Daily Papers

Spatial proteomics technologies have transformed our understanding of complex tissue architectures by enabling simultaneous analysis of multiple molecular markers and their spatial organization. The high dimensionality of these data, varying marker combinations across experiments and heterogeneous study designs pose unique challenges for computational analysis. Here, we present Virtual Tissues (VirTues), a foundation model framework for biological tissues that operates across the molecular, cellular and tissue scale. VirTues introduces innovations in transformer architecture design, including a novel tokenization scheme that captures both spatial and marker dimensions, and attention mechanisms that scale to high-dimensional multiplex data while maintaining interpretability. Trained on diverse cancer and non-cancer tissue datasets, VirTues demonstrates strong generalization capabilities without task-specific fine-tuning, enabling cross-study analysis and novel marker integration. As a generalist model, VirTues outperforms existing approaches across clinical diagnostics, biological discovery and patient case retrieval tasks, while providing insights into tissue function and disease mechanisms.

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.

Spatial Transcriptomics (ST) technologies provide biologists with rich insights into single-cell biology by preserving spatial context of cells. Building foundational models for ST can significantly enhance the analysis of vast and complex data sources, unlocking new perspectives on the intricacies of biological tissues. However, modeling ST data is inherently challenging due to the need to extract multi-scale information from tissue slices containing vast numbers of cells. This process requires integrating macro-scale tissue morphology, micro-scale cellular microenvironment, and gene-scale gene expression profile. To address this challenge, we propose SToFM, a multi-scale Spatial Transcriptomics Foundation Model. SToFM first performs multi-scale information extraction on each ST slice, to construct a set of ST sub-slices that aggregate macro-, micro- and gene-scale information. Then an SE(2) Transformer is used to obtain high-quality cell representations from the sub-slices. Additionally, we construct SToCorpus-88M, the largest high-resolution spatial transcriptomics corpus for pretraining. SToFM achieves outstanding performance on a variety of downstream tasks, such as tissue region semantic segmentation and cell type annotation, demonstrating its comprehensive understanding of ST data through capturing and integrating multi-scale information.

Spatial transcriptomics (ST) enables interrogating the molecular composition of tissue with ever-increasing resolution, depth, and sensitivity. However, costs, rapidly evolving technology, and lack of standards have constrained computational methods in ST to narrow tasks and small cohorts. In addition, the underlying tissue morphology as reflected by H&E-stained whole slide images (WSIs) encodes rich information often overlooked in ST studies. Here, we introduce HEST-1k, a collection of 1,108 spatial transcriptomic profiles, each linked to a WSI and metadata. HEST-1k was assembled using HEST-Library from 131 public and internal cohorts encompassing 25 organs, two species (Homo Sapiens and Mus Musculus), and 320 cancer samples from 25 cancer types. HEST-1k processing enabled the identification of 1.5 million expression--morphology pairs and 60 million nuclei. HEST-1k is tested on three use cases: (1) benchmarking foundation models for histopathology (HEST-Benchmark), (2) biomarker identification, and (3) multimodal representation learning. HEST-1k, HEST-Library, and HEST-Benchmark can be freely accessed via https://github.com/mahmoodlab/hest.

Spatial transcriptomics (ST) provides spatially resolved measurements of gene expression, enabling characterization of the molecular landscape of human tissue beyond histological assessment as well as localized readouts that can be aligned with morphology. Concurrently, the success of multimodal foundation models that integrate vision with complementary modalities suggests that morphomolecular coupling between local expression and morphology can be systematically used to improve histological representations themselves. We introduce Spatial Expression-Aligned Learning (SEAL), a vision-omics self-supervised learning framework that infuses localized molecular information into pathology vision encoders. Rather than training new encoders from scratch, SEAL is designed as a parameter-efficient vision-omics finetuning method that can be flexibly applied to widely used pathology foundation models. We instantiate SEAL by training on over 700,000 paired gene expression spot-tissue region examples spanning tumor and normal samples from 14 organs. Tested across 38 slide-level and 15 patch-level downstream tasks, SEAL provides a drop-in replacement for pathology foundation models that consistently improves performance over widely used vision-only and ST prediction baselines on slide-level molecular status, pathway activity, and treatment response prediction, as well as patch-level gene expression prediction tasks. Additionally, SEAL encoders exhibit robust domain generalization on out-of-distribution evaluations and enable new cross-modal capabilities such as gene-to-image retrieval. Our work proposes a general framework for ST-guided finetuning of pathology foundation models, showing that augmenting existing models with localized molecular supervision is an effective and practical step for improving visual representations and expanding their cross-modal utility.

Spatial transcriptomics (ST) provides high-resolution pathological images and whole-transcriptomic expression profiles at individual spots across whole-slide scales. This setting makes it an ideal data source to develop multimodal foundation models. Although recent studies attempted to fine-tune visual encoders with trainable gene encoders based on spot-level, the absence of a wider slide perspective and spatial intrinsic relationships limits their ability to capture ST-specific insights effectively. Here, we introduce ST-Align, the first foundation model designed for ST that deeply aligns image-gene pairs by incorporating spatial context, effectively bridging pathological imaging with genomic features. We design a novel pretraining framework with a three-target alignment strategy for ST-Align, enabling (1) multi-scale alignment across image-gene pairs, capturing both spot- and niche-level contexts for a comprehensive perspective, and (2) cross-level alignment of multimodal insights, connecting localized cellular characteristics and broader tissue architecture. Additionally, ST-Align employs specialized encoders tailored to distinct ST contexts, followed by an Attention-Based Fusion Network (ABFN) for enhanced multimodal fusion, effectively merging domain-shared knowledge with ST-specific insights from both pathological and genomic data. We pre-trained ST-Align on 1.3 million spot-niche pairs and evaluated its performance through two downstream tasks across six datasets, demonstrating superior zero-shot and few-shot capabilities. ST-Align highlights the potential for reducing the cost of ST and providing valuable insights into the distinction of critical compositions within human tissue.

Spatial computing is a technological advancement that facilitates the seamless integration of devices into the physical environment, resulting in a more natural and intuitive digital world user experience. Spatial computing has the potential to become a significant advancement in the field of computing. From GPS and location-based services to healthcare, spatial computing technologies have influenced and improved our interactions with the digital world. The use of spatial computing in creating interactive digital environments has become increasingly popular and effective. This is explained by its increasing significance among researchers and industrial organisations, which motivated us to conduct this review. This review provides a detailed overview of spatial computing, including its enabling technologies and its impact on various applications. Projects related to spatial computing are also discussed. In this review, we also explored the potential challenges and limitations of spatial computing. Furthermore, we discuss potential solutions and future directions. Overall, this paper aims to provide a comprehensive understanding of spatial computing, its enabling technologies, their impact on various applications, emerging challenges, and potential solutions.

Proteins perform nearly all cellular functions and constitute most drug targets, making their analysis fundamental to understanding human biology in health and disease. Tandem mass spectrometry (MS^2) is the major analytical technique in proteomics that identifies peptides by ionizing them, fragmenting them, and using the resulting mass spectra to identify and quantify proteins in biological samples. In MS^2 analysis, peptide fragment ion probability prediction plays a critical role, enhancing the accuracy of peptide identification from mass spectra as a complement to the intensity information. Current approaches rely on global statistics of fragmentation, which assumes that a fragment's probability is uniform across all peptides. Nevertheless, this assumption is oversimplified from a biochemical principle point of view and limits accurate prediction. To address this gap, we present Pep2Prob, the first comprehensive dataset and benchmark designed for peptide-specific fragment ion probability prediction. The proposed dataset contains fragment ion probability statistics for 608,780 unique precursors (each precursor is a pair of peptide sequence and charge state), summarized from more than 183 million high-quality, high-resolution, HCD MS^2 spectra with validated peptide assignments and fragmentation annotations. We establish baseline performance using simple statistical rules and learning-based methods, and find that models leveraging peptide-specific information significantly outperform previous methods using only global fragmentation statistics. Furthermore, performance across benchmark models with increasing capacities suggests that the peptide-fragmentation relationship exhibits complex nonlinearities requiring sophisticated machine learning approaches.

Tandem mass spectrometry has played a pivotal role in advancing proteomics, enabling the high-throughput analysis of protein composition in biological tissues. Many deep learning methods have been developed for de novo peptide sequencing task, i.e., predicting the peptide sequence for the observed mass spectrum. However, two key challenges seriously hinder the further advancement of this important task. Firstly, since there is no consensus for the evaluation datasets, the empirical results in different research papers are often not comparable, leading to unfair comparison. Secondly, the current methods are usually limited to amino acid-level or peptide-level precision and recall metrics. In this work, we present the first unified benchmark NovoBench for de novo peptide sequencing, which comprises diverse mass spectrum data, integrated models, and comprehensive evaluation metrics. Recent impressive methods, including DeepNovo, PointNovo, Casanovo, InstaNovo, AdaNovo and pi-HelixNovo are integrated into our framework. In addition to amino acid-level and peptide-level precision and recall, we evaluate the models' performance in terms of identifying post-tranlational modifications (PTMs), efficiency and robustness to peptide length, noise peaks and missing fragment ratio, which are important influencing factors while seldom be considered. Leveraging this benchmark, we conduct a large-scale study of current methods, report many insightful findings that open up new possibilities for future development.

In this paper, we propose HiPoNet, an end-to-end differentiable neural network for regression, classification, and representation learning on high-dimensional point clouds. Our work is motivated by single-cell data which can have very high-dimensionality --exceeding the capabilities of existing methods for point clouds which are mostly tailored for 3D data. Moreover, modern single-cell and spatial experiments now yield entire cohorts of datasets (i.e., one data set for every patient), necessitating models that can process large, high-dimensional point-clouds at scale. Most current approaches build a single nearest-neighbor graph, discarding important geometric and topological information. In contrast, HiPoNet models the point-cloud as a set of higher-order simplicial complexes, with each particular complex being created using a reweighting of features. This method thus generates multiple constructs corresponding to different views of high-dimensional data, which in biology offers the possibility of disentangling distinct cellular processes. It then employs simplicial wavelet transforms to extract multiscale features, capturing both local and global topology from each view. We show that geometric and topological information is preserved in this framework both theoretically and empirically. We showcase the utility of HiPoNet on point-cloud level tasks, involving classification and regression of entire point-clouds in data cohorts. Experimentally, we find that HiPoNet outperforms other point-cloud and graph-based models on single-cell data. We also apply HiPoNet to spatial transcriptomics datasets using spatial coordinates as one of the views. Overall, HiPoNet offers a robust and scalable solution for high-dimensional data analysis.

The advent of single-cell technology has significantly improved our understanding of cellular states and subpopulations in various tissues under normal and diseased conditions by employing data-driven approaches such as clustering and trajectory inference. However, these methods consider cells as independent data points of population distributions. With spatial transcriptomics, we can represent cellular organization, along with dynamic cell-cell interactions that lead to changes in cell state. Still, key computational advances are necessary to enable the data-driven learning of such complex interactive cellular dynamics. While agent-based modeling (ABM) provides a powerful framework, traditional approaches rely on handcrafted rules derived from domain knowledge rather than data-driven approaches. To address this, we introduce Spatio Temporal Agent-Based Graph Evolution Dynamics(STAGED) integrating ABM with deep learning to model intercellular communication, and its effect on the intracellular gene regulatory network. Using graph ODE networks (GDEs) with shared weights per cell type, our approach represents genes as vertices and interactions as directed edges, dynamically learning their strengths through a designed attention mechanism. Trained to match continuous trajectories of simulated as well as inferred trajectories from spatial transcriptomics data, the model captures both intercellular and intracellular interactions, enabling a more adaptive and accurate representation of cellular dynamics.

Predicting spatial gene expression from H&E histology offers a scalable and clinically accessible alternative to sequencing, but realizing clinical impact requires models that generalize across cancer types and capture biologically coherent signals. Prior work is often limited to per-cancer settings and variance-based evaluation, leaving functional relevance underexplored. We introduce HistoPrism, an efficient transformer-based architecture for pan-cancer prediction of gene expression from histology. To evaluate biological meaning, we introduce a pathway-level benchmark, shifting assessment from isolated gene-level variance to coherent functional pathways. HistoPrism not only surpasses prior state-of-the-art models on highly variable genes , but also more importantly, achieves substantial gains on pathway-level prediction, demonstrating its ability to recover biologically coherent transcriptomic patterns. With strong pan-cancer generalization and improved efficiency, HistoPrism establishes a new standard for clinically relevant transcriptomic modeling from routinely available histology.

Recent advances in multi-modal algorithms have driven and been driven by the increasing availability of large image-text datasets, leading to significant strides in various fields, including computational pathology. However, in most existing medical image-text datasets, the text typically provides high-level summaries that may not sufficiently describe sub-tile regions within a large pathology image. For example, an image might cover an extensive tissue area containing cancerous and healthy regions, but the accompanying text might only specify that this image is a cancer slide, lacking the nuanced details needed for in-depth analysis. In this study, we introduce STimage-1K4M, a novel dataset designed to bridge this gap by providing genomic features for sub-tile images. STimage-1K4M contains 1,149 images derived from spatial transcriptomics data, which captures gene expression information at the level of individual spatial spots within a pathology image. Specifically, each image in the dataset is broken down into smaller sub-image tiles, with each tile paired with 15,000-30,000 dimensional gene expressions. With 4,293,195 pairs of sub-tile images and gene expressions, STimage-1K4M offers unprecedented granularity, paving the way for a wide range of advanced research in multi-modal data analysis an innovative applications in computational pathology, and beyond.

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 .

This paper introduces the concept of Microscopic Spatial Intelligence (MiSI), the capability to perceive and reason about the spatial relationships of invisible microscopic entities, which is fundamental to scientific discovery. To assess the potential of Vision-Language Models (VLMs) in this domain, we propose a systematic benchmark framework MiSI-Bench. This framework features over 163,000 question-answer pairs and 587,000 images derived from approximately 4,000 molecular structures, covering nine complementary tasks that evaluate abilities ranging from elementary spatial transformations to complex relational identifications. Experimental results reveal that current state-of-the-art VLMs perform significantly below human level on this benchmark. However, a fine-tuned 7B model demonstrates substantial potential, even surpassing humans in spatial transformation tasks, while its poor performance in scientifically-grounded tasks like hydrogen bond recognition underscores the necessity of integrating explicit domain knowledge for progress toward scientific AGI. The datasets are available at https://huggingface.co/datasets/zongzhao/MiSI-bench.

Subcellular localization is a crucial biological task for drug target identification and function annotation. Although it has been biologically realized that subcellular localization is closely associated with protein structure, no existing dataset offers comprehensive 3D structural information with detailed subcellular localization annotations, thus severely hindering the application of promising structure-based models on this task. To address this gap, we introduce a new benchmark called CAPSUL, a Comprehensive humAn Protein benchmark for SUbcellular Localization. It features a dataset that integrates diverse 3D structural representations with fine-grained subcellular localization annotations carefully curated by domain experts. We evaluate this benchmark using a variety of state-of-the-art sequence-based and structure-based models, showcasing the importance of involving structural features in this task. Furthermore, we explore reweighting and single-label classification strategies to facilitate future investigation on structure-based methods for this task. Lastly, we showcase the powerful interpretability of structure-based methods through a case study on the Golgi apparatus, where we discover a decisive localization pattern α-helix from attention mechanisms, demonstrating the potential for bridging the gap with intuitive biological interpretability and paving the way for data-driven discoveries in cell biology.

Spatial reasoning is a crucial component of both biological and artificial intelligence. In this work, we present a comprehensive study of the capability of current state-of-the-art large language models (LLMs) on spatial reasoning. To support our study, we created and contribute a novel Spatial Reasoning Characterization (SpaRC) framework and Spatial Reasoning Paths (SpaRP) datasets, to enable an in-depth understanding of the spatial relations and compositions as well as the usefulness of spatial reasoning chains. We found that all the state-of-the-art LLMs do not perform well on the datasets -- their performances are consistently low across different setups. The spatial reasoning capability improves substantially as model sizes scale up. Finetuning both large language models (e.g., Llama-2-70B) and smaller ones (e.g., Llama-2-13B) can significantly improve their F1-scores by 7--32 absolute points. We also found that the top proprietary LLMs still significantly outperform their open-source counterparts in topological spatial understanding and reasoning.

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.

Spatial intelligence is a critical frontier for Multimodal Large Language Models (MLLMs), empowering them to comprehend the physical world. Drawing inspiration from human perception mechanisms, existing studies attempt to construct a coherent spatial understanding via grid-based cognitive maps from multi-frame visual inputs. However, current grid-based map methods rely on discretized raster representations, which limit the model's ability in fine-grained spatial reasoning. To overcome this limitation, we propose Video2Layout, a framework for reconstructing metric-grounded spatial layouts from video. The framework employs continuous object boundary coordinates to quantify inter-object physical distances and object size. This empowers the model with quantitative spatial computation capabilities, effectively alleviating the inherent ambiguity when describing spatial relationships in natural language. Specifically, our method comprises two core stages. First, in supervised fine-tuning stage, we construct a high-quality dataset from the AI2THOR simulator, which enables the model to learn the mapping from visual inputs to precise boundary coordinates. Subsequently, a reinforcement fine-tuning stage further enhances the model's real-world generalization capabilities. To systematically evaluate the correlation between cognitive map accuracy and image quantity, as well as how the quantity of image inputs affects spatial reasoning accuracy, we introduce QVS-Bench, a diagnostic benchmark designed to analyze the relevant mechanisms. Evaluated on QVS-Bench and mainstream spatial reasoning benchmarks, our model, V2LO-7B achieves an average improvement of 4.92% over the model trained on grid maps, validating the superiority of our method. Our code is available at https://github.com/ybrrraway/Video2Layout.

Spatial transcriptomics enables simultaneous measurement of gene expression and tissue morphology, offering unprecedented insights into cellular organization and disease mechanisms. However, the field lacks comprehensive benchmarks for evaluating multimodal learning methods that leverage both histology images and gene expression data. Here, we present HESCAPE, a large-scale benchmark for cross-modal contrastive pretraining in spatial transcriptomics, built on a curated pan-organ dataset spanning 6 different gene panels and 54 donors. We systematically evaluated state-of-the-art image and gene expression encoders across multiple pretraining strategies and assessed their effectiveness on two downstream tasks: gene mutation classification and gene expression prediction. Our benchmark demonstrates that gene expression encoders are the primary determinant of strong representational alignment, and that gene models pretrained on spatial transcriptomics data outperform both those trained without spatial data and simple baseline approaches. However, downstream task evaluation reveals a striking contradiction: while contrastive pretraining consistently improves gene mutation classification performance, it degrades direct gene expression prediction compared to baseline encoders trained without cross-modal objectives. We identify batch effects as a key factor that interferes with effective cross-modal alignment. Our findings highlight the critical need for batch-robust multimodal learning approaches in spatial transcriptomics. To accelerate progress in this direction, we release HESCAPE, providing standardized datasets, evaluation protocols, and benchmarking tools for the community

The cycle of scientific discovery is frequently bottlenecked by the slow, manual creation of software to support computational experiments. To address this, we present an AI system that creates expert-level scientific software whose goal is to maximize a quality metric. The system uses a Large Language Model (LLM) and Tree Search (TS) to systematically improve the quality metric and intelligently navigate the large space of possible solutions. The system achieves expert-level results when it explores and integrates complex research ideas from external sources. The effectiveness of tree search is demonstrated across a wide range of benchmarks. In bioinformatics, it discovered 40 novel methods for single-cell data analysis that outperformed the top human-developed methods on a public leaderboard. In epidemiology, it generated 14 models that outperformed the CDC ensemble and all other individual models for forecasting COVID-19 hospitalizations. Our method also produced state-of-the-art software for geospatial analysis, neural activity prediction in zebrafish, time series forecasting and numerical solution of integrals. By devising and implementing novel solutions to diverse tasks, the system represents a significant step towards accelerating scientific progress.

Answering real-world geospatial questions--such as finding restaurants along a travel route or amenities near a landmark--requires reasoning over both geographic relationships and semantic user intent. However, existing large language models (LLMs) lack spatial computing capabilities and access to up-to-date, ubiquitous real-world geospatial data, while traditional geospatial systems fall short in interpreting natural language. To bridge this gap, we introduce Spatial-RAG, a Retrieval-Augmented Generation (RAG) framework designed for geospatial question answering. Spatial-RAG integrates structured spatial databases with LLMs via a hybrid spatial retriever that combines sparse spatial filtering and dense semantic matching. It formulates the answering process as a multi-objective optimization over spatial and semantic relevance, identifying Pareto-optimal candidates and dynamically selecting the best response based on user intent. Experiments across multiple tourism and map-based QA datasets show that Spatial-RAG significantly improves accuracy, precision, and ranking performance over strong baselines.

Humans perceive and understand real-world spaces through a stream of visual observations. Therefore, the ability to streamingly maintain and update spatial evidence from potentially unbounded video streams is essential for spatial intelligence. The core challenge is not simply longer context windows but how spatial information is selected, organized, and retained over time. In this paper, we propose Spatial-TTT towards streaming visual-based spatial intelligence with test-time training (TTT), which adapts a subset of parameters (fast weights) to capture and organize spatial evidence over long-horizon scene videos. Specifically, we design a hybrid architecture and adopt large-chunk updates parallel with sliding-window attention for efficient spatial video processing. To further promote spatial awareness, we introduce a spatial-predictive mechanism applied to TTT layers with 3D spatiotemporal convolution, which encourages the model to capture geometric correspondence and temporal continuity across frames. Beyond architecture design, we construct a dataset with dense 3D spatial descriptions, which guides the model to update its fast weights to memorize and organize global 3D spatial signals in a structured manner. Extensive experiments demonstrate that Spatial-TTT improves long-horizon spatial understanding and achieves state-of-the-art performance on video spatial benchmarks. Project page: https://liuff19.github.io/Spatial-TTT.

The increasing availability of large-scale global datasets has generated a demand for scalable spatial prediction methods defined on spherical domains. Classical spatial models that rely on Euclidean distance representations are inappropriate for spherical data because planar projections distort geodesic distances and spatial neighborhood structures, while traditional kriging-based prediction methods are often computationally prohibitive for massive datasets. To address these challenges, we propose a Spherical DeepKriging framework for spatial prediction on S^2. The proposed approach constructs a flexible prediction model by integrating thin-plate spline (TPS) basis functions defined intrinsically on the sphere. Simulation studies and real data analyses are presented to demonstrate the superior predictive performance of the proposed method.

Histopathological analysis is a cornerstone of cancer diagnosis, with Hematoxylin and Eosin (H&E) staining routinely acquired for every patient to visualize cell morphology and tissue architecture. On the other hand, multiplex immunofluorescence (mIF) enables more precise cell type identification via proteomic markers, but has yet to achieve widespread clinical adoption due to cost and logistical constraints. To bridge this gap, we introduce MIPHEI (Multiplex Immunofluorescence Prediction from H&E), a U-Net-inspired architecture that integrates state-of-the-art ViT foundation models as encoders to predict mIF signals from H&E images. MIPHEI targets a comprehensive panel of markers spanning nuclear content, immune lineages (T cells, B cells, myeloid), epithelium, stroma, vasculature, and proliferation. We train our model using the publicly available ORION dataset of restained H&E and mIF images from colorectal cancer tissue, and validate it on two independent datasets. MIPHEI achieves accurate cell-type classification from H&E alone, with F1 scores of 0.88 for Pan-CK, 0.57 for CD3e, 0.56 for SMA, 0.36 for CD68, and 0.30 for CD20, substantially outperforming both a state-of-the-art baseline and a random classifier for most markers. Our results indicate that our model effectively captures the complex relationships between nuclear morphologies in their tissue context, as visible in H&E images and molecular markers defining specific cell types. MIPHEI offers a promising step toward enabling cell-type-aware analysis of large-scale H&E datasets, in view of uncovering relationships between spatial cellular organization and patient outcomes.

Visual spatial intelligence is critical for medical image interpretation, yet remains largely unexplored in Multimodal Large Language Models (MLLMs) for 3D imaging. This gap persists due to a systemic lack of datasets featuring structured 3D spatial annotations beyond basic labels. In this study, we introduce an agentic pipeline that autonomously synthesizes spatial visual question-answering (VQA) data by orchestrating computational tools such as volume and distance calculators with multi-agent collaboration and expert radiologist validation. We present SpatialMed, the first comprehensive benchmark for evaluating 3D spatial intelligence in medical MLLMs, comprising nearly 10K question-answer pairs across multiple organs and tumor types. Our evaluations on 14 state-of-the-art MLLMs and extensive analyses reveal that current models lack robust spatial reasoning capabilities for medical imaging.

We propose SpatialLLM, a novel approach advancing spatial intelligence tasks in complex urban scenes. Unlike previous methods requiring geographic analysis tools or domain expertise, SpatialLLM is a unified language model directly addressing various spatial intelligence tasks without any training, fine-tuning, or expert intervention. The core of SpatialLLM lies in constructing detailed and structured scene descriptions from raw spatial data to prompt pre-trained LLMs for scene-based analysis. Extensive experiments show that, with our designs, pretrained LLMs can accurately perceive spatial distribution information and enable zero-shot execution of advanced spatial intelligence tasks, including urban planning, ecological analysis, traffic management, etc. We argue that multi-field knowledge, context length, and reasoning ability are key factors influencing LLM performances in urban analysis. We hope that SpatialLLM will provide a novel viable perspective for urban intelligent analysis and management. The code and dataset are available at https://github.com/WHU-USI3DV/SpatialLLM.

Protein biology focuses on the intricate relationships among sequences, structures, and functions. Deciphering protein functions is crucial for understanding biological processes, advancing drug discovery, and enabling synthetic biology applications. Since protein sequences determine tertiary structures, which in turn govern functions, integrating sequence and structure information is essential for accurate prediction of protein functions. Traditional protein language models (pLMs) have advanced protein-related tasks by learning representations from large-scale sequence and structure data. However, pLMs are limited in integrating broader contextual knowledge, particularly regarding functional modalities that are fundamental to protein biology. In contrast, large language models (LLMs) have exhibited outstanding performance in contextual understanding, reasoning, and generation across diverse domains. Leveraging these capabilities, STELLA is proposed as a multimodal LLM integrating protein sequence-structure representations with general knowledge to address protein function prediction. Through multimodal instruction tuning (MMIT) using the proposed OPI-Struc dataset, STELLA achieves state-of-the-art performance in two function-related tasks-functional description prediction (FP) and enzyme-catalyzed reaction prediction (EP). This study highlights the potential of multimodal LLMs as an alternative paradigm to pLMs to advance protein biology research.

Proteins are essential to life's processes, underpinning evolution and diversity. Advances in sequencing technology have revealed millions of proteins, underscoring the need for sophisticated pre-trained protein models for biological analysis and AI development. Facebook's ESM2, the most advanced protein language model to date, leverages a masked prediction task for unsupervised learning, crafting amino acid representations with notable biochemical accuracy. Yet, it lacks in delivering functional protein insights, signaling an opportunity for enhancing representation quality.Our study addresses this gap by incorporating protein family classification into ESM2's training.This approach, augmented with Community Propagation-Based Clustering Algorithm, improves global protein representations, while a contextual prediction task fine-tunes local amino acid accuracy. Significantly, our model achieved state-of-the-art results in several downstream experiments, demonstrating the power of combining global and local methodologies to substantially boost protein representation quality.

The diverse nature of protein prediction tasks has traditionally necessitated specialized models, hindering the development of broadly applicable and computationally efficient Protein Language Models (PLMs). In this work, we introduce Prot2Token, a unified framework that overcomes these challenges by converting a wide spectrum of protein-related predictions, from sequence-level properties and residue-specific attributes to complex inter-protein interactions, into a standardized next-token prediction format. At its core, Prot2Token employs an autoregressive decoder, conditioned on embeddings from pre-trained protein encoders and guided by learnable task tokens, to perform diverse predictions. This architecture uniquely facilitates multi-task learning, enabling a single model to master numerous tasks with improved efficiency. We present extensive experimental validation across a variety of benchmarks, demonstrating Prot2Tokens strong predictive power in different types of protein-prediction tasks. Key results include significant speedups (e.g., near 1000x over AlphaFold2 with MSA) and performance often matching or exceeding specialized approaches. Beyond that, we introduce an auxiliary self-supervised decoder pre-training approach to improve spatially sensitive task performance. Prot2Token thus offers a significant step towards a versatile, high-throughput paradigm for protein modeling, promising to accelerate biological discovery and the development of novel therapeutics. The code is available at https://github.com/mahdip72/prot2token .

Spatial relation reasoning is a crucial task for multimodal large language models (MLLMs) to understand the objective world. However, current benchmarks have issues like relying on bounding boxes, ignoring perspective substitutions, or allowing questions to be answered using only the model's prior knowledge without image understanding. To address these issues, we introduce SpatialMQA, a human-annotated spatial relation reasoning benchmark based on COCO2017, which enables MLLMs to focus more on understanding images in the objective world. To ensure data quality, we design a well-tailored annotation procedure, resulting in SpatialMQA consisting of 5,392 samples. Based on this benchmark, a series of closed- and open-source MLLMs are implemented and the results indicate that the current state-of-the-art MLLM achieves only 48.14% accuracy, far below the human-level accuracy of 98.40%. Extensive experimental analyses are also conducted, suggesting the future research directions. The benchmark and codes are available at https://github.com/ziyan-xiaoyu/SpatialMQA.git.

Many fields use search algorithms, which automatically explore a search space to find high-performing solutions: chemists search through the space of molecules to discover new drugs; engineers search for stronger, cheaper, safer designs, scientists search for models that best explain data, etc. The goal of search algorithms has traditionally been to return the single highest-performing solution in a search space. Here we describe a new, fundamentally different type of algorithm that is more useful because it provides a holistic view of how high-performing solutions are distributed throughout a search space. It creates a map of high-performing solutions at each point in a space defined by dimensions of variation that a user gets to choose. This Multi-dimensional Archive of Phenotypic Elites (MAP-Elites) algorithm illuminates search spaces, allowing researchers to understand how interesting attributes of solutions combine to affect performance, either positively or, equally of interest, negatively. For example, a drug company may wish to understand how performance changes as the size of molecules and their cost-to-produce vary. MAP-Elites produces a large diversity of high-performing, yet qualitatively different solutions, which can be more helpful than a single, high-performing solution. Interestingly, because MAP-Elites explores more of the search space, it also tends to find a better overall solution than state-of-the-art search algorithms. We demonstrate the benefits of this new algorithm in three different problem domains ranging from producing modular neural networks to designing simulated and real soft robots. Because MAP- Elites (1) illuminates the relationship between performance and dimensions of interest in solutions, (2) returns a set of high-performing, yet diverse solutions, and (3) improves finding a single, best solution, it will advance science and engineering.

Multimodal Large Language Models (MLLMs) have achieved remarkable progress in various multimodal tasks. To pursue higher intelligence in space, MLLMs require integrating multiple atomic spatial capabilities to handle complex and dynamic tasks. However, existing benchmarks struggle to comprehensively evaluate the spatial intelligence of common MLLMs from the atomic level to the compositional level. To fill this gap, we present SpaCE-10, a comprehensive benchmark for compositional spatial evaluations. In SpaCE-10, we define 10 atomic spatial capabilities, which are combined to form 8 compositional capabilities. Based on these definitions, we propose a novel hierarchical annotation pipeline to generate high-quality and diverse question-answer (QA) pairs. With over 150+ hours of human expert effort, we obtain over 5k QA pairs for 811 real indoor scenes in SpaCE-10, which covers various evaluation settings like point cloud input and multi-choice QA. We conduct an extensive evaluation of common MLLMs on SpaCE-10 and find that even the most advanced MLLM still lags behind humans by large margins. Through our careful study, we also draw several significant findings that benefit the MLLM community. For example, we reveal that the shortcoming of counting capability greatly limits the compositional spatial capabilities of existing MLLMs. The evaluation code and benchmark datasets are available at https://github.com/Cuzyoung/SpaCE-10.

Recent advancements in Multimodal Large Language Models (MLLMs) have significantly enhanced performance on 2D visual tasks. However, improving their spatial intelligence remains a challenge. Existing 3D MLLMs always rely on additional 3D or 2.5D data to incorporate spatial awareness, restricting their utility in scenarios with only 2D inputs, such as images or videos. In this paper, we present Spatial-MLLM, a novel framework for visual-based spatial reasoning from purely 2D observations. Unlike conventional video MLLMs which rely on CLIP-based visual encoders optimized for semantic understanding, our key insight is to unleash the strong structure prior from the feed-forward visual geometry foundation model. Specifically, we propose a dual-encoder architecture: a pretrained 2D visual encoder to extract semantic features, and a spatial encoder-initialized from the backbone of the visual geometry model-to extract 3D structure features. A connector then integrates both features into unified visual tokens for enhanced spatial understanding. Furthermore, we propose a space-aware frame sampling strategy at inference time, which selects the spatially informative frames of a video sequence, ensuring that even under limited token length, the model focuses on frames critical for spatial reasoning. Beyond architecture improvements, we construct the Spatial-MLLM-120k dataset and train the model on it using supervised fine-tuning and GRPO. Extensive experiments on various real-world datasets demonstrate that our spatial-MLLM achieves state-of-the-art performance in a wide range of visual-based spatial understanding and reasoning tasks. Project page: https://diankun-wu.github.io/Spatial-MLLM/.

The pursuit of spatial intelligence fundamentally relies on access to large-scale, fine-grained 3D data. However, existing approaches predominantly construct spatial understanding benchmarks by generating question-answer (QA) pairs from a limited number of manually annotated datasets, rather than systematically annotating new large-scale 3D scenes from raw web data. As a result, their scalability is severely constrained, and model performance is further hindered by domain gaps inherent in these narrowly curated datasets. In this work, we propose Holi-Spatial, the first fully automated, large-scale, spatially-aware multimodal dataset, constructed from raw video inputs without human intervention, using the proposed data curation pipeline. Holi-Spatial supports multi-level spatial supervision, ranging from geometrically accurate 3D Gaussian Splatting (3DGS) reconstructions with rendered depth maps to object-level and relational semantic annotations, together with corresponding spatial Question-Answer (QA) pairs. Following a principled and systematic pipeline, we further construct Holi-Spatial-4M, the first large-scale, high-quality 3D semantic dataset, containing 12K optimized 3DGS scenes, 1.3M 2D masks, 320K 3D bounding boxes, 320K instance captions, 1.2M 3D grounding instances, and 1.2M spatial QA pairs spanning diverse geometric, relational, and semantic reasoning tasks. Holi-Spatial demonstrates exceptional performance in data curation quality, significantly outperforming existing feed-forward and per-scene optimized methods on datasets such as ScanNet, ScanNet++, and DL3DV. Furthermore, fine-tuning Vision-Language Models (VLMs) on spatial reasoning tasks using this dataset has also led to substantial improvements in model performance.

Incorporating spatial information, particularly those influenced by climate, weather, and demographic factors, is crucial for improving underwriting precision and enhancing risk management in insurance. However, spatial data are often unstructured, high-dimensional, and difficult to integrate into predictive models. Embedding methods are needed to convert spatial data into meaningful representations for modelling tasks. We propose a novel multi-view contrastive learning framework for generating spatial embeddings that combine information from multiple spatial data sources. To train the model, we construct a spatial dataset that merges satellite imagery and OpenStreetMap features across Europe. The framework aligns these spatial views with coordinate-based encodings, producing low-dimensional embeddings that capture both spatial structure and contextual similarity. Once trained, the model generates embeddings directly from latitude-longitude pairs, enabling any dataset with coordinates to be enriched with meaningful spatial features without requiring access to the original spatial inputs. In a case study on French real estate prices, we compare models trained on raw coordinates against those using our spatial embeddings as inputs. The embeddings consistently improve predictive accuracy across generalised linear, additive, and boosting models, while providing interpretable spatial effects and demonstrating transferability to unseen regions.

Protein function prediction is a crucial task in bioinformatics, with significant implications for understanding biological processes and disease mechanisms. While the relationship between sequence and function has been extensively explored, translating protein structure to function continues to present substantial challenges. Various models, particularly, CNN and graph-based deep learning approaches that integrate structural and functional data, have been proposed to address these challenges. However, these methods often fall short in elucidating the functional significance of key residues essential for protein functionality, as they predominantly adopt a retrospective perspective, leading to suboptimal performance. Inspired by region proposal networks in computer vision, we introduce the Protein Region Proposal Network (ProteinRPN) for accurate protein function prediction. Specifically, the region proposal module component of ProteinRPN identifies potential functional regions (anchors) which are refined through the hierarchy-aware node drop pooling layer favoring nodes with defined secondary structures and spatial proximity. The representations of the predicted functional nodes are enriched using attention mechanisms and subsequently fed into a Graph Multiset Transformer, which is trained with supervised contrastive (SupCon) and InfoNCE losses on perturbed protein structures. Our model demonstrates significant improvements in predicting Gene Ontology (GO) terms, effectively localizing functional residues within protein structures. The proposed framework provides a robust, scalable solution for protein function annotation, advancing the understanding of protein structure-function relationships in computational biology.

Machine learning has markedly advanced de novo peptide sequencing (DNS) for mass spectrometry-based proteomics. DNS tools offer a reliable way to identify peptides without relying on reference databases, extending proteomic analysis and unlocking applications into less-charted regions of the proteome. However, they still face a key limitation. DNS tools lack principled methods for estimating false discovery rates (FDR) and instead rely on model-specific confidence scores that are often miscalibrated. This limits trust in results, hinders cross-model comparisons and reduces validation success. Here we present Winnow, a model-agnostic framework for estimating FDR from calibrated DNS outputs. Winnow maps raw model scores to calibrated confidences using a neural network trained on peptide-spectrum match (PSM)-derived features. From these calibrated scores, Winnow computes PSM-specific error metrics and an experiment-wide FDR estimate using a novel decoy-free FDR estimator. It supports both zero-shot and dataset-specific calibration, enabling flexible application via direct inference, fine-tuning, or training a custom model. We demonstrate that, when applied to InstaNovo predictions, Winnow's calibrator improves recall at fixed FDR thresholds, and its FDR estimator tracks true error rates when benchmarked against reference proteomes and database search. Winnow ensures accurate FDR control across datasets, helping unlock the full potential of DNS.

Deep learning has advanced mass spectrometry data interpretation, yet most models remain feature extractors rather than unified scoring frameworks. We present pUniFind, the first large-scale multimodal pre-trained model in proteomics that integrates end-to-end peptide-spectrum scoring with open, zero-shot de novo sequencing. Trained on over 100 million open search-derived spectra, pUniFind aligns spectral and peptide modalities via cross modality prediction and outperforms traditional engines across diverse datasets, particularly achieving a 42.6 percent increase in the number of identified peptides in immunopeptidomics. Supporting over 1,300 modifications, pUniFind identifies 60 percent more PSMs than existing de novo methods despite a 300-fold larger search space. A deep learning based quality control module further recovers 38.5 percent additional peptides including 1,891 mapped to the genome but absent from reference proteomes while preserving full fragment ion coverage. These results establish a unified, scalable deep learning framework for proteomic analysis, offering improved sensitivity, modification coverage, and interpretability.

Small object-centric spatial understanding in indoor videos remains a significant challenge for multimodal large language models (MLLMs), despite its practical value for object search and assistive applications. Although existing benchmarks have advanced video spatial intelligence, embodied reasoning, and diagnostic perception, no existing benchmark directly evaluates whether a model can localize a target object in video and express its position with sufficient precision for downstream use. In this work, we introduce PinpointQA, the first dataset and benchmark for small object-centric spatial understanding in indoor videos. Built from ScanNet++ and ScanNet200, PinpointQA comprises 1,024 scenes and 10,094 QA pairs organized into four progressively challenging tasks: Target Presence Verification (TPV), Nearest Reference Identification (NRI), Fine-Grained Spatial Description (FSD), and Structured Spatial Prediction (SSP). The dataset is built from intermediate spatial representations, with QA pairs generated automatically and further refined through quality control. Experiments on representative MLLMs reveal a consistent capability gap along the progressive chain, with SSP remaining particularly difficult. Supervised fine-tuning on PinpointQA yields substantial gains, especially on the harder tasks, demonstrating that PinpointQA serves as both a diagnostic benchmark and an effective training dataset. The dataset and project page are available at https://rainchowz.github.io/PinpointQA.

Large Language Models (LLMs) have demonstrated unprecedented capabilities across various natural language processing tasks. Their ability to process and generate viable text and code has made them ubiquitous in many fields, while their deployment as knowledge bases and "reasoning" tools remains an area of ongoing research. In geography, a growing body of literature has been focusing on evaluating LLMs' geographical knowledge and their ability to perform spatial reasoning. However, very little is still known about the internal functioning of these models, especially about how they process geographical information. In this chapter, we establish a novel framework for the study of geospatial mechanistic interpretability - using spatial analysis to reverse engineer how LLMs handle geographical information. Our aim is to advance our understanding of the internal representations that these complex models generate while processing geographical information - what one might call "how LLMs think about geographic information" if such phrasing was not an undue anthropomorphism. We first outline the use of probing in revealing internal structures within LLMs. We then introduce the field of mechanistic interpretability, discussing the superposition hypothesis and the role of sparse autoencoders in disentangling polysemantic internal representations of LLMs into more interpretable, monosemantic features. In our experiments, we use spatial autocorrelation to show how features obtained for placenames display spatial patterns related to their geographic location and can thus be interpreted geospatially, providing insights into how these models process geographical information. We conclude by discussing how our framework can help shape the study and use of foundation models in geography.

Significant progress has been made in spatial intelligence, spanning both spatial reconstruction and world exploration. However, the scalability and real-world fidelity of current models remain severely constrained by the scarcity of large-scale, high-quality training data. While several datasets provide camera pose information, they are typically limited in scale, diversity, and annotation richness, particularly for real-world dynamic scenes with ground-truth camera motion. To this end, we collect SpatialVID, a dataset consists of a large corpus of in-the-wild videos with diverse scenes, camera movements and dense 3D annotations such as per-frame camera poses, depth, and motion instructions. Specifically, we collect more than 21,000 hours of raw video, and process them into 2.7 million clips through a hierarchical filtering pipeline, totaling 7,089 hours of dynamic content. A subsequent annotation pipeline enriches these clips with detailed spatial and semantic information, including camera poses, depth maps, dynamic masks, structured captions, and serialized motion instructions. Analysis of SpatialVID's data statistics reveals a richness and diversity that directly foster improved model generalization and performance, establishing it as a key asset for the video and 3D vision research community.

Spatial intelligence (SI) represents a cognitive ability encompassing the visualization, manipulation, and reasoning about spatial relationships, underpinning disciplines from neuroscience to robotics. We introduce SITE, a benchmark dataset towards SI Thorough Evaluation in a standardized format of multi-choice visual question-answering, designed to assess large vision-language models' spatial intelligence across diverse visual modalities (single-image, multi-image, and video) and SI factors (figural to environmental scales, spatial visualization and orientation, intrinsic and extrinsic, static and dynamic). Our approach to curating the benchmark combines a bottom-up survey about 31 existing datasets and a top-down strategy drawing upon three classification systems in cognitive science, which prompt us to design two novel types of tasks about view-taking and dynamic scenes. Extensive experiments reveal that leading models fall behind human experts especially in spatial orientation, a fundamental SI factor. Moreover, we demonstrate a positive correlation between a model's spatial reasoning proficiency and its performance on an embodied AI task.

In recent years, a standard computational pathology workflow has emerged where whole slide images are cropped into tiles, these tiles are processed using a foundation model, and task-specific models are built using the resulting representations. At least 15 different foundation models have been proposed, and the vast majority are trained exclusively with tiles using the 20times magnification. However, it is well known that certain histologic features can only be discerned with larger context windows and requires a pathologist to zoom in and out when analyzing a whole slide image. Furthermore, creating 224times224 pixel crops at 20times leads to a large number of tiles per slide, which can be gigapixel in size. To more accurately capture multi-resolution features and investigate the possibility of reducing the number of representations per slide, we propose a region-level mixing encoder. Our approach jointly fuses image tile representations of a mixed magnification foundation model using a masked embedding modeling pretraining step. We explore a design space for pretraining the proposed mixed-magnification region aggregators and evaluate our models on transfer to biomarker prediction tasks representing various cancer types. Results demonstrate cancer dependent improvements in predictive performance, highlighting the importance of spatial context and understanding.

The spatio-temporal relations of impacts of extreme events and their drivers in climate data are not fully understood and there is a need of machine learning approaches to identify such spatio-temporal relations from data. The task, however, is very challenging since there are time delays between extremes and their drivers, and the spatial response of such drivers is inhomogeneous. In this work, we propose a first approach and benchmarks to tackle this challenge. Our approach is trained end-to-end to predict spatio-temporally extremes and spatio-temporally drivers in the physical input variables jointly. By enforcing the network to predict extremes from spatio-temporal binary masks of identified drivers, the network successfully identifies drivers that are correlated with extremes. We evaluate our approach on three newly created synthetic benchmarks, where two of them are based on remote sensing or reanalysis climate data, and on two real-world reanalysis datasets. The source code and datasets are publicly available at the project page https://hakamshams.github.io/IDE.

Hit-like molecular generation with therapeutic potential is essential for target-specific drug discovery. However, the field lacks heterogeneous data and unified frameworks for integrating diverse molecular representations. To bridge this gap, we introduce TextOmics, a pioneering benchmark that establishes one-to-one correspondences between omics expressions and molecular textual descriptions. TextOmics provides a heterogeneous dataset that facilitates molecular generation through representations alignment. Built upon this foundation, we propose ToDi, a generative framework that jointly conditions on omics expressions and molecular textual descriptions to produce biologically relevant, chemically valid, hit-like molecules. ToDi leverages two encoders (OmicsEn and TextEn) to capture multi-level biological and semantic associations, and develops conditional diffusion (DiffGen) for controllable generation. Extensive experiments confirm the effectiveness of TextOmics and demonstrate ToDi outperforms existing state-of-the-art approaches, while also showcasing remarkable potential in zero-shot therapeutic molecular generation. Sources are available at: https://github.com/hala-ToDi.

The next Point-of-Interest (POI) recommendation task aims to predict users' next destinations based on their historical movement data and plays a key role in location-based services and personalized applications. Accurate next POI recommendation depends on effectively modeling geographic information and POI transition relations, which are crucial for capturing spatial dependencies and user movement patterns. While Large Language Models (LLMs) exhibit strong capabilities in semantic understanding and contextual reasoning, applying them to spatial tasks like next POI recommendation remains challenging. First, the infrequent nature of specific GPS coordinates makes it difficult for LLMs to model precise spatial contexts. Second, the lack of knowledge about POI transitions limits their ability to capture potential POI-POI relationships. To address these issues, we propose GA-LLM (Geography-Aware Large Language Model), a novel framework that enhances LLMs with two specialized components. The Geographic Coordinate Injection Module (GCIM) transforms GPS coordinates into spatial representations using hierarchical and Fourier-based positional encoding, enabling the model to understand geographic features from multiple perspectives. The POI Alignment Module (PAM) incorporates POI transition relations into the LLM's semantic space, allowing it to infer global POI relationships and generalize to unseen POIs. Experiments on three real-world datasets demonstrate the state-of-the-art performance of GA-LLM.

Holistic 3D modeling of molecularly defined brain structures is crucial for understanding complex brain functions. Emerging tissue profiling technologies enable the construction of a comprehensive atlas of the mammalian brain with sub-cellular resolution and spatially resolved gene expression data. However, such tera-scale volumetric datasets present significant computational challenges in understanding complex brain functions within their native 3D spatial context. Here, we propose the novel generative approach Tera-MIND, which can simulate Tera-scale Mouse braINs in 3D using a patch-based and boundary-aware Diffusion model. Taking spatial transcriptomic data as the conditional input, we generate virtual mouse brains with comprehensive cellular morphological detail at teravoxel scale. Through the lens of 3D gene-gene self-attention, we identify spatial molecular interactions for key transcriptomic pathways in the murine brain, exemplified by glutamatergic and dopaminergic neuronal systems. Importantly, these in-silico biological findings are consistent and reproducible across three tera-scale virtual mouse brains. Therefore, Tera-MIND showcases a promising path toward efficient and generative simulations of whole organ systems for biomedical research. Project website: http://musikisomorphie.github.io/Tera-MIND.html{https}

Spatial understanding is a fundamental cornerstone of human-level intelligence. Nonetheless, current research predominantly focuses on domain-specific data production, leaving a critical void: the absence of a principled, open-source engine capable of fully unleashing the potential of high-quality spatial data. To bridge this gap, we elucidate the design principles of a robust data generation system and introduce OpenSpatial -- an open-source data engine engineered for high quality, extensive scalability, broad task diversity, and optimized efficiency. OpenSpatial adopts 3D bounding boxes as the fundamental primitive to construct a comprehensive data hierarchy across five foundational tasks: Spatial Measurement (SM), Spatial Relationship (SR), Camera Perception (CP), Multi-view Consistency (MC), and Scene-Aware Reasoning (SAR). Leveraging this scalable infrastructure, we curate OpenSpatial-3M, a large-scale dataset comprising 3 million high-fidelity samples. Extensive evaluations demonstrate that versatile models trained on our dataset achieve state-of-the-art performance across a wide spectrum of spatial reasoning benchmarks. Notably, the best-performing model exhibits a substantial average improvement of 19 percent, relatively. Furthermore, we provide a systematic analysis of how data attributes influence spatial perception. By open-sourcing both the engine and the 3M-scale dataset, we provide a robust foundation to accelerate future research in spatial intelligence.

Multimodal large language models (MLLMs) have achieved remarkable progress in vision-language tasks, but they continue to struggle with spatial understanding. Existing spatial MLLMs often rely on explicit 3D inputs or architecture-specific modifications, and remain constrained by large-scale datasets or sparse supervision. To address these limitations, we introduce SpatialThinker, a 3D-aware MLLM trained with RL to integrate structured spatial grounding with multi-step reasoning. The model simulates human-like spatial perception by constructing a scene graph of task-relevant objects and spatial relations, and reasoning towards an answer via dense spatial rewards. SpatialThinker consists of two key contributions: (1) a data synthesis pipeline that generates STVQA-7K, a high-quality spatial VQA dataset, and (2) online RL with a multi-objective dense spatial reward enforcing spatial grounding. SpatialThinker-7B outperforms supervised fine-tuning and the sparse RL baseline on spatial understanding and real-world VQA benchmarks, nearly doubling the base-model gain compared to sparse RL, and surpassing GPT-4o. These results showcase the effectiveness of combining spatial supervision with reward-aligned reasoning in enabling robust 3D spatial understanding with limited data and advancing MLLMs towards human-level visual reasoning.

Spatial intelligence is essential for multimodal large language models, yet current benchmarks largely assess it only from an understanding perspective. We ask whether modern generative or unified multimodal models also possess generative spatial intelligence (GSI), the ability to respect and manipulate 3D spatial constraints during image generation, and whether such capability can be measured or improved. We introduce GSI-Bench, the first benchmark designed to quantify GSI through spatially grounded image editing. It consists of two complementary components: GSI-Real, a high-quality real-world dataset built via a 3D-prior-guided generation and filtering pipeline, and GSI-Syn, a large-scale synthetic benchmark with controllable spatial operations and fully automated labeling. Together with a unified evaluation protocol, GSI-Bench enables scalable, model-agnostic assessment of spatial compliance and editing fidelity. Experiments show that fine-tuning unified multimodal models on GSI-Syn yields substantial gains on both synthetic and real tasks and, strikingly, also improves downstream spatial understanding. This provides the first clear evidence that generative training can tangibly strengthen spatial reasoning, establishing a new pathway for advancing spatial intelligence in multimodal models.

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

A principal component analysis of the TCGA data for 15 cancer localizations unveils the following qualitative facts about tumors: 1) The state of a tissue in gene expression space may be described by a few variables. In particular, there is a single variable describing the progression from a normal tissue to a tumor. 2) Each cancer localization is characterized by a gene expression profile, in which genes have specific weights in the definition of the cancer state. There are no less than 2500 differentially-expressed genes, which lead to power-like tails in the expression distribution functions. 3) Tumors in different localizations share hundreds or even thousands of differentially expressed genes. There are 6 genes common to the 15 studied tumor localizations. 4) The tumor region is a kind of attractor. Tumors in advanced stages converge to this region independently of patient age or genetic variability. 5) There is a landscape of cancer in gene expression space with an approximate border separating normal tissues from tumors.

The discovery and identification of molecules in biological and environmental samples is crucial for advancing biomedical and chemical sciences. Tandem mass spectrometry (MS/MS) is the leading technique for high-throughput elucidation of molecular structures. However, decoding a molecular structure from its mass spectrum is exceptionally challenging, even when performed by human experts. As a result, the vast majority of acquired MS/MS spectra remain uninterpreted, thereby limiting our understanding of the underlying (bio)chemical processes. Despite decades of progress in machine learning applications for predicting molecular structures from MS/MS spectra, the development of new methods is severely hindered by the lack of standard datasets and evaluation protocols. To address this problem, we propose MassSpecGym -- the first comprehensive benchmark for the discovery and identification of molecules from MS/MS data. Our benchmark comprises the largest publicly available collection of high-quality labeled MS/MS spectra and defines three MS/MS annotation challenges: de novo molecular structure generation, molecule retrieval, and spectrum simulation. It includes new evaluation metrics and a generalization-demanding data split, therefore standardizing the MS/MS annotation tasks and rendering the problem accessible to the broad machine learning community. MassSpecGym is publicly available at https://github.com/pluskal-lab/MassSpecGym.

Multimodal large language models (MLLMs) have achieved impressive success in question-answering tasks, yet their capabilities for spatial understanding are less explored. This work investigates a critical question: do existing MLLMs possess 3D spatial perception and understanding abilities? Concretely, we make the following contributions in this paper: (i) we introduce VGBench, a benchmark specifically designed to assess MLLMs for visual geometry perception, e.g., camera pose and motion estimation; (ii) we propose SpatialScore, the most comprehensive and diverse multimodal spatial understanding benchmark to date, integrating VGBench with relevant data from the other 11 existing datasets. This benchmark comprises 28K samples across various spatial understanding tasks, modalities, and QA formats, along with a carefully curated challenging subset, SpatialScore-Hard; (iii) we develop SpatialAgent, a novel multi-agent system incorporating 9 specialized tools for spatial understanding, supporting both Plan-Execute and ReAct reasoning paradigms; (iv) we conduct extensive evaluations to reveal persistent challenges in spatial reasoning while demonstrating the effectiveness of SpatialAgent. We believe SpatialScore will offer valuable insights and serve as a rigorous benchmark for the next evolution of MLLMs.

Single-cell technologies generate high-dimensional point clouds of cells, enabling detailed characterization of complex patient states and treatment responses. Yet each patient is represented by an irregular point cloud rather than a simple vector, making it difficult to directly quantify and compare biological differences between individuals. Nonlinear methods such as kernels and neural networks achieve predictive accuracy but act as black boxes, offering little biological interpretability. To address these limitations, we adapt the Linear Optimal Transport (LOT) framework to this setting, embedding irregular point clouds into a fixed-dimensional Euclidean space while preserving distributional structure. This embedding provides a principled linear representation that preserves optimal transport geometry while enabling downstream analysis. It also forms a registration between any two patients, enabling direct comparison of their cellular distributions. Within this space, LOT enables: (i) accurate and interpretable classification of COVID-19 patient states, where classifier weights map back to specific markers and spatial regions driving predictions; and (ii) synthetic data generation for patient-derived organoids, exploiting the linearity of the LOT embedding. LOT barycenters yield averaged cellular profiles representing combined conditions or samples, supporting drug interaction testing. Together, these results establish LOT as a unified framework that bridges predictive performance, interpretability, and generative modeling. By transforming heterogeneous point clouds into structured embeddings directly traceable to the original data, LOT opens new opportunities for understanding immune variation and treatment effects in high-dimensional biological systems.

The molecular characterization of tumor samples by multiple omics data sets of different types or modalities (e.g. gene expression, mutation, CpG methylation) has become an invaluable source of information for assessing the expected performance of individual drugs and their combinations. Merging the relevant information from the omics data modalities provides the statistical basis for determining suitable therapies for specific cancer patients. Different data modalities may each have their specific structures that need to be taken into account during inference. In this paper, we assume that each omics data modality has a low-rank structure with only few relevant features that affect the prediction and we propose to use a composite local nuclear norm penalization for learning drug sensitivity. Numerical results show that the composite low-rank structure can improve the prediction performance compared to using a global low-rank approach or elastic net regression.

Self-supervised training of language models (LMs) has seen great success for protein sequences in learning meaningful representations and for generative drug design. Most protein LMs are based on the Transformer architecture trained on individual proteins with short context lengths. Such protein LMs cannot extrapolate to longer proteins and protein complexes well. They also fail to account for the underlying biological mechanisms carried out by biomolecular interactions and dynamics i.e., proteins often interact with other proteins, molecules, and pathways in complex biological systems. In this work, we propose LC-PLM based on an alternative protein LM architecture, BiMamba-S, built off selective structured state-space models, to learn high-quality universal protein representations at the amino acid token level using masked language modeling. We also introduce its graph-contextual variant, LC-PLM-G, which contextualizes protein-protein interaction (PPI) graphs for a second stage of training. LC-PLM demonstrates favorable neural scaling laws, better length extrapolation capability, and a 7% to 34% improvement on protein downstream tasks than Transformer-based ESM-2. LC-PLM-G further trained within the context of PPI graphs shows promising results on protein structure and function prediction tasks. Our study demonstrates the benefit of increasing the context size with computationally efficient LM architecture (e.g. structured state space models) in learning universal protein representations and incorporating molecular interaction context contained in biological graphs.

Learning feature representations of geographical space is vital for any machine learning model that integrates geolocated data, spanning application domains such as remote sensing, ecology, or epidemiology. Recent work mostly embeds coordinates using sine and cosine projections based on Double Fourier Sphere (DFS) features -- these embeddings assume a rectangular data domain even on global data, which can lead to artifacts, especially at the poles. At the same time, relatively little attention has been paid to the exact design of the neural network architectures these functional embeddings are combined with. This work proposes a novel location encoder for globally distributed geographic data that combines spherical harmonic basis functions, natively defined on spherical surfaces, with sinusoidal representation networks (SirenNets) that can be interpreted as learned Double Fourier Sphere embedding. We systematically evaluate the cross-product of positional embeddings and neural network architectures across various classification and regression benchmarks and synthetic evaluation datasets. In contrast to previous approaches that require the combination of both positional encoding and neural networks to learn meaningful representations, we show that both spherical harmonics and sinusoidal representation networks are competitive on their own but set state-of-the-art performances across tasks when combined. We provide source code at www.github.com/marccoru/locationencoder

As deep learning technology advances and more urban spatial-temporal data accumulates, an increasing number of deep learning models are being proposed to solve urban spatial-temporal prediction problems. However, there are limitations in the existing field, including open-source data being in various formats and difficult to use, few papers making their code and data openly available, and open-source models often using different frameworks and platforms, making comparisons challenging. A standardized framework is urgently needed to implement and evaluate these methods. To address these issues, we propose LibCity, an open-source library that offers researchers a credible experimental tool and a convenient development framework. In this library, we have reproduced 65 spatial-temporal prediction models and collected 55 spatial-temporal datasets, allowing researchers to conduct comprehensive experiments conveniently. By enabling fair model comparisons, designing a unified data storage format, and simplifying the process of developing new models, LibCity is poised to make significant contributions to the spatial-temporal prediction field.

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.

Protein modeling is an increasingly popular area of machine learning research. Semi-supervised learning has emerged as an important paradigm in protein modeling due to the high cost of acquiring supervised protein labels, but the current literature is fragmented when it comes to datasets and standardized evaluation techniques. To facilitate progress in this field, we introduce the Tasks Assessing Protein Embeddings (TAPE), a set of five biologically relevant semi-supervised learning tasks spread across different domains of protein biology. We curate tasks into specific training, validation, and test splits to ensure that each task tests biologically relevant generalization that transfers to real-life scenarios. We benchmark a range of approaches to semi-supervised protein representation learning, which span recent work as well as canonical sequence learning techniques. We find that self-supervised pretraining is helpful for almost all models on all tasks, more than doubling performance in some cases. Despite this increase, in several cases features learned by self-supervised pretraining still lag behind features extracted by state-of-the-art non-neural techniques. This gap in performance suggests a huge opportunity for innovative architecture design and improved modeling paradigms that better capture the signal in biological sequences. TAPE will help the machine learning community focus effort on scientifically relevant problems. Toward this end, all data and code used to run these experiments are available at https://github.com/songlab-cal/tape.

Over the past year, the development of large language models (LLMs) has brought spatial intelligence into focus, with much attention on vision-based embodied intelligence. However, spatial intelligence spans a broader range of disciplines and scales, from navigation and urban planning to remote sensing and earth science. What are the differences and connections between spatial intelligence across these fields? In this paper, we first review human spatial cognition and its implications for spatial intelligence in LLMs. We then examine spatial memory, knowledge representations, and abstract reasoning in LLMs, highlighting their roles and connections. Finally, we analyze spatial intelligence across scales -- from embodied to urban and global levels -- following a framework that progresses from spatial memory and understanding to spatial reasoning and intelligence. Through this survey, we aim to provide insights into interdisciplinary spatial intelligence research and inspire future studies.

Advances in peptide identification are revolutionizing our ability to decipher protein functions and accelerate therapeutic discovery. We present PDeepPP, a deep learning framework that integrates pretrained protein language models with parallel transformer-CNN architectures, achieving state-of-the-art performance in peptide characterization tasks. The model's hybrid architecture demonstrates unique capabilities in capturing both local sequence motifs and global structural features, as evidenced by 29% improved cluster separation in UMAP visualizations compared to conventional approaches. Evaluated across 33 biological recognition tasks - including post-translational modification site prediction and bioactive peptide identification - PDeepPP outperformed existing methods in 25 tasks with average AUC improvements of 4.2%. Notably, it achieved 0.9726 accuracy with PR AUC 0.9977 in antimicrobial peptide detection while reducing false negatives by 37.5% in antimalarial recognition scenarios. This framework enables accurate large-scale peptide analysis, achieving 218* acceleration over sequence-alignment-based methods while maintaining 99.5% specificity in critical glycosylation site detection.PDeepPP establishes a new paradigm for computational peptide analysis through its synergistic architecture design, enabling rapid yet precise functional annotation that bridges molecular pattern recognition with translational biomedical applications.We have made our implementation, including code, data, and pretrained models, publicly available via GitHub (https://github.com/fondress/PDeepPP) and Hugging Face (https://huggingface.co/fondress/PDeppPP).

Large language models (LLMs) and emerging agentic frameworks are beginning to transform single-cell biology by enabling natural-language reasoning, generative annotation, and multimodal data integration. However, progress remains fragmented across data modalities, architectures, and evaluation standards. LLM4Cell presents the first unified survey of 58 foundation and agentic models developed for single-cell research, spanning RNA, ATAC, multi-omic, and spatial modalities. We categorize these methods into five families-foundation, text-bridge, spatial, multimodal, epigenomic, and agentic-and map them to eight key analytical tasks including annotation, trajectory and perturbation modeling, and drug-response prediction. Drawing on over 40 public datasets, we analyze benchmark suitability, data diversity, and ethical or scalability constraints, and evaluate models across 10 domain dimensions covering biological grounding, multi-omics alignment, fairness, privacy, and explainability. By linking datasets, models, and evaluation domains, LLM4Cell provides the first integrated view of language-driven single-cell intelligence and outlines open challenges in interpretability, standardization, and trustworthy model development.

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

The emergence of tool-calling-based agent systems introduces a more evidence-driven paradigm for pathology image analysis in contrast to the coarse-grained text-image diagnostic approaches. With the recent large-scale experimental adoption of spatial transcriptomics technologies, molecularly validated pathological diagnosis is becoming increasingly open and accessible. In this work, we propose LAMMI-Pathology (LVLM-Agent System for Molecularly Informed Medical Intelligence in Pathology), a scalable agent framework for domain-specific agent tool-calling. LAMMI-Pathology adopts a tool-centric, bottom-up architecture in which customized domain-adaptive tools serve as the foundation. These tools are clustered by domain style to form component agents, which are then coordinated through a top-level planner hierarchically, avoiding excessively long context lengths that could induce task drift. Based on that, we introduce a novel trajectory construction mechanism based on Atomic Execution Nodes (AENs), which serve as reliable and composable units for building semi-simulated reasoning trajectories that capture credible agent-tool interactions. Building on this foundation, we develop a trajectory-aware fine-tuning strategy that aligns the planner's decision-making process with these multi-step reasoning trajectories, thereby enhancing inference robustness in pathology understanding and its adaptive use of the customized toolset.

High-throughput screening techniques, such as microscopy imaging of cellular responses to genetic and chemical perturbations, play a crucial role in drug discovery and biomedical research. However, robust perturbation screening for de novo cell lines remains challenging due to the significant morphological and biological heterogeneity across cell lines. To address this, we propose a novel framework that integrates external biological knowledge into existing pretraining strategies to enhance microscopy image profiling models. Our approach explicitly disentangles perturbation-specific and cell line-specific representations using external biological information. Specifically, we construct a knowledge graph leveraging protein interaction data from STRING and Hetionet databases to guide models toward perturbation-specific features during pretraining. Additionally, we incorporate transcriptomic features from single-cell foundation models to capture cell line-specific representations. By learning these disentangled features, our method improves the generalization of imaging models to de novo cell lines. We evaluate our framework on the RxRx database through one-shot fine-tuning on an RxRx1 cell line and few-shot fine-tuning on cell lines from the RxRx19a dataset. Experimental results demonstrate that our method enhances microscopy image profiling for de novo cell lines, highlighting its effectiveness in real-world phenotype-based drug discovery applications.

The rapid advancement of multimodal large language models (LLMs) has opened new frontiers in artificial intelligence, enabling the integration of diverse large-scale data types such as text, images, and spatial information. In this paper, we explore the potential of multimodal LLMs (MLLM) for geospatial artificial intelligence (GeoAI), a field that leverages spatial data to address challenges in domains including Geospatial Semantics, Health Geography, Urban Geography, Urban Perception, and Remote Sensing. We propose a MLLM (OmniGeo) tailored to geospatial applications, capable of processing and analyzing heterogeneous data sources, including satellite imagery, geospatial metadata, and textual descriptions. By combining the strengths of natural language understanding and spatial reasoning, our model enhances the ability of instruction following and the accuracy of GeoAI systems. Results demonstrate that our model outperforms task-specific models and existing LLMs on diverse geospatial tasks, effectively addressing the multimodality nature while achieving competitive results on the zero-shot geospatial tasks. Our code will be released after publication.

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.

Multimodal Large Language Models (MLLMs) have demonstrated impressive performance in general vision-language tasks. However, recent studies have exposed critical limitations in their spatial reasoning capabilities. This deficiency in spatial reasoning significantly constrains MLLMs' ability to interact effectively with the physical world, thereby limiting their broader applications. We argue that spatial reasoning capabilities will not naturally emerge from merely scaling existing architectures and training methodologies. Instead, this challenge demands dedicated attention to fundamental modifications in the current MLLM development approach. In this position paper, we first establish a comprehensive framework for spatial reasoning within the context of MLLMs. We then elaborate on its pivotal role in real-world applications. Through systematic analysis, we examine how individual components of the current methodology, from training data to reasoning mechanisms, influence spatial reasoning capabilities. This examination reveals critical limitations while simultaneously identifying promising avenues for advancement. Our work aims to direct the AI research community's attention toward these crucial yet underexplored aspects. By highlighting these challenges and opportunities, we seek to catalyze progress toward achieving human-like spatial reasoning capabilities in MLLMs.

Many data have an underlying dependence on spatial location; it may be weather on the Earth, a simulation on a mesh, or a registered image. Yet this feature is rarely taken advantage of, and violates common assumptions made by many neural network layers, such as translation equivariance. Further, many works that do incorporate locality fail to capture fine-grained structure. To address this, we introduce the Spatial Mixture-of-Experts (SMoE) layer, a sparsely-gated layer that learns spatial structure in the input domain and routes experts at a fine-grained level to utilize it. We also develop new techniques to train SMoEs, including a self-supervised routing loss and damping expert errors. Finally, we show strong results for SMoEs on numerous tasks, and set new state-of-the-art results for medium-range weather prediction and post-processing ensemble weather forecasts.

Understanding and reasoning about spatial relationships is a fundamental capability for Visual Question Answering (VQA) and robotics. While Vision Language Models (VLM) have demonstrated remarkable performance in certain VQA benchmarks, they still lack capabilities in 3D spatial reasoning, such as recognizing quantitative relationships of physical objects like distances or size differences. We hypothesize that VLMs' limited spatial reasoning capability is due to the lack of 3D spatial knowledge in training data and aim to solve this problem by training VLMs with Internet-scale spatial reasoning data. To this end, we present a system to facilitate this approach. We first develop an automatic 3D spatial VQA data generation framework that scales up to 2 billion VQA examples on 10 million real-world images. We then investigate various factors in the training recipe, including data quality, training pipeline, and VLM architecture. Our work features the first internet-scale 3D spatial reasoning dataset in metric space. By training a VLM on such data, we significantly enhance its ability on both qualitative and quantitative spatial VQA. Finally, we demonstrate that this VLM unlocks novel downstream applications in chain-of-thought spatial reasoning and robotics due to its quantitative estimation capability. Project website: https://spatial-vlm.github.io/

SpatialLM is a large language model designed to process 3D point cloud data and generate structured 3D scene understanding outputs. These outputs include architectural elements like walls, doors, windows, and oriented object boxes with their semantic categories. Unlike previous methods which exploit task-specific network designs, our model adheres to the standard multimodal LLM architecture and is fine-tuned directly from open-source LLMs. To train SpatialLM, we collect a large-scale, high-quality synthetic dataset consisting of the point clouds of 12,328 indoor scenes (54,778 rooms) with ground-truth 3D annotations, and conduct a careful study on various modeling and training decisions. On public benchmarks, our model gives state-of-the-art performance in layout estimation and competitive results in 3D object detection. With that, we show a feasible path for enhancing the spatial understanding capabilities of modern LLMs for applications in augmented reality, embodied robotics, and more.

The application of deep learning methods, particularly foundation models, in biological research has surged in recent years. These models can be text-based or trained on underlying biological data, especially omics data of various types. However, comparing the performance of these models consistently has proven to be a challenge due to differences in training data and downstream tasks. To tackle this problem, we developed an architecture-agnostic benchmarking approach that, instead of evaluating the models directly, leverages entity representation vectors from each model and trains simple predictive models for each benchmarking task. This ensures that all types of models are evaluated using the same input and output types. Here we focus on gene properties collected from professionally curated bioinformatics databases. These gene properties are categorized into five major groups: genomic properties, regulatory functions, localization, biological processes, and protein properties. Overall, we define hundreds of tasks based on these databases, which include binary, multi-label, and multi-class classification tasks. We apply these benchmark tasks to evaluate expression-based models, large language models, protein language models, DNA-based models, and traditional baselines. Our findings suggest that text-based models and protein language models generally outperform expression-based models in genomic properties and regulatory functions tasks, whereas expression-based models demonstrate superior performance in localization tasks. These results should aid in the development of more informed artificial intelligence strategies for biological understanding and therapeutic discovery. To ensure the reproducibility and transparency of our findings, we have made the source code and benchmark data publicly accessible for further investigation and expansion at github.com/BiomedSciAI/gene-benchmark.

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.

Precise spatial understanding in Earth Observation is essential for translating raw aerial imagery into actionable insights for critical applications like urban planning, environmental monitoring and disaster management. However, Multimodal Large Language Models exhibit critical deficiencies in fine-grained spatial understanding within Remote Sensing, primarily due to a reliance on limited or repurposed legacy datasets. To bridge this gap, we introduce a large-scale dataset grounded in verifiable cadastral vector data, comprising 3.8 million annotated objects across 510k high-resolution images with 135 granular semantic categories. We validate this resource through a comprehensive instruction-tuning benchmark spanning seven spatial reasoning tasks. Our evaluation establishes a robust baseline using a standard LLaVA architecture. We show that while current RS-specialized and commercial models (e.g., Gemini) struggle in zero-shot settings, high-fidelity supervision effectively bridges this gap, enabling standard architectures to master fine-grained spatial grounding without complex architectural modifications.

The application of machine learning (ML) in a range of geospatial tasks is increasingly common but often relies on globally available covariates such as satellite imagery that can either be expensive or lack predictive power. Here we explore the question of whether the vast amounts of knowledge found in Internet language corpora, now compressed within large language models (LLMs), can be leveraged for geospatial prediction tasks. We first demonstrate that LLMs embed remarkable spatial information about locations, but naively querying LLMs using geographic coordinates alone is ineffective in predicting key indicators like population density. We then present GeoLLM, a novel method that can effectively extract geospatial knowledge from LLMs with auxiliary map data from OpenStreetMap. We demonstrate the utility of our approach across multiple tasks of central interest to the international community, including the measurement of population density and economic livelihoods. Across these tasks, our method demonstrates a 70% improvement in performance (measured using Pearson's r^2) relative to baselines that use nearest neighbors or use information directly from the prompt, and performance equal to or exceeding satellite-based benchmarks in the literature. With GeoLLM, we observe that GPT-3.5 outperforms Llama 2 and RoBERTa by 19% and 51% respectively, suggesting that the performance of our method scales well with the size of the model and its pretraining dataset. Our experiments reveal that LLMs are remarkably sample-efficient, rich in geospatial information, and robust across the globe. Crucially, GeoLLM shows promise in mitigating the limitations of existing geospatial covariates and complementing them well. Code is available on the project website: https://rohinmanvi.github.io/GeoLLM

The complex nature of big biological systems pushed some scientists to classify its understanding under the inconceivable missions. Different leveled challenges complicated this task, one of is the prediction of a protein's function. In recent years, significant progress has been made in this field through the development of various machine learning approaches. However, most existing methods formulate the task as a multi-classification problem, i.e assigning predefined labels to proteins. In this work, we propose a novel approach, Prot2Text, which predicts a protein function's in a free text style, moving beyond the conventional binary or categorical classifications. By combining Graph Neural Networks(GNNs) and Large Language Models(LLMs), in an encoder-decoder framework, our model effectively integrates diverse data types including proteins' sequences, structures, and textual annotations. This multimodal approach allows for a holistic representation of proteins' functions, enabling the generation of detailed and accurate descriptions. To evaluate our model, we extracted a multimodal protein dataset from SwissProt, and demonstrate empirically the effectiveness of Prot2Text. These results highlight the transformative impact of multimodal models, specifically the fusion of GNNs and LLMs, empowering researchers with powerful tools for more accurate prediction of proteins' functions. The code, the models and a demo will be publicly released.

Understanding cellular machinery requires atomic-scale reconstruction of large biomolecular assemblies. However, predicting the structures of these systems has been constrained by hardware memory requirements of models like AlphaFold 3, imposing a practical ceiling of a few thousand residues that can be processed on a single GPU. Here we present NVIDIA BioNeMo Fold-CP, a context parallelism framework that overcomes this barrier by distributing the inference and training pipelines of co-folding models across multiple GPUs. We use the Boltz models as open source reference architectures and implement custom multidimensional primitives that efficiently parallelize both the dense triangular updates and the irregular, data-dependent pattern of window-batched local attention. Our approach achieves efficient memory scaling; for an N-token input distributed across P GPUs, per-device memory scales as O(N^2/P), enabling the structure prediction of assemblies exceeding 30,000 residues on 64 NVIDIA B300 GPUs. We demonstrate the scientific utility of this approach through successful developer use cases: Fold-CP enabled the scoring of over 90% of Comprehensive Resource of Mammalian protein complexes (CORUM) database, as well as folding of disease-relevant PI4KA lipid kinase complex bound to an intrinsically disordered region without cropping. By providing a scalable pathway for modeling massive systems with full global context, Fold-CP represents a significant step toward the realization of a virtual cell.

Understanding the spatial relations between objects in images is a surprisingly challenging task. A chair may be "behind" a person even if it appears to the left of the person in the image (depending on which way the person is facing). Two students that appear close to each other in the image may not in fact be "next to" each other if there is a third student between them. We introduce SpatialSense, a dataset specializing in spatial relation recognition which captures a broad spectrum of such challenges, allowing for proper benchmarking of computer vision techniques. SpatialSense is constructed through adversarial crowdsourcing, in which human annotators are tasked with finding spatial relations that are difficult to predict using simple cues such as 2D spatial configuration or language priors. Adversarial crowdsourcing significantly reduces dataset bias and samples more interesting relations in the long tail compared to existing datasets. On SpatialSense, state-of-the-art recognition models perform comparably to simple baselines, suggesting that they rely on straightforward cues instead of fully reasoning about this complex task. The SpatialSense benchmark provides a path forward to advancing the spatial reasoning capabilities of computer vision systems. The dataset and code are available at https://github.com/princeton-vl/SpatialSense.

Vision Language Models (VLMs) have demonstrated remarkable performance in 2D vision and language tasks. However, their ability to reason about spatial arrangements remains limited. In this work, we introduce Spatial Region GPT (SpatialRGPT) to enhance VLMs' spatial perception and reasoning capabilities. SpatialRGPT advances VLMs' spatial understanding through two key innovations: (1) a data curation pipeline that enables effective learning of regional representation from 3D scene graphs, and (2) a flexible plugin module for integrating depth information into the visual encoder of existing VLMs. During inference, when provided with user-specified region proposals, SpatialRGPT can accurately perceive their relative directions and distances. Additionally, we propose SpatialRGBT-Bench, a benchmark with ground-truth 3D annotations encompassing indoor, outdoor, and simulated environments, for evaluating 3D spatial cognition in VLMs. Our results demonstrate that SpatialRGPT significantly enhances performance in spatial reasoning tasks, both with and without local region prompts. The model also exhibits strong generalization capabilities, effectively reasoning about complex spatial relations and functioning as a region-aware dense reward annotator for robotic tasks. Code, dataset, and benchmark are released at https://www.anjiecheng.me/SpatialRGPT

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.

Spatial intelligence spans a rich suite of abilities, including visualising and transforming shapes, mentally rotating objects, judging relational positions and containment, and estimating numerosity. However, it still remains a critical unresolved challenge for Multimodal Large Language Models (MLLMs).To fill this gap, we propose to treat Euclidean geometry problem-solving as a surrogate task. Specifically, we meticulously constructed a curated multimodal dataset, called Euclid30K, comprising approximately 30K plane and solid geometry problems. To enable the model to acquire and apply Euclidean principles from these geometry problems, we employed Group Relative Policy Optimization (GRPO) to finetune the Qwen2.5VL family and RoboBrain2.0 family, inspiring the models to identify shapes, count, and relate entities, and perform multi-step deductive reasoning using Euclidean principles. Our experiments demonstrate that the resulting models achieve substantial zero-shot gains across four spatial reasoning benchmarks (Super-CLEVR, Omni3DBench, VSI-Bench, and MindCube) without any task-specific adaptations. Notably, after training on the Euclid30K, the mean VSI-Bench accuracy of all evaluated models rose from 34.5% to 40.5%, improving by 5.5 percentage points. Among them, RoboBrain2.0-Euclid-7B achieves 49.6\% accuracy, surpassing the previous state-of-the-art model, Spatial-MLLM.To our knowledge, this is the first systematic study showing that geometry-centric fine-tuning can confer vision-language models with broadly transferable spatial skills. Code and Euclid30K dataset can be found in https://zgca-ai4edu.github.io/Euclids_Gift.

Not yet. We present SPACE, a benchmark that systematically evaluates spatial cognition in frontier models. Our benchmark builds on decades of research in cognitive science. It evaluates large-scale mapping abilities that are brought to bear when an organism traverses physical environments, smaller-scale reasoning about object shapes and layouts, and cognitive infrastructure such as spatial attention and memory. For many tasks, we instantiate parallel presentations via text and images, allowing us to benchmark both large language models and large multimodal models. Results suggest that contemporary frontier models fall short of the spatial intelligence of animals, performing near chance level on a number of classic tests of animal cognition.

Rapid growth of high-dimensional datasets in fields such as single-cell RNA sequencing and spatial genomics has led to unprecedented opportunities for scientific discovery, but it also presents unique computational and statistical challenges. Traditional methods struggle with geometry-aware data generation, interpolation along meaningful trajectories, and transporting populations via feasible paths. To address these issues, we introduce Geometry-Aware Generative Autoencoder (GAGA), a novel framework that combines extensible manifold learning with generative modeling. GAGA constructs a neural network embedding space that respects the intrinsic geometries discovered by manifold learning and learns a novel warped Riemannian metric on the data space. This warped metric is derived from both the points on the data manifold and negative samples off the manifold, allowing it to characterize a meaningful geometry across the entire latent space. Using this metric, GAGA can uniformly sample points on the manifold, generate points along geodesics, and interpolate between populations across the learned manifold using geodesic-guided flows. GAGA shows competitive performance in simulated and real-world datasets, including a 30% improvement over the state-of-the-art methods in single-cell population-level trajectory inference.

In recent years, researchers have increasingly been interested in how to enable Multimodal Large Language Models (MLLM) to possess spatial understanding and reasoning capabilities. However, most existing methods overlook the importance of the ability to continuously work in an ever-changing world, and lack the possibility of deployment on embodied systems in real-world environments. In this work, we introduce OnlineSI, a framework that can continuously improve its spatial understanding of its surroundings given a video stream. Our core idea is to maintain a finite spatial memory to retain past observations, ensuring the size of the spatial memory does not increase as the input accumulates. We further integrate 3D point cloud information with semantic information, helping MLLM to better locate and identify objects in the scene. To evaluate our method, we introduce the Fuzzy F_1-Score to mitigate ambiguity, and test our method on two representative datasets. Experiments demonstrate the effectiveness of our method, paving the way towards real-world embodied systems.

Accurately predicting gene expression from histopathology images offers a scalable and non-invasive approach to molecular profiling, with significant implications for precision medicine and computational pathology. However, existing methods often underutilize the cross-modal representation alignment between histopathology images and gene expression profiles across multiple representational levels, thereby limiting their prediction performance. To address this, we propose Gene-DML, a unified framework that structures latent space through Dual-pathway Multi-Level discrimination to enhance correspondence between morphological and transcriptional modalities. The multi-scale instance-level discrimination pathway aligns hierarchical histopathology representations extracted at local, neighbor, and global levels with gene expression profiles, capturing scale-aware morphological-transcriptional relationships. In parallel, the cross-level instance-group discrimination pathway enforces structural consistency between individual (image/gene) instances and modality-crossed (gene/image, respectively) groups, strengthening the alignment across modalities. By jointly modelling fine-grained and structural-level discrimination, Gene-DML is able to learn robust cross-modal representations, enhancing both predictive accuracy and generalization across diverse biological contexts. Extensive experiments on public spatial transcriptomics datasets demonstrate that Gene-DML achieves state-of-the-art performance in gene expression prediction. The code and checkpoints will be released soon.

Spatial reasoning is a fundamental aspect of human cognition, yet it remains a major challenge for contemporary vision-language models (VLMs). Prior work largely relied on synthetic or LLM-generated environments with limited task designs and puzzle-like setups, failing to capture the real-world complexity, visual noise, and diverse spatial relationships that VLMs encounter. To address this, we introduce SpatiaLab, a comprehensive benchmark for evaluating VLMs' spatial reasoning in realistic, unconstrained contexts. SpatiaLab comprises 1,400 visual question-answer pairs across six major categories: Relative Positioning, Depth & Occlusion, Orientation, Size & Scale, Spatial Navigation, and 3D Geometry, each with five subcategories, yielding 30 distinct task types. Each subcategory contains at least 25 questions, and each main category includes at least 200 questions, supporting both multiple-choice and open-ended evaluation. Experiments across diverse state-of-the-art VLMs, including open- and closed-source models, reasoning-focused, and specialized spatial reasoning models, reveal a substantial gap in spatial reasoning capabilities compared with humans. In the multiple-choice setup, InternVL3.5-72B achieves 54.93% accuracy versus 87.57% for humans. In the open-ended setting, all models show a performance drop of around 10-25%, with GPT-5-mini scoring highest at 40.93% versus 64.93% for humans. These results highlight key limitations in handling complex spatial relationships, depth perception, navigation, and 3D geometry. By providing a diverse, real-world evaluation framework, SpatiaLab exposes critical challenges and opportunities for advancing VLMs' spatial reasoning, offering a benchmark to guide future research toward robust, human-aligned spatial understanding. SpatiaLab is available at: https://spatialab-reasoning.github.io/.

Multimodal large language models (MLLMs) have shown remarkable capabilities across a broad range of tasks but their knowledge and abilities in the geographic and geospatial domains are yet to be explored, despite potential wide-ranging benefits to navigation, environmental research, urban development, and disaster response. We conduct a series of experiments exploring various vision capabilities of MLLMs within these domains, particularly focusing on the frontier model GPT-4V, and benchmark its performance against open-source counterparts. Our methodology involves challenging these models with a small-scale geographic benchmark consisting of a suite of visual tasks, testing their abilities across a spectrum of complexity. The analysis uncovers not only where such models excel, including instances where they outperform humans, but also where they falter, providing a balanced view of their capabilities in the geographic domain. To enable the comparison and evaluation of future models, our benchmark will be publicly released.

3D spatial understanding is essential in real-world applications such as robotics, autonomous vehicles, virtual reality, and medical imaging. Recently, Large Language Models (LLMs), having demonstrated remarkable success across various domains, have been leveraged to enhance 3D understanding tasks, showing potential to surpass traditional computer vision methods. In this survey, we present a comprehensive review of methods integrating LLMs with 3D spatial understanding. We propose a taxonomy that categorizes existing methods into three branches: image-based methods deriving 3D understanding from 2D visual data, point cloud-based methods working directly with 3D representations, and hybrid modality-based methods combining multiple data streams. We systematically review representative methods along these categories, covering data representations, architectural modifications, and training strategies that bridge textual and 3D modalities. Finally, we discuss current limitations, including dataset scarcity and computational challenges, while highlighting promising research directions in spatial perception, multi-modal fusion, and real-world applications.

Spatial intelligence refers to the ability to perceive, reason about, and describe objects and their relationships within three-dimensional environments, forming a foundation for embodied perception and scene understanding. 3D captioning aims to describe 3D scenes in natural language; however, it remains challenging due to the sparsity and irregularity of point clouds and, more critically, the weak grounding and limited out-of-distribution (OOD) generalization of existing captioners across drastically different environments, including indoor and outdoor 3D scenes. To address this challenge, we propose 3D CoCa v2, a generalizable 3D captioning framework that unifies contrastive vision-language learning with 3D caption generation and further improves robustness via test-time search (TTS) without updating the captioner parameters. 3D CoCa v2 builds on a frozen CLIP-based semantic prior, a spatially-aware 3D scene encoder for geometry, and a multimodal decoder jointly optimized with contrastive and captioning objectives, avoiding external detectors or handcrafted proposals. At inference, TTS produces diverse caption candidates and performs reward-guided selection using a compact scene summary. Experiments show improvements over 3D CoCa of +1.50 CIDEr@0.5IoU on ScanRefer and +1.61 CIDEr@0.5IoU on Nr3D, and +3.8 CIDEr@0.25 in zero-shot OOD evaluation on TOD3Cap. Code will be released at https://github.com/AIGeeksGroup/3DCoCav2.

Many proteins useful in modern medicine or bioengineering are challenging to make in the lab, fuse with other proteins in cells, or deliver to tissues in the body, because their sequences are too long. Shortening these sequences typically involves costly, time-consuming experimental campaigns. Ideally, we could instead use modern models of massive databases of sequences from nature to learn how to propose shrunken proteins that resemble sequences found in nature. Unfortunately, these models struggle to efficiently search the combinatorial space of all deletions, and are not trained with inductive biases to learn how to delete. To address this gap, we propose SCISOR, a novel discrete diffusion model that deletes letters from sequences to generate protein samples that resemble those found in nature. To do so, SCISOR trains a de-noiser to reverse a forward noising process that adds random insertions to natural sequences. As a generative model, SCISOR fits evolutionary sequence data competitively with previous large models. In evaluation, SCISOR achieves state-of-the-art predictions of the functional effects of deletions on ProteinGym. Finally, we use the SCISOR de-noiser to shrink long protein sequences, and show that its suggested deletions result in significantly more realistic proteins and more often preserve functional motifs than previous models of evolutionary sequences.

Understanding the 3D structures of protein multimers is crucial, as they play a vital role in regulating various cellular processes. It has been empirically confirmed that the multimer structure prediction~(MSP) can be well handled in a step-wise assembly fashion using provided dimer structures and predicted protein-protein interactions~(PPIs). However, due to the biological gap in the formation of dimers and larger multimers, directly applying PPI prediction techniques can often cause a poor generalization to the MSP task. To address this challenge, we aim to extend the PPI knowledge to multimers of different scales~(i.e., chain numbers). Specifically, we propose \textsc{PromptMSP}, a pre-training and Prompt tuning framework for Multimer Structure Prediction. First, we tailor the source and target tasks for effective PPI knowledge learning and efficient inference, respectively. We design PPI-inspired prompt learning to narrow the gaps of two task formats and generalize the PPI knowledge to multimers of different scales. We provide a meta-learning strategy to learn a reliable initialization of the prompt model, enabling our prompting framework to effectively adapt to limited data for large-scale multimers. Empirically, we achieve both significant accuracy (RMSD and TM-Score) and efficiency improvements compared to advanced MSP models. The code, data and checkpoints are released at https://github.com/zqgao22/PromptMSP.

Spatial intelligence is a critical component of embodied AI, promoting robots to understand and interact with their environments. While recent advances have enhanced the ability of VLMs to perceive object locations and positional relationships, they still lack the capability to precisely understand object orientations-a key requirement for tasks involving fine-grained manipulations. Addressing this limitation not only requires geometric reasoning but also an expressive and intuitive way to represent orientation. In this context, we propose that natural language offers a more flexible representation space than canonical frames, making it particularly suitable for instruction-following robotic systems. In this paper, we introduce the concept of semantic orientation, which defines object orientations using natural language in a reference-frame-free manner (e.g., the ''plug-in'' direction of a USB or the ''handle'' direction of a knife). To support this, we construct OrienText300K, a large-scale dataset of 3D models annotated with semantic orientations that link geometric understanding to functional semantics. By integrating semantic orientation into a VLM system, we enable robots to generate manipulation actions with both positional and orientational constraints. Extensive experiments in simulation and real world demonstrate that our approach significantly enhances robotic manipulation capabilities, e.g., 48.7% accuracy on Open6DOR and 74.9% accuracy on SIMPLER.

Worldwide Geo-localization aims to pinpoint the precise location of images taken anywhere on Earth. This task has considerable challenges due to immense variation in geographic landscapes. The image-to-image retrieval-based approaches fail to solve this problem on a global scale as it is not feasible to construct a large gallery of images covering the entire world. Instead, existing approaches divide the globe into discrete geographic cells, transforming the problem into a classification task. However, their performance is limited by the predefined classes and often results in inaccurate localizations when an image's location significantly deviates from its class center. To overcome these limitations, we propose GeoCLIP, a novel CLIP-inspired Image-to-GPS retrieval approach that enforces alignment between the image and its corresponding GPS locations. GeoCLIP's location encoder models the Earth as a continuous function by employing positional encoding through random Fourier features and constructing a hierarchical representation that captures information at varying resolutions to yield a semantically rich high-dimensional feature suitable to use even beyond geo-localization. To the best of our knowledge, this is the first work employing GPS encoding for geo-localization. We demonstrate the efficacy of our method via extensive experiments and ablations on benchmark datasets. We achieve competitive performance with just 20% of training data, highlighting its effectiveness even in limited-data settings. Furthermore, we qualitatively demonstrate geo-localization using a text query by leveraging CLIP backbone of our image encoder. The project webpage is available at: https://vicentevivan.github.io/GeoCLIP

Tandem mass spectrometry has played a pivotal role in advancing proteomics, enabling the analysis of protein composition in biological samples. Despite the development of various deep learning methods for identifying amino acid sequences (peptides) responsible for observed spectra, challenges persist in de novo peptide sequencing. Firstly, prior methods struggle to identify amino acids with post-translational modifications (PTMs) due to their lower frequency in training data compared to canonical amino acids, further resulting in decreased peptide-level identification precision. Secondly, diverse types of noise and missing peaks in mass spectra reduce the reliability of training data (peptide-spectrum matches, PSMs). To address these challenges, we propose AdaNovo, a novel framework that calculates conditional mutual information (CMI) between the spectrum and each amino acid/peptide, using CMI for adaptive model training. Extensive experiments demonstrate AdaNovo's state-of-the-art performance on a 9-species benchmark, where the peptides in the training set are almost completely disjoint from the peptides of the test sets. Moreover, AdaNovo excels in identifying amino acids with PTMs and exhibits robustness against data noise. The supplementary materials contain the official code.

Spatial understanding is essential for Multimodal Large Language Models (MLLMs) to support perception, reasoning, and planning in embodied environments. Despite recent progress, existing studies reveal that MLLMs still struggle with spatial understanding. However, existing research lacks a comprehensive and systematic evaluation of these limitations, often restricted to isolated scenarios, such as single-view or video. In this work, we present a systematic analysis of spatial understanding from both data and architectural perspectives across three representative scenarios: single-view, multi-view, and video. We propose a benchmark named MulSeT (Multi-view Spatial Understanding Tasks), and design a series of experiments to analyze the spatial reasoning capabilities of MLLMs. From the data perspective, the performance of spatial understanding converges quickly as the training data increases, and the upper bound is relatively low, especially for tasks that require spatial imagination. This indicates that merely expanding training data is insufficient to achieve satisfactory performance. From the architectural perspective, we find that spatial understanding relies more heavily on the positional encoding within the visual encoder than within the language model, in both cascaded and native MLLMs. Moreover, we explore reasoning injection and envision future improvements through architectural design to optimize spatial understanding. These insights shed light on the limitations of current MLLMs and suggest new directions for improving spatial reasoning capabilities through data scaling and architectural tuning.

The advances in Vision-Language models (VLMs) offer exciting opportunities for robotic applications involving image geo-localization, the problem of identifying the geo-coordinates of a place based on visual data only. Recent research works have focused on using a VLM as embeddings extractor for geo-localization, however, the most sophisticated VLMs may only be available as black boxes that are accessible through an API, and come with a number of limitations: there is no access to training data, model features and gradients; retraining is not possible; the number of predictions may be limited by the API; training on model outputs is often prohibited; and queries are open-ended. The utilization of a VLM as a stand-alone, zero-shot geo-localization system using a single text-based prompt is largely unexplored. To bridge this gap, this paper undertakes the first systematic study, to the best of our knowledge, to investigate the potential of some of the state-of-the-art VLMs as stand-alone, zero-shot geo-localization systems in a black-box setting with realistic constraints. We consider three main scenarios for this thorough investigation: a) fixed text-based prompt; b) semantically-equivalent text-based prompts; and c) semantically-equivalent query images. We also take into account the auto-regressive and probabilistic generation process of the VLMs when investigating their utility for geo-localization task by using model consistency as a metric in addition to traditional accuracy. Our work provides new insights in the capabilities of different VLMs for the above-mentioned scenarios.

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.

Language models now constitute essential tools for improving efficiency for many professional tasks such as writing, coding, or learning. For this reason, it is imperative to identify inherent biases. In the field of Natural Language Processing, five sources of bias are well-identified: data, annotation, representation, models, and research design. This study focuses on biases related to geographical knowledge. We explore the connection between geography and language models by highlighting their tendency to misrepresent spatial information, thus leading to distortions in the representation of geographical distances. This study introduces four indicators to assess these distortions, by comparing geographical and semantic distances. Experiments are conducted from these four indicators with ten widely used language models. Results underscore the critical necessity of inspecting and rectifying spatial biases in language models to ensure accurate and equitable representations.

The choice of representation for geographic location significantly impacts the accuracy of models for a broad range of geospatial tasks, including fine-grained species classification, population density estimation, and biome classification. Recent works like SatCLIP and GeoCLIP learn such representations by contrastively aligning geolocation with co-located images. While these methods work exceptionally well, in this paper, we posit that the current training strategies fail to fully capture the important visual features. We provide an information-theoretic perspective on why the resulting embeddings from these methods discard crucial visual information that is important for many downstream tasks. To solve this problem, we propose a novel retrieval-augmented strategy called RANGE. We build our method on the intuition that the visual features of a location can be estimated by combining the visual features from multiple similar-looking locations. We evaluate our method across a wide variety of tasks. Our results show that RANGE outperforms the existing state-of-the-art models with significant margins in most tasks. We show gains of up to 13.1% on classification tasks and 0.145 R^2 on regression tasks. All our code and models will be made available at: https://github.com/mvrl/RANGE.

Recent advances in LVLMs have improved vision-language understanding, but they still struggle with spatial perception, limiting their ability to reason about complex 3D scenes. Unlike previous approaches that incorporate 3D representations into models to improve spatial understanding, we aim to unlock the potential of VLMs by leveraging spatially relevant image data. To this end, we introduce a novel 2D spatial data generation and annotation pipeline built upon scene data with 3D ground-truth. This pipeline enables the creation of a diverse set of spatial tasks, ranging from basic perception tasks to more complex reasoning tasks. Leveraging this pipeline, we construct SPAR-7M, a large-scale dataset generated from thousands of scenes across multiple public datasets. In addition, we introduce SPAR-Bench, a benchmark designed to offer a more comprehensive evaluation of spatial capabilities compared to existing spatial benchmarks, supporting both single-view and multi-view inputs. Training on both SPAR-7M and large-scale 2D datasets enables our models to achieve state-of-the-art performance on 2D spatial benchmarks. Further fine-tuning on 3D task-specific datasets yields competitive results, underscoring the effectiveness of our dataset in enhancing spatial reasoning.

Vector data is one of the two core data structures in geographic information science (GIS), essential for accurately storing and representing geospatial information. Shapefile, the most widely used vector data format, has become the industry standard supported by all major geographic information systems. However, processing this data typically requires specialized GIS knowledge and skills, creating a barrier for researchers from other fields and impeding interdisciplinary research in spatial data analysis. Moreover, while large language models (LLMs) have made significant advancements in natural language processing and task automation, they still face challenges in handling the complex spatial and topological relationships inherent in GIS vector data. To address these challenges, we propose ShapefileGPT, an innovative framework powered by LLMs, specifically designed to automate Shapefile tasks. ShapefileGPT utilizes a multi-agent architecture, in which the planner agent is responsible for task decomposition and supervision, while the worker agent executes the tasks. We developed a specialized function library for handling Shapefiles and provided comprehensive API documentation, enabling the worker agent to operate Shapefiles efficiently through function calling. For evaluation, we developed a benchmark dataset based on authoritative textbooks, encompassing tasks in categories such as geometric operations and spatial queries. ShapefileGPT achieved a task success rate of 95.24%, outperforming the GPT series models. In comparison to traditional LLMs, ShapefileGPT effectively handles complex vector data analysis tasks, overcoming the limitations of traditional LLMs in spatial analysis. This breakthrough opens new pathways for advancing automation and intelligence in the GIS field, with significant potential in interdisciplinary data analysis and application contexts.

Spatial intelligence is essential for multimodal large language models (MLLMs) operating in the complex physical world. Existing benchmarks, however, probe only single-image relations and thus fail to assess the multi-image spatial reasoning that real-world deployments demand. We introduce MMSI-Bench, a VQA benchmark dedicated to multi-image spatial intelligence. Six 3D-vision researchers spent more than 300 hours meticulously crafting 1,000 challenging, unambiguous multiple-choice questions from over 120,000 images, each paired with carefully designed distractors and a step-by-step reasoning process. We conduct extensive experiments and thoroughly evaluate 34 open-source and proprietary MLLMs, observing a wide gap: the strongest open-source model attains roughly 30% accuracy and OpenAI's o3 reasoning model reaches 40%, while humans score 97%. These results underscore the challenging nature of MMSI-Bench and the substantial headroom for future research. Leveraging the annotated reasoning processes, we also provide an automated error analysis pipeline that diagnoses four dominant failure modes, including (1) grounding errors, (2) overlap-matching and scene-reconstruction errors, (3) situation-transformation reasoning errors, and (4) spatial-logic errors, offering valuable insights for advancing multi-image spatial intelligence. Project page: https://runsenxu.com/projects/MMSI_Bench .

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.

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.

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

Large Multimodal Models (LMMs) have achieved strong performance across a range of vision and language tasks. However, their spatial reasoning capabilities are under-investigated. In this paper, we construct a novel VQA dataset, Spatial-MM, to comprehensively study LMMs' spatial understanding and reasoning capabilities. Our analyses on object-relationship and multi-hop reasoning reveal several important findings. Firstly, bounding boxes and scene graphs, even synthetic ones, can significantly enhance LMMs' spatial reasoning. Secondly, LMMs struggle more with questions posed from the human perspective than the camera perspective about the image. Thirdly, chain of thought (CoT) prompting does not improve model performance on complex multi-hop questions involving spatial relations. % Moreover, spatial reasoning steps are much less accurate than non-spatial ones across MLLMs. Lastly, our perturbation analysis on GQA-spatial reveals that LMMs are much stronger at basic object detection than complex spatial reasoning. We believe our benchmark dataset and in-depth analyses can spark further research on LMMs spatial reasoning. Spatial-MM benchmark is available at: https://github.com/FatemehShiri/Spatial-MM

Controlling the COVID-19 pandemic largely hinges upon the existence of fast, safe, and highly-available diagnostic tools. Ultrasound, in contrast to CT or X-Ray, has many practical advantages and can serve as a globally-applicable first-line examination technique. We provide the largest publicly available lung ultrasound (US) dataset for COVID-19 consisting of 106 videos from three classes (COVID-19, bacterial pneumonia, and healthy controls); curated and approved by medical experts. On this dataset, we perform an in-depth study of the value of deep learning methods for differential diagnosis of COVID-19. We propose a frame-based convolutional neural network that correctly classifies COVID-19 US videos with a sensitivity of 0.98+-0.04 and a specificity of 0.91+-08 (frame-based sensitivity 0.93+-0.05, specificity 0.87+-0.07). We further employ class activation maps for the spatio-temporal localization of pulmonary biomarkers, which we subsequently validate for human-in-the-loop scenarios in a blindfolded study with medical experts. Aiming for scalability and robustness, we perform ablation studies comparing mobile-friendly, frame- and video-based architectures and show reliability of the best model by aleatoric and epistemic uncertainty estimates. We hope to pave the road for a community effort toward an accessible, efficient and interpretable screening method and we have started to work on a clinical validation of the proposed method. Data and code are publicly available.

Enhancing the spatial reasoning capabilities of Multi-modal Large Language Models (MLLMs) for video understanding is crucial yet challenging. We present Spatial-R1, a targeted approach involving two key contributions: the curation of SR, a new video spatial reasoning dataset from ScanNet with automatically generated QA pairs across seven task types, and the application of Task-Specific Group Relative Policy Optimization (GRPO) for fine-tuning. By training the Qwen2.5-VL-7B-Instruct model on SR using GRPO, Spatial-R1 significantly advances performance on the VSI-Bench benchmark, achieving a 7.4\% gain over the baseline and outperforming strong contemporary models. This work validates the effectiveness of specialized data curation and optimization techniques for improving complex spatial reasoning in video MLLMs.

In this paper, we present an integrated approach to real-time mosquito detection using our multiclass dataset (MosquitoFusion) containing 1204 diverse images and leverage cutting-edge technologies, specifically computer vision, to automate the identification of Mosquitoes, Swarms, and Breeding Sites. The pre-trained YOLOv8 model, trained on this dataset, achieved a mean Average Precision (mAP@50) of 57.1%, with precision at 73.4% and recall at 50.5%. The integration of Geographic Information Systems (GIS) further enriches the depth of our analysis, providing valuable insights into spatial patterns. The dataset and code are available at https://github.com/faiyazabdullah/MosquitoFusion.

This research is aimed to solve the tweet/user geolocation prediction task and provide a flexible methodology for the geotagging of textual big data. The suggested approach implements neural networks for natural language processing (NLP) to estimate the location as coordinate pairs (longitude, latitude) and two-dimensional Gaussian Mixture Models (GMMs). The scope of proposed models has been finetuned on a Twitter dataset using pretrained Bidirectional Encoder Representations from Transformers (BERT) as base models. Performance metrics show a median error of fewer than 30 km on a worldwide-level, and fewer than 15 km on the US-level datasets for the models trained and evaluated on text features of tweets' content and metadata context.

We report DynaCLR, a self-supervised method for embedding cell and organelle Dynamics via Contrastive Learning of Representations of time-lapse images. DynaCLR integrates single-cell tracking and time-aware contrastive sampling to learn robust, temporally regularized representations of cell dynamics. DynaCLR embeddings generalize effectively to in-distribution and out-of-distribution datasets, and can be used for several downstream tasks with sparse human annotations. We demonstrate efficient annotations of cell states with a human-in-the-loop using fluorescence and label-free imaging channels. DynaCLR method enables diverse downstream biological analyses: classification of cell division and infection, clustering heterogeneous cell migration patterns, cross-modal distillation of cell states from fluorescence to label-free channel, alignment of asynchronous cellular responses and broken cell tracks, and discovering organelle response due to infection. DynaCLR is a flexible method for comparative analyses of dynamic cellular responses to pharmacological, microbial, and genetic perturbations. We provide PyTorch-based implementations of the model training and inference pipeline (https://github.com/mehta-lab/viscy) and a GUI (https://github.com/czbiohub-sf/napari-iohub) for the visualization and annotation of trajectories of cells in the real space and the embedding space.

Single cell analysis of human skeletal muscle (SM) tissue cross-sections is a fundamental tool for understanding many neuromuscular disorders. For this analysis to be reliable and reproducible, identification of individual fibres within microscopy images (segmentation) of SM tissue should be automatic and precise. Biomedical scientists in this field currently rely on custom tools and general machine learning (ML) models, both followed by labour intensive and subjective manual interventions to fine-tune segmentation. We believe that fully automated, precise, reproducible segmentation is possible by training ML models. However, in this important biomedical domain, there are currently no good quality, publicly available annotated imaging datasets available for ML model training. In this paper we release NCL-SM: a high quality bioimaging dataset of 46 human SM tissue cross-sections from both healthy control subjects and from patients with genetically diagnosed muscle pathology. These images include > 50k manually segmented muscle fibres (myofibres). In addition we also curated high quality myofibre segmentations, annotating reasons for rejecting low quality myofibres and low quality regions in SM tissue images, making these annotations completely ready for downstream analysis. This, we believe, will pave the way for development of a fully automatic pipeline that identifies individual myofibres within images of tissue sections and, in particular, also classifies individual myofibres that are fit for further analysis.

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.

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

Recently, there has been great interest in learning how to best represent proteins, specifically with fixed-length embeddings. Deep learning has become a popular tool for protein representation learning as a model's hidden layers produce potentially useful vector embeddings. TAPE introduced a number of benchmark tasks and showed that semi-supervised learning, via pretraining language models on a large protein corpus, improved performance on downstream tasks. Two of the tasks (fluorescence prediction and stability prediction) involve learning fitness landscapes. In this paper, we show that CNN models trained solely using supervised learning both compete with and sometimes outperform the best models from TAPE that leverage expensive pretraining on large protein datasets. These CNN models are sufficiently simple and small that they can be trained using a Google Colab notebook. We also find for the fluorescence task that linear regression outperforms our models and the TAPE models. The benchmarking tasks proposed by TAPE are excellent measures of a model's ability to predict protein function and should be used going forward. However, we believe it is important to add baselines from simple models to put the performance of the semi-supervised models that have been reported so far into perspective.

PROTACs are a promising therapeutic modality that harnesses the cell's built-in degradation machinery to degrade specific proteins. Despite their potential, developing new PROTACs is challenging and requires significant domain expertise, time, and cost. Meanwhile, machine learning has transformed drug design and development. In this work, we present a strategy for curating open-source PROTAC data and an open-source deep learning tool for predicting the degradation activity of novel PROTAC molecules. The curated dataset incorporates important information such as pDC_{50}, D_{max}, E3 ligase type, POI amino acid sequence, and experimental cell type. Our model architecture leverages learned embeddings from pretrained machine learning models, in particular for encoding protein sequences and cell type information. We assessed the quality of the curated data and the generalization ability of our model architecture against new PROTACs and targets via three tailored studies, which we recommend other researchers to use in evaluating their degradation activity models. In each study, three models predict protein degradation in a majority vote setting, reaching a top test accuracy of 82.6% and 0.848 ROC AUC, and a test accuracy of 61% and 0.615 ROC AUC when generalizing to novel protein targets. Our results are not only comparable to state-of-the-art models for protein degradation prediction, but also part of an open-source implementation which is easily reproducible and less computationally complex than existing approaches.

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