cellular responses to genetic and chemical perturbations, enabling cell-based inference of drug-target interactions (DTI). However, the adoption of representation learning methods for HCS data has been hindered by the lack of accessible datasets and robust benchmarks. To address this gap, we present RxRx3-core, a curated and compressed subset of the RxRx3 dataset, and an associated DTI benchmarking task. At just 18GB, RxRx3-core significantly reduces the size barrier associated with large-scale HCS datasets while preserving critical data necessary for benchmarking representation learning models against a zero-shot DTI prediction task. RxRx3-core includes 222,601 microscopy images spanning 736 CRISPR knockouts and 1,674 compounds at 8 concentrations. RxRx3-core is available on HuggingFace and Polaris, along with pre-trained embeddings and benchmarking code, ensuring accessibility for the research community. By providing a compact dataset and robust benchmarks, we aim to accelerate innovation in representation learning methods for HCS data and support the discovery of novel biological insights.

Antibodies are proteins produced by the immune system that can identify and neutralise a wide variety of antigens with high specificity and affinity, and constitute the most successful class of biotherapeutics. With the advent of next-generation sequencing, billions of antibody sequences have been collected in recent years, though their application in the design of better therapeutics has been constrained by the sheer volume and complexity of the data. To address this challenge, we present IgBert and IgT5, the best performing antibody-specific language models developed to date which can consistently handle both paired and unpaired variable region sequences as input. These models are trained comprehensively using the more than two billion unpaired sequences and two million paired sequences of light and heavy chains present in the Observed Antibody Space dataset. We show that our models outperform existing antibody and protein language models on a diverse range of design and regression tasks relevant to antibody engineering. This advancement marks a significant leap forward in leveraging machine learning, large scale data sets and high-performance computing for enhancing antibody design for therapeutic development.

Whole-slide image (WSI) preprocessing, typically comprising tissue detection followed by patch extraction, is foundational to AI-driven computational pathology workflows. This remains a major computational bottleneck as existing tools either rely on inaccurate heuristic thresholding for tissue detection, or adopt AI-based approaches trained on limited-diversity data that operate at the patch level, incurring substantial computational complexity. We present AtlasPatch, an efficient and scalable slide preprocessing framework for accurate tissue detection and high-throughput patch extraction with minimal computational overhead. AtlasPatch's tissue detection module is trained on a heterogeneous and semi-manually annotated dataset of ~30,000 WSI thumbnails, using efficient fine-tuning of the Segment-Anything model. The tool extrapolates tissue masks from thumbnails to full-resolution slides to extract patch coordinates at user-specified magnifications, with options to stream patches directly into common image encoders for embedding or store patch images, all efficiently parallelized across CPUs and GPUs. We assess AtlasPatch across segmentation precision, computational complexity, and downstream multiple-instance learning, matching state-of-the-art performance while operating at a fraction of their computational cost. AtlasPatch is open-source and available at https://github.com/AtlasAnalyticsLab/AtlasPatch.

Integrating molecular, morphological, and clinical data is essential for basic and translational biomedical research, yet systematic frameworks for jointly modeling these modalities remain limited. Here we present Haiku, a tri-modal contrastive learning model trained on multiplexed immunofluorescence (mIF). It comprises 26.7 million spatial proteomics patches from 3,218 tissue sections across 1,606 patients spanning 11 organ types, with matched hematoxylin and eosin (H&E) histology and clinical metadata aligned in a shared embedding space. Haiku enables three-way cross-modal retrieval, improves downstream classification and clinical prediction tasks over unimodal baselines, and supports zero-shot biomarker inference through fusion retrieval conditioned on clinical metadata-only text descriptions. Across tasks, Haiku outperforms competing approaches, achieving cross-modal retrieval (Recall@50 up to 0.611 versus near-zero baseline), survival prediction (C-index 0.737, +7.91% relative improvement), and zero-shot biomarker inference (mean Pearson correlation 0.718 across 52 biomarkers). Furthermore, we introduce a counterfactual prediction framework in which modifying only clinical metadata while fixing tissue morphology surfaces niche-specific molecular shifts associated with breast cancer stage progression and lung cancer survival outcomes. In a lung adenocarcinoma case study, the counterfactual analysis recovers niche-specific shifts characterized by increased CD8 and granzyme B, reduced PD-L1, and decreased Ki67, broadly consistent with patterns reported for favorable outcomes. We present these counterfactual results as exploratory, hypothesis-generating signals rather than mechanistic claims. These capabilities demonstrate that tri-modal alignment via Haiku enables integrative analysis of spatial biology, bridging molecular measurements with clinical context for biological exploration.

Virtual immunohistochemistry (IHC) staining from hematoxylin and eosin (H&E) images can accelerate diagnostics by providing preliminary molecular insight directly from routine sections, reducing the need for repeat sectioning when tissue is limited. Existing methods improve realism through contrastive objectives, prototype matching, or domain alignment, yet the generator itself receives no direct guidance from pathology foundation models. We present UNIStainNet, a SPADE-UNet conditioned on dense spatial tokens from a frozen pathology foundation model (UNI), providing tissue-level semantic guidance for stain translation. A misalignment-aware loss suite preserves stain quantification accuracy, and learned stain embeddings enable a single model to serve multiple IHC markers simultaneously. On MIST, UNIStainNet achieves state-of-the-art distributional metrics on all four stains (HER2, Ki67, ER, PR) from a single unified model, where prior methods typically train separate per-stain models. On BCI, it also achieves the best distributional metrics. A tissue-type stratified failure analysis reveals that remaining errors are systematic, concentrating in non-tumor tissue. Code is available at https://github.com/facevoid/UNIStainNet.

Computational antibody design has seen rapid methodological progress, with dozens of deep generative methods proposed in the past three years, yet the field lacks a standardized benchmark for fair comparison and model development. These methods are evaluated on different SAbDab snapshots, non-overlapping test sets, and incompatible metrics, and the literature fragments the design problem into numerous sub-tasks with no common definition. We introduce Chimera-Bench (CDR Modeling with Epitope-guided Redesign), a unified benchmark built around a single canonical task: epitope-conditioned CDR sequence-structure co-design. Chimera-Bench provides (1) a curated, deduplicated dataset of 2,922 antibody-antigen complexes with epitope and paratope annotations; (2) three biologically motivated splits testing generalization to unseen epitopes, unseen antigen folds, and prospective temporal targets; and (3) a comprehensive evaluation protocol with five metric groups including novel epitope-specificity measures. We benchmark representative methods spanning different generative paradigms and report results across all splits. Chimera-Bench is the largest dataset of its kind for the antibody design problem, allowing the community to develop and test novel methods and evaluate their generalizability. The source code and data are available at: https://github.com/mansoor181/chimera-bench.git

The rapid evolution of generative AI has expanded the breadth of risks associated with AI systems. While various taxonomies and frameworks exist to classify these risks, the lack of interoperability between them creates challenges for researchers, practitioners, and policymakers seeking to operationalise AI governance. To address this gap, we introduce the AI Risk Atlas, a structured taxonomy that consolidates AI risks from diverse sources and aligns them with governance frameworks. Additionally, we present the Risk Atlas Nexus, a collection of open-source tools designed to bridge the divide between risk definitions, benchmarks, datasets, and mitigation strategies. This knowledge-driven approach leverages ontologies and knowledge graphs to facilitate risk identification, prioritization, and mitigation. By integrating AI-assisted compliance workflows and automation strategies, our framework lowers the barrier to responsible AI adoption. We invite the broader research and open-source community to contribute to this evolving initiative, fostering cross-domain collaboration and ensuring AI governance keeps pace with technological advancements.

Antibodies are crucial proteins produced by the immune system to eliminate harmful foreign substances and have become pivotal therapeutic agents for treating human diseases. To accelerate the discovery of antibody therapeutics, there is growing interest in constructing language models using antibody sequences. However, the applicability of pre-trained language models for antibody discovery has not been thoroughly evaluated due to the scarcity of labeled datasets. To overcome these limitations, we introduce AVIDa-SARS-CoV-2, a dataset featuring the antigen-variable domain of heavy chain of heavy chain antibody (VHH) interactions obtained from two alpacas immunized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins. AVIDa-SARS-CoV-2 includes binary labels indicating the binding or non-binding of diverse VHH sequences to 12 SARS-CoV-2 mutants, such as the Delta and Omicron variants. Furthermore, we release VHHCorpus-2M, a pre-training dataset for antibody language models, containing over two million VHH sequences. We report benchmark results for predicting SARS-CoV-2-VHH binding using VHHBERT pre-trained on VHHCorpus-2M and existing general protein and antibody-specific pre-trained language models. These results confirm that AVIDa-SARS-CoV-2 provides valuable benchmarks for evaluating the representation capabilities of antibody language models for binding prediction, thereby facilitating the development of AI-driven antibody discovery. The datasets are available at https://datasets.cognanous.com.

Foundation models have demonstrated remarkable success across diverse domains and tasks, primarily due to the thrive of large-scale, diverse, and high-quality datasets. However, in the field of medical imaging, the curation and assembling of such medical datasets are highly challenging due to the reliance on clinical expertise and strict ethical and privacy constraints, resulting in a scarcity of large-scale unified medical datasets and hindering the development of powerful medical foundation models. In this work, we present the largest survey to date of medical image datasets, covering over 1,000 open-access datasets with a systematic catalog of their modalities, tasks, anatomies, annotations, limitations, and potential for integration. Our analysis exposes a landscape that is modest in scale, fragmented across narrowly scoped tasks, and unevenly distributed across organs and modalities, which in turn limits the utility of existing medical image datasets for developing versatile and robust medical foundation models. To turn fragmentation into scale, we propose a metadata-driven fusion paradigm (MDFP) that integrates public datasets with shared modalities or tasks, thereby transforming multiple small data silos into larger, more coherent resources. Building on MDFP, we release an interactive discovery portal that enables end-to-end, automated medical image dataset integration, and compile all surveyed datasets into a unified, structured table that clearly summarizes their key characteristics and provides reference links, offering the community an accessible and comprehensive repository. By charting the current terrain and offering a principled path to dataset consolidation, our survey provides a practical roadmap for scaling medical imaging corpora, supporting faster data discovery, more principled dataset creation, and more capable medical foundation models.

Accurate prediction of protein-ligand binding poses is crucial for structure-based drug design, yet existing methods struggle to balance speed, accuracy, and physical plausibility. We introduce Matcha, a novel molecular docking pipeline that combines multi-stage flow matching with learned scoring and physical validity filtering. Our approach consists of three sequential stages applied consecutively to refine docking predictions, each implemented as a flow matching model operating on appropriate geometric spaces (R^3, SO(3), and SO(2)). We enhance the prediction quality through a dedicated scoring model and apply unsupervised physical validity filters to eliminate unrealistic poses. Compared to various approaches, Matcha demonstrates superior performance on Astex and PDBbind test sets in terms of docking success rate and physical plausibility. Moreover, our method works approximately 25 times faster than modern large-scale co-folding models. The model weights and inference code to reproduce our results are available at https://github.com/LigandPro/Matcha.

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

The computational prediction and design of peptide binders targeting specific linear epitopes is crucial in biological and biomedical research, yet it remains challenging due to their highly dynamic nature and the scarcity of experimentally solved binding data. To address this problem, we built an unprecedentedly large-scale library of peptide pairs within stable secondary structures (beta sheets), leveraging newly available AlphaFold predicted structures. We then developed a machine learning method based on the Transformer architecture for the design of specific linear binders, in analogy to a language translation task. Our method, TransformerBeta, accurately predicts specific beta strand interactions and samples sequences with beta sheet-like molecular properties, while capturing interpretable physico-chemical interaction patterns. As such, it can propose specific candidate binders targeting linear epitope for experimental validation to inform protein design.

We present ScienceClaw + Infinite, a framework for autonomous scientific investigation in which independent agents conduct research without central coordination, and any contributor can deploy new agents into a shared ecosystem. The system is built around three components: an extensible registry of over 300 interoperable scientific skills, an artifact layer that preserves full computational lineage as a directed acyclic graph (DAG), and a structured platform for agent-based scientific discourse with provenance-aware governance. Agents select and chain tools based on their scientific profiles, produce immutable artifacts with typed metadata and parent lineage, and broadcast unsatisfied information needs to a shared global index. The ArtifactReactor enables plannerless coordination: peer agents discover and fulfill open needs through pressure-based scoring, while schema-overlap matching triggers multi-parent synthesis across independent analyses. An autonomous mutation layer actively prunes the expanding artifact DAG to resolve conflicting or redundant workflows, while persistent memory allows agents to continuously build upon complex epistemic states across multiple cycles. Infinite converts these outputs into auditable scientific records through structured posts, provenance views, and machine-readable discourse relations, with community feedback steering subsequent investigation cycles. Across four autonomous investigations, peptide design for the somatostatin receptor SSTR2, lightweight impact-resistant ceramic screening, cross-domain resonance bridging biology, materials, and music, and formal analogy construction between urban morphology and grain-boundary evolution, the framework demonstrates heterogeneous tool chaining, emergent convergence among independently operating agents, and traceable reasoning from raw computation to published finding.

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.

Large Language Models (LLMs) and LLM-based agents show great promise in accelerating scientific research. Existing benchmarks for measuring this potential and guiding future development continue to evolve from pure recall and rote knowledge tasks, towards more practical work such as literature review and experimental planning. Bioinformatics is a domain where fully autonomous AI-driven discovery may be near, but no extensive benchmarks for measuring progress have been introduced to date. We therefore present the Bioinformatics Benchmark (BixBench), a dataset comprising over 50 real-world scenarios of practical biological data analysis with nearly 300 associated open-answer questions designed to measure the ability of LLM-based agents to explore biological datasets, perform long, multi-step analytical trajectories, and interpret the nuanced results of those analyses. We evaluate the performance of two frontier LLMs (GPT-4o and Claude 3.5 Sonnet) using a custom agent framework we open source. We find that even the latest frontier models only achieve 17% accuracy in the open-answer regime, and no better than random in a multiple-choice setting. By exposing the current limitations of frontier models, we hope BixBench can spur the development of agents capable of conducting rigorous bioinformatic analysis and accelerate scientific discovery.

Agentic systems operating over large tool ecosystems must plan and execute long-horizon workflows under weak or non-verifiable supervision. While frontier models mitigate these challenges through scale and large context budgets, small language models (SLMs) remain brittle: eager tool loading saturates context, execution errors compound over time, and sparse rewards limit learning. We introduce ATLAS, a reinforcement finetuning framework that enables SLMs to operate effectively in large-scale toolspace environments by learning how to acquire context and how to execute actions. Our approach makes two key contributions. First, we treat context control and execution structure as learnable decisions, combining iterative tool loading with programmatic tool orchestration to bound context growth and stabilize long-horizon trajectories. Second, we propose rubric-based reinforcement finetuning, which decomposes task success into structured, task-aligned criteria and enables scalable training using small judge models. Across MCP benchmarks, these design choices yield large and consistent gains over generic RL baselines, allowing a 4B SLM to approach frontier-agent performance under far tighter parameter and context budgets.

We present a vector-based method to balance chemical reactions. The algorithm builds candidates in a deterministic way, removes duplicates, and always prints coefficients in the lowest whole-number form. For redox cases, electrons and protons/hydroxide are treated explicitly, so both mass and charge are balanced. We also outline the basic principles of the vector formulation of stoichiometry, interpreting reactions as integer vectors in composition space, this geometric view supports compact visualizations of reagent-product interactions and helps surface distinct reaction families. The method enumerates valid balances for arbitrary user-specified species lists without special-case balancing rules or symbolic tricks, and it provides a clean foundation for developing new algorithmic variants (e.g., alternative objectives or constraints). On representative examples (neutralization, double displacement, decomposition, classical redox, small multicomponent sets) and a negative control, the method produced correct integer balances. When multiple balances exist, we report a canonical one - minimizing the total coefficient sum with a simple tie-breaker - without claiming global optimality beyond the solutions the search enumerates. The procedure applies per reaction and extends to reaction networks via consistent per-reaction application. We do not report runtimes, broader benchmarking and code/data release are planned.

Predicting how a drug-like molecule binds to a specific protein target is a core problem in drug discovery. An extremely fast computational binding method would enable key applications such as fast virtual screening or drug engineering. Existing methods are computationally expensive as they rely on heavy candidate sampling coupled with scoring, ranking, and fine-tuning steps. We challenge this paradigm with EquiBind, an SE(3)-equivariant geometric deep learning model performing direct-shot prediction of both i) the receptor binding location (blind docking) and ii) the ligand's bound pose and orientation. EquiBind achieves significant speed-ups and better quality compared to traditional and recent baselines. Further, we show extra improvements when coupling it with existing fine-tuning techniques at the cost of increased running time. Finally, we propose a novel and fast fine-tuning model that adjusts torsion angles of a ligand's rotatable bonds based on closed-form global minima of the von Mises angular distance to a given input atomic point cloud, avoiding previous expensive differential evolution strategies for energy minimization.

Protein design aims to compose amino-acid sequences that fold into stable three-dimensional structures while satisfying targeted functional properties. The field is increasingly shifting toward vibe protein design, where a single model is expected to generate novel sequences, engineer existing proteins, and reason about protein characteristics through flexible natural-language constraints. Large language models (LLMs) have emerged as a leading paradigm in this space. However, existing evaluation benchmarks often limit their scope to a partial aspect of protein design, while others restrict design objectives to structured input schemas, lacking an integrated framework that evaluates the broad spectrum of protein design competence under open-ended intents. To this end, we present Vibe Protein design Benchmark (VibeProteinBench), a language-interfaced benchmark that probes generalist capabilities through three complementary stages mirroring a computational protein design workflow: recognition, engineering, and generation. Each stage is grounded in expert-curated mechanistic rationales and multi-faceted in silico validation, to computationally verify whether model outputs are biologically plausible. Evaluations across diverse general-purpose and domain-specialized LLMs reveal that no model achieves strong performance across all three stages, suggesting that generalist protein design remains a substantial open challenge for current LLMs.

Molecular function is largely determined by structure. Accurately aligning molecular structure with natural language is therefore essential for enabling large language models (LLMs) to reason about downstream chemical tasks. However, the substantial cost of human annotation makes it infeasible to construct large-scale, high-quality datasets of structure-grounded descriptions. In this work, we propose a fully automated annotation framework for generating precise molecular structure descriptions at scale. Our approach builds upon and extends a rule-based chemical nomenclature parser to interpret IUPAC names and construct enriched, structured XML metadata that explicitly encodes molecular structure. This metadata is then used to guide LLMs in producing accurate natural-language descriptions. Using this framework, we curate a large-scale dataset of approximately 163k molecule-description pairs. A rigorous validation protocol combining LLM-based and expert human evaluation on a subset of 2,000 molecules demonstrates a high description precision of 98.6%. The resulting dataset provides a reliable foundation for future molecule-language alignment, and the proposed annotation method is readily extensible to larger datasets and broader chemical tasks that rely on structural descriptions.

Docking is a crucial component in drug discovery aimed at predicting the binding conformation and affinity between small molecules and target proteins. ML-based docking has recently emerged as a prominent approach, outpacing traditional methods like DOCK and AutoDock Vina in handling the growing scale and complexity of molecular libraries. However, the availability of comprehensive and user-friendly datasets for training and benchmarking ML-based docking algorithms remains limited. We introduce Smiles2Dock, an open large-scale multi-task dataset for molecular docking. We created a framework combining P2Rank and AutoDock Vina to dock 1.7 million ligands from the ChEMBL database against 15 AlphaFold proteins, giving us more than 25 million protein-ligand binding scores. The dataset leverages a wide range of high-accuracy AlphaFold protein models, encompasses a diverse set of biologically relevant compounds and enables researchers to benchmark all major approaches for ML-based docking such as Graph, Transformer and CNN-based methods. We also introduce a novel Transformer-based architecture for docking scores prediction and set it as an initial benchmark for our dataset. Our dataset and code are publicly available to support the development of novel ML-based methods for molecular docking to advance scientific research in this field.

Radiology plays an integral role in modern medicine, yet rising imaging volumes have far outpaced workforce growth. Foundation models offer a path toward assisting with the full spectrum of radiology tasks, but existing medical models remain limited: they process volumetric CT and MRI as low-fidelity 2D slices, discard critical grayscale contrast information, and lack evaluation frameworks that reflect real clinical practice. We introduce Pillar-0, a radiology foundation model pretrained on 42,990 abdomen-pelvis CTs, 86,411 chest CTs, 14,348 head CTs, and 11,543 breast MRIs from a large academic center, together with RATE, a scalable framework that extracts structured labels for 366 radiologic findings with near-perfect accuracy using LLMs. Across internal test sets of 14,230 abdomen-pelvis CTs, 10,646 chest CTs, 4,906 head CTs, and 1,585 breast MRIs, Pillar-0 establishes a new performance frontier, achieving mean AUROCs of 86.4, 88.0, 90.1, and 82.9, outperforming MedGemma (Google), MedImageInsight (Microsoft), Lingshu (Alibaba), and Merlin (Stanford) by 7.8-15.8 AUROC points and ranking best in 87.2\% (319/366) tasks. Pillar-0 similarly outperforms all baselines in an external validation on the Stanford Abdominal CT dataset, including Merlin (82.2 vs 80.6 AUROC). Pillar-0 extends to tasks beyond its pretraining, such as long-horizon lung cancer risk prediction, where it improves upon the state-of-the-art Sybil by 3.0 C-index points on NLST, and generalizes with gains of 5.9 (MGH) and 1.9 (CGMH). In brain hemorrhage detection, Pillar-0 obtained a >95 AUROC when using only 1/20th of the data of the next most sample efficient baseline. Pillar-0 and RATE together provide an open, clinically rigorous foundation for building high-performance radiology systems, enabling applications that were previously infeasible due to computational, data, and evaluation constraints.

Understanding protein dynamics is critical for elucidating their biological functions. The increasing availability of molecular dynamics (MD) data enables the training of deep generative models to efficiently explore the conformational space of proteins. However, existing approaches either fail to explicitly capture the temporal dependencies between conformations or do not support direct generation of time-independent samples. To address these limitations, we introduce ConfRover, an autoregressive model that simultaneously learns protein conformation and dynamics from MD trajectories, supporting both time-dependent and time-independent sampling. At the core of our model is a modular architecture comprising: (i) an encoding layer, adapted from protein folding models, that embeds protein-specific information and conformation at each time frame into a latent space; (ii) a temporal module, a sequence model that captures conformational dynamics across frames; and (iii) an SE(3) diffusion model as the structure decoder, generating conformations in continuous space. Experiments on ATLAS, a large-scale protein MD dataset of diverse structures, demonstrate the effectiveness of our model in learning conformational dynamics and supporting a wide range of downstream tasks. ConfRover is the first model to sample both protein conformations and trajectories within a single framework, offering a novel and flexible approach for learning from protein MD data.

Developing artificial intelligence (AI) for vertical domains requires a solid data foundation for both training and evaluation. In this work, we introduce TrialPanorama, a large-scale, structured database comprising 1,657,476 clinical trial records aggregated from 15 global sources. The database captures key aspects of trial design and execution, including trial setups, interventions, conditions, biomarkers, and outcomes, and links them to standard biomedical ontologies such as DrugBank and MedDRA. This structured and ontology-grounded design enables TrialPanorama to serve as a unified, extensible resource for a wide range of clinical trial tasks, including trial planning, design, and summarization. To demonstrate its utility, we derive a suite of benchmark tasks directly from the TrialPanorama database. The benchmark spans eight tasks across two categories: three for systematic review (study search, study screening, and evidence summarization) and five for trial design (arm design, eligibility criteria, endpoint selection, sample size estimation, and trial completion assessment). The experiments using five state-of-the-art large language models (LLMs) show that while general-purpose LLMs exhibit some zero-shot capability, their performance is still inadequate for high-stakes clinical trial workflows. We release TrialPanorama database and the benchmark to facilitate further research on AI for clinical trials.

We present a novel dual-head deep learning architecture for protein-protein interaction modeling that enables simultaneous prediction of binding affinity (ΔG) and mutation-induced affinity changes (ΔΔG) using only protein sequence information. Our approach offers a significant advancement over existing methods by employing specialized prediction heads that operate on a shared representation network, allowing direct and optimized prediction of both values. To ensure robust generalization, we integrated complementary datasets from SKEMPI v2 and PDBbind with a rigorous protein domain-based splitting strategy that prevents information leakage between training and validation sets. Our architecture combines transformer-based encoders with a novel cross-attention mechanism that processes paired protein sequences directly, without requiring any structural information. The network embeds input sequences using ESM3 representations, then employs a learnable sliced window embedding layer to manage variable-length sequences efficiently. A multi-layer transformer encoder with bidirectional self-attention captures intra-protein patterns, while cross-attention layers enable explicit modeling of interactions between protein pairs. This shared representation network feeds into separate ΔG and ΔΔG prediction heads, allowing task-specific optimization while leveraging common features. The model achieves ΔΔG validation of Pearson correlation at 0.485, while maintaining strong ΔG predictions (Pearson: 0.638). While existing approaches require protein structure data and binding interface information, our model eliminates these constraints. This provides a critical advantage for the numerous proteins with unknown structures or those challenging to crystallize, such as viral and intrinsically disordered proteins.

Medication Extraction and Mining play an important role in healthcare NLP research due to its practical applications in hospital settings, such as their mapping into standard clinical knowledge bases (SNOMED-CT, BNF, etc.). In this work, we investigate state-of-the-art LLMs in text mining tasks on medications and their related attributes such as dosage, route, strength, and adverse effects. In addition, we explore different ensemble learning methods (Stack-Ensemble and Voting-Ensemble) to augment the model performances from individual LLMs. Our ensemble learning result demonstrated better performances than individually fine-tuned base models BERT, RoBERTa, RoBERTa-L, BioBERT, BioClinicalBERT, BioMedRoBERTa, ClinicalBERT, and PubMedBERT across general and specific domains. Finally, we build up an entity linking function to map extracted medical terminologies into the SNOMED-CT codes and the British National Formulary (BNF) codes, which are further mapped to the Dictionary of Medicines and Devices (dm+d), and ICD. Our model's toolkit and desktop applications are publicly available at https://github.com/HECTA-UoM/ensemble-NER.

Foundation models have begun to transform image analysis by acting as pretrained generalist backbones that can be adapted to many tasks even when post-training data are limited, yet their impact on spatial proteomics, imaging that maps proteins at single-cell resolution, remains limited. Here, we introduce KRONOS, a foundation model built for spatial proteomics. KRONOS was trained in a self-supervised manner on over 47 million image patches covering 175 protein markers, 16 tissue types, and 8 fluorescence-based imaging platforms. We introduce key architectural adaptations to address the high-dimensional, multi-channel, and heterogeneous nature of multiplex imaging. We demonstrate that KRONOS learns biologically meaningful representations across multiple scales, ranging from cellular and microenvironment to tissue levels, enabling it to address diverse downstream tasks, including cell phenotyping, region classification, and patient stratification. Evaluated across 11 independent cohorts, KRONOS achieves state-of-the-art performance across cell phenotyping, treatment response prediction, and retrieval tasks, and is highly data-efficient. KRONOS also introduces the paradigm of segmentation-free patch-level processing for efficient and scalable spatial proteomics analysis, allowing cross-institutional comparisons, and as an image reverse search engine for spatial patterns. Together, these results position KRONOS as a flexible and scalable tool for spatial proteomics. The model is publicly accessible at https://github.com/mahmoodlab/KRONOS.

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.

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.

Though end-to-end neural approaches have recently been dominating NLP tasks in both performance and ease-of-use, they lack interpretability and robustness. We propose Binder, a training-free neural-symbolic framework that maps the task input to a program, which (1) allows binding a unified API of language model (LM) functionalities to a programming language (e.g., SQL, Python) to extend its grammar coverage and thus tackle more diverse questions, (2) adopts an LM as both the program parser and the underlying model called by the API during execution, and (3) requires only a few in-context exemplar annotations. Specifically, we employ GPT-3 Codex as the LM. In the parsing stage, with only a few in-context exemplars, Codex is able to identify the part of the task input that cannot be answerable by the original programming language, correctly generate API calls to prompt Codex to solve the unanswerable part, and identify where to place the API calls while being compatible with the original grammar. In the execution stage, Codex can perform versatile functionalities (e.g., commonsense QA, information extraction) given proper prompts in the API calls. Binder achieves state-of-the-art results on WikiTableQuestions and TabFact datasets, with explicit output programs that benefit human debugging. Note that previous best systems are all finetuned on tens of thousands of task-specific samples, while Binder only uses dozens of annotations as in-context exemplars without any training. Our code is available at https://github.com/HKUNLP/Binder .

Scientific machine learning research spans diverse domains and data modalities, yet existing benchmark efforts remain siloed and lack standardization. This makes novel and transformative applications of machine learning to critical scientific use-cases more fragmented and less clear in pathways to impact. This paper introduces an ontology for scientific benchmarking developed through a unified, community-driven effort that extends the MLCommons ecosystem to cover physics, chemistry, materials science, biology, climate science, and more. Building on prior initiatives such as XAI-BENCH, FastML Science Benchmarks, PDEBench, and the SciMLBench framework, our effort consolidates a large set of disparate benchmarks and frameworks into a single taxonomy of scientific, application, and system-level benchmarks. New benchmarks can be added through an open submission workflow coordinated by the MLCommons Science Working Group and evaluated against a six-category rating rubric that promotes and identifies high-quality benchmarks, enabling stakeholders to select benchmarks that meet their specific needs. The architecture is extensible, supporting future scientific and AI/ML motifs, and we discuss methods for identifying emerging computing patterns for unique scientific workloads. The MLCommons Science Benchmarks Ontology provides a standardized, scalable foundation for reproducible, cross-domain benchmarking in scientific machine learning. A companion webpage for this work has also been developed as the effort evolves: https://mlcommons-science.github.io/benchmark/

Protein function is often controlled by ligands that bias the direction of state transitions, such as agonists and antagonists, rather than stabilizing a single conformation. This is especially important for clinically relevant G protein-coupled receptors (GPCRs), where therapeutic efficacy depends on functional directionality. Structure-based design methods optimize binding to static conformations and cannot represent non-reversible, directional effects or systematically distinguish agonist from antagonist behavior. To address this gap, we introduce Transition-Directed Discrete Diffusion for Allosteric Binder Design (TD3B), a sequence-based generative framework that designs binders with specified agonist or antagonist behavior via a directional transition control objective. TD3B combines a target-aware Direction Oracle, a soft binding-affinity gate, and amortized fine-tuning of a pre-trained discrete diffusion model, enabling targeted agonist and antagonist generation decoupled from binding affinity and unattainable by equilibrium-based or inference-only guidance baselines. The code and checkpoints are available at https://huggingface.co/ChatterjeeLab/TD3B.

Recently, pre-trained foundation models have enabled significant advancements in multiple fields. In molecular machine learning, however, where datasets are often hand-curated, and hence typically small, the lack of datasets with labeled features, and codebases to manage those datasets, has hindered the development of foundation models. In this work, we present seven novel datasets categorized by size into three distinct categories: ToyMix, LargeMix and UltraLarge. These datasets push the boundaries in both the scale and the diversity of supervised labels for molecular learning. They cover nearly 100 million molecules and over 3000 sparsely defined tasks, totaling more than 13 billion individual labels of both quantum and biological nature. In comparison, our datasets contain 300 times more data points than the widely used OGB-LSC PCQM4Mv2 dataset, and 13 times more than the quantum-only QM1B dataset. In addition, to support the development of foundational models based on our proposed datasets, we present the Graphium graph machine learning library which simplifies the process of building and training molecular machine learning models for multi-task and multi-level molecular datasets. Finally, we present a range of baseline results as a starting point of multi-task and multi-level training on these datasets. Empirically, we observe that performance on low-resource biological datasets show improvement by also training on large amounts of quantum data. This indicates that there may be potential in multi-task and multi-level training of a foundation model and fine-tuning it to resource-constrained downstream tasks.

Cluster workload allocation often requires complex configurations, creating a usability gap. This paper introduces a semantic, intent-driven scheduling paradigm for cluster systems using Natural Language Processing. The system employs a Large Language Model (LLM) integrated via a Kubernetes scheduler extender to interpret natural language allocation hint annotations for soft affinity preferences. A prototype featuring a cluster state cache and an intent analyzer (using AWS Bedrock) was developed. Empirical evaluation demonstrated high LLM parsing accuracy (>95% Subset Accuracy on an evaluation ground-truth dataset) for top-tier models like Amazon Nova Pro/Premier and Mistral Pixtral Large, significantly outperforming a baseline engine. Scheduling quality tests across six scenarios showed the prototype achieved superior or equivalent placement compared to standard Kubernetes configurations, particularly excelling in complex and quantitative scenarios and handling conflicting soft preferences. The results validate using LLMs for accessible scheduling but highlight limitations like synchronous LLM latency, suggesting asynchronous processing for production readiness. This work confirms the viability of semantic soft affinity for simplifying workload orchestration.

Measurements of Higgs boson production cross-sections are carried out in the diphoton decay channel using 139 fb^{-1} of pp collision data at s = 13 TeV collected by the ATLAS experiment at the LHC. The analysis is based on the definition of 101 distinct signal regions using machine-learning techniques. The inclusive Higgs boson signal strength in the diphoton channel is measured to be 1.04^{+0.10}_{-0.09}. Cross-sections for gluon-gluon fusion, vector-boson fusion, associated production with a W or Z boson, and top associated production processes are reported. An upper limit of 10 times the Standard Model prediction is set for the associated production process of a Higgs boson with a single top quark, which has a unique sensitivity to the sign of the top quark Yukawa coupling. Higgs boson production is further characterized through measurements of Simplified Template Cross-Sections (STXS). In total, cross-sections of 28 STXS regions are measured. The measured STXS cross-sections are compatible with their Standard Model predictions, with a p-value of 93%. The measurements are also used to set constraints on Higgs boson coupling strengths, as well as on new interactions beyond the Standard Model in an effective field theory approach. No significant deviations from the Standard Model predictions are observed in these measurements, which provide significant sensitivity improvements compared to the previous ATLAS results.

In precision medicine, quantitative multi-omic features, topological context, and textual biological knowledge play vital roles in identifying disease-critical signaling pathways and targets. Existing pipelines capture only part of these-numerical omics ignore topological context, text-centric LLMs lack quantitative grounded reasoning, and graph-only models underuse node semantics and the generalization of LLMs-limiting mechanistic interpretability. Although Process Reward Models (PRMs) aim to guide reasoning in LLMs, they remain limited by unreliable intermediate evaluation, and vulnerability to reward hacking with computational cost. These gaps motivate integrating quantitative multi-omic signals, topological structure with node annotations, and literature-scale text via LLMs, using subgraph reasoning as the principle bridge linking numeric evidence, topological knowledge and language context. Therefore, we propose GALAX (Graph Augmented LAnguage model with eXplainability), an innovative framework that integrates pretrained Graph Neural Networks (GNNs) into Large Language Models (LLMs) via reinforcement guided by a Graph Process Reward Model (GPRM), which generates disease-relevant subgraphs in a step-wise manner initiated by an LLM and iteratively evaluated by a pretrained GNN, enabling process-level supervision without explicit intermediate reasoning annotations. As an application, we also introduced Target-QA, a benchmark combining CRISPR-identified targets, multi-omic profiles, and biomedical graph knowledge across diverse cancer cell lines, which enables GNN pretraining for supervising step-wise graph construction and supports long-context reasoning over text-numeric graphs (TNGs), providing a scalable and biologically grounded framework for explainable, reinforcement-guided subgraph reasoning toward reliable and interpretable target and pathway discovery in precision medicine.

Existing research infrastructure is fundamentally document-centric, providing citation links between papers but lacking explicit representations of methodological evolution. In particular, it does not capture the structured relationships that explain how and why research methods emerge, adapt, and build upon one another. With the rise of AI-driven research agents as a new class of consumers of scientific knowledge, this limitation becomes increasingly consequential, as such agents cannot reliably reconstruct method evolution topologies from unstructured text. We introduce Intern-Atlas, a methodological evolution graph that automatically identifies method-level entities, infers lineage relationships among methodologies, and captures the bottlenecks that drive transitions between successive innovations. Built from 1,030,314 papers spanning AI conferences, journals, and arXiv preprints, the resulting graph comprises 9,410,201 semantically typed edges, each grounded in verbatim source evidence, forming a queryable causal network of methodological development. To operationalize this structure, we further propose a self-guided temporal tree search algorithm for constructing evolution chains that trace the progression of methods over time. We evaluate the quality of the resulting graph against expert-curated ground-truth evolution chains and observe strong alignment. In addition, we demonstrate that Intern-Atlas enables downstream applications in idea evaluation and automated idea generation. We position methodological evolution graphs as a foundational data layer for the emerging automated scientific discovery.

Recent advancements in protein structure determination are revolutionizing our understanding of proteins. Still, a significant gap remains in the availability of comprehensive datasets that focus on the dynamics of proteins, which are crucial for understanding protein function, folding, and interactions. To address this critical gap, we introduce mdCATH, a dataset generated through an extensive set of all-atom molecular dynamics simulations of a diverse and representative collection of protein domains. This dataset comprises all-atom systems for 5,398 domains, modeled with a state-of-the-art classical force field, and simulated in five replicates each at five temperatures from 320 K to 413 K. The mdCATH dataset records coordinates and forces every 1 ns, for over 62 ms of accumulated simulation time, effectively capturing the dynamics of the various classes of domains and providing a unique resource for proteome-wide statistical analyses of protein unfolding thermodynamics and kinetics. We outline the dataset structure and showcase its potential through four easily reproducible case studies, highlighting its capabilities in advancing protein science.

The static synaptic connectivity of neuronal circuits stands in direct contrast to the dynamics of their function. As in changing community interactions, different neurons can participate actively in various combinations to effect behaviors at different times. We introduce an unsupervised approach to learn the dynamic affinities between neurons in live, behaving animals, and to reveal which communities form among neurons at different times. The inference occurs in two major steps. First, pairwise non-linear affinities between neuronal traces from brain-wide calcium activity are organized by non-negative tensor factorization (NTF). Each factor specifies which groups of neurons are most likely interacting for an inferred interval in time, and for which animals. Finally, a generative model that allows for weighted community detection is applied to the functional motifs produced by NTF to reveal a dynamic functional connectome. Since time codes the different experimental variables (e.g., application of chemical stimuli), this provides an atlas of neural motifs active during separate stages of an experiment (e.g., stimulus application or spontaneous behaviors). Results from our analysis are experimentally validated, confirming that our method is able to robustly predict causal interactions between neurons to generate behavior. Code is available at https://github.com/dyballa/dynamic-connectomes.

The integration of large language models (LLMs) with external tools has significantly expanded the capabilities of AI agents. However, as the diversity of both LLMs and tools increases, selecting the optimal model-tool combination becomes a high-dimensional optimization challenge. Existing approaches often rely on a single model or fixed tool-calling logic, failing to exploit the performance variations across heterogeneous model-tool pairs. In this paper, we present ATLAS (Adaptive Tool-LLM Alignment and Synergistic Invocation), a dual-path framework for dynamic tool usage in cross-domain complex reasoning. ATLAS operates via a dual-path approach: (1) training-free cluster-based routing that exploits empirical priors for domain-specific alignment, and (2) RL-based multi-step routing that explores autonomous trajectories for out-of-distribution generalization. Extensive experiments across 15 benchmarks demonstrate that our method outperforms closed-source models like GPT-4o, surpassing existing routing methods on both in-distribution (+10.1%) and out-of-distribution (+13.1%) tasks. Furthermore, our framework shows significant gains in visual reasoning by orchestrating specialized multi-modal tools.

Ligand molecule conformation generation is a critical challenge in drug discovery. Deep learning models have been developed to tackle this problem, particularly through the use of generative models in recent years. However, these models often generate conformations that lack meaningful structure and randomness due to the absence of essential side information. Examples of such side information include the chemical and geometric features of the target protein, ligand-target compound interactions, and ligand chemical properties. Without these constraints, the generated conformations may not be suitable for further selection and design of new drugs. To address this limitation, we propose a novel method for generating ligand conformations that leverage side information and incorporate flexible constraints into standard diffusion models. Drawing inspiration from the concept of message passing, we introduce ligand-target massage passing block, a mechanism that facilitates the exchange of information between target nodes and ligand nodes, thereby incorporating target node features. To capture non-covalent interactions, we introduce ligand-target compound inter and intra edges. To further improve the biological relevance of the generated conformations, we train energy models using scalar chemical features. These models guide the progress of the standard Denoising Diffusion Probabilistic Models, resulting in more biologically meaningful conformations. We evaluate the performance of SIDEGEN using the PDBBind-2020 dataset, comparing it against other methods. The results demonstrate improvements in both Aligned RMSD and Ligand RMSD evaluations. Specifically, our model outperforms GeoDiff (trained on PDBBind-2020) by 20% in terms of the median aligned RMSD metric.

Drug discovery can be viewed as a combinatorial search over an immense chemical space, motivating the development of deep generative models for de novo molecular design. Among these, GPT-based molecular language models (MLM) have shown strong molecular design performance by learning chemical syntax and semantics from large-scale data. However, existing MLMs face two fundamental limitations: they inadequately capture the graph-structured nature of molecules when formulated as next-token prediction problems, and they typically lack explicit mechanisms for target-aware generation. Here, we propose SoftMol, a unified framework that co-designs molecular representation, model architecture, and search strategy for target-aware molecular generation. SoftMol introduces soft fragments, a rule-free block representation of SMILES that enables diffusion-native modeling, and develops SoftBD, the first block-diffusion molecular language model that combines local bidirectional diffusion with autoregressive generation under molecular structural constraints. To favor generated molecules with high drug-likeness and synthetic accessibility, SoftBD is trained on a carefully curated dataset named ZINC-Curated. SoftMol further integrates a gated Monte Carlo tree search to assemble fragments in a target-aware manner. Experimental results show that, compared with current state-of-the-art models, SoftMol achieves 100% chemical validity, improves binding affinity by 9.7%, yields a 2-3x increase in molecular diversity, and delivers a 6.6x speedup in inference efficiency. Code is available at https://github.com/szu-aicourse/softmol

Personalized nutrition intervention for patients with multimorbidity is critical for improving health outcomes, yet remains challenging because it requires the simultaneous integration of heterogeneous clinical conditions, medications, and dietary guidelines. Single-agent large language models (LLMs) often suffer from context overload and attention dilution when processing such high-dimensional patient profiles. We introduce NutriOrion, a hierarchical multi-agent framework with a parallel-then-sequential reasoning topology. NutriOrion decomposes nutrition planning into specialized domain agents with isolated contexts to mitigate anchoring bias, followed by a conditional refinement stage. The framework includes a multi-objective prioritization algorithm to resolve conflicting dietary requirements and a safety constraint mechanism that injects pharmacological contraindications as hard negative constraints during synthesis, ensuring clinical validity by construction rather than post-hoc filtering. For clinical interoperability, NutriOrion maps synthesized insights into the ADIME standard and FHIR R4 resources. Evaluated on 330 stroke patients with multimorbidity, NutriOrion outperforms multiple baselines, including GPT-4.1 and alternative multi-agent architectures. It achieves a 12.1 percent drug-food interaction violation rate, demonstrates strong personalization with negative correlations (-0.26 to -0.35) between patient biomarkers and recommended risk nutrients, and yields clinically meaningful dietary improvements, including a 167 percent increase in fiber and a 27 percent increase in potassium, alongside reductions in sodium (9 percent) and sugars (12 percent).

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

Multimodal large language models (MLLMs) hold significant potential in medical applications, including disease diagnosis and clinical decision-making. However, these tasks require highly accurate, context-sensitive, and professionally aligned responses, making reliable reward models and judges critical. Despite their importance, medical reward models (MRMs) and judges remain underexplored, with no dedicated benchmarks addressing clinical requirements. Existing benchmarks focus on general MLLM capabilities or evaluate models as solvers, neglecting essential evaluation dimensions like diagnostic accuracy and clinical relevance. To address this, we introduce Med-RewardBench, the first benchmark specifically designed to evaluate MRMs and judges in medical scenarios. Med-RewardBench features a multimodal dataset spanning 13 organ systems and 8 clinical departments, with 1,026 expert-annotated cases. A rigorous three-step process ensures high-quality evaluation data across six clinically critical dimensions. We evaluate 32 state-of-the-art MLLMs, including open-source, proprietary, and medical-specific models, revealing substantial challenges in aligning outputs with expert judgment. Additionally, we develop baseline models that demonstrate substantial performance improvements through fine-tuning.

Magnetic resonance imaging (MRI) is the standard modality to understand human brain structure and function in vivo (antemortem). Decades of research in human neuroimaging has led to the widespread development of methods and tools to provide automated volume-based segmentations and surface-based parcellations which help localize brain functions to specialized anatomical regions. Recently ex vivo (postmortem) imaging of the brain has opened-up avenues to study brain structure at sub-millimeter ultra high-resolution revealing details not possible to observe with in vivo MRI. Unfortunately, there has been limited methodological development in ex vivo MRI primarily due to lack of datasets and limited centers with such imaging resources. Therefore, in this work, we present one-of-its-kind dataset of 82 ex vivo T2w whole brain hemispheres MRI at 0.3 mm isotropic resolution spanning Alzheimer's disease and related dementias. We adapted and developed a fast and easy-to-use automated surface-based pipeline to parcellate, for the first time, ultra high-resolution ex vivo brain tissue at the native subject space resolution using the Desikan-Killiany-Tourville (DKT) brain atlas. This allows us to perform vertex-wise analysis in the template space and thereby link morphometry measures with pathology measurements derived from histology. We will open-source our dataset docker container, Jupyter notebooks for ready-to-use out-of-the-box set of tools and command line options to advance ex vivo MRI clinical brain imaging research on the project webpage.

Scholarly data are largely fragmented across siloed databases with divergent metadata and missing linkages among them. We present the Science Data Lake, a locally-deployable infrastructure built on DuckDB and simple Parquet files that unifies eight open sources - Semantic Scholar, OpenAlex, SciSciNet, Papers with Code, Retraction Watch, Reliance on Science, a preprint-to-published mapping, and Crossref - via DOI normalization while preserving source-level schemas. The resource comprises approximately 960GB of Parquet files spanning ~293 million uniquely identifiable papers across ~22 schemas and ~153 SQL views. An embedding-based ontology alignment using BGE-large sentence embeddings maps 4,516 OpenAlex topics to 13 scientific ontologies (~1.3 million terms), yielding 16,150 mappings covering 99.8% of topics (geq 0.65 threshold) with F1 = 0.77 at the recommended geq 0.85 operating point, outperforming TF-IDF, BM25, and Jaro-Winkler baselines on a 300-pair gold-standard evaluation. We validate through 10 automated checks, cross-source citation agreement analysis (pairwise Pearson r = 0.76 - 0.87), and stratified manual annotation. Four vignettes demonstrate cross-source analyses infeasible with any single database. The resource is open source, deployable on a single drive or queryable remotely via HuggingFace, and includes structured documentation suitable for large language model (LLM) based research agents.