Single-cell light microscopy images have become an important data source for characterizing cell phenotypes, but their complexity and heterogeneity pose challenges to high-throughput automated analysis. Existing representation learning methods mostly rely on task-oriented modeling, which is limited by specific datasets and predefined tasks, making them difficult to generalize across different cell types and microscopy modalities, and experimental conditions. Although general-purpose methods have improved the generalization ability of image representation in recent years, their limited utilization of experimental background and biological context information still poses challenges in complex phenotypic analysis. Here, we propose scMIR, a vision-language foundation model for single-cell light microscopy image representation. By synergistically combining self-supervised image reconstruction with text-guided cross-modal alignment, scMIR can simultaneously encode morphological and biological semantic information in a unified representation space. scMIR is pre-trained on 207,957 image-text pairs, covering various cell types, microscopy modalities, and perturbation conditions. scMIR outperforms existing general models and task-oriented methods as systematically evaluated on various complex tasks using 16 benchmark datasets, including cell classification, clustering, phenotype inference, and batch effect correction tasks. Furthermore, scMIR shows a strong generalization ability across various tasks without requiring task-specific fine-tuning. With its unique advantages, we envision scMIR may promote the standardization and automation of high-throughput phenotyping workflows through supporting various downstream analysis tasks.
Jueqi Wang, Zachary Jacokes, John Darrell Van Horn +3cs.LG
The interaction between brain structure and genetic influences is key to understanding neuropsychiatric disorders. However, most large-scale datasets are unimodal, providing either neuroimaging or genetics data. We propose CALM, a framework that learns interpretable associations between brain ROIs and genetic pathways from completely disjoint populations. CALM aligns the two modalities in a shared latent space via linear projections that simultaneously match the class-conditional latent distributions and ensure group separability. These projections provide interpretable pathway--ROI associations. When trained on unimodal imaging and genetics datasets, CALM generalizes to an unseen paired dataset, outperforming several state-of-the-art methods and ablation baselines. We also demonstrate stability of the learned associations against a paired baseline. Our experiments on autism spectrum disorder reveal immune and metabolic pathways linked to specific cortical regions and are consistent with established literature. Thus, CALM opens the door to leveraging large unimodal repositories for studying cross-modal interactions in brain disorders across disparate datasets.
Language-guided Medical Image Segmentation (LMIS) has shown great potential to improve the delineation of anatomical structures and lesions by integrating clinical textual information. Existing methods generally rely on either implicit interaction between textual and visual features or auxiliary coarse-grained supervision for cross-modal alignment. However, these methods lack explicit and fine-grained constraints to ensure semantic consistency, causing a mismatch between language and the segmentation outputs. To address this issue, we propose Text-as-Illumination Retinex Network (TIRNet), a novel Retinex-inspired framework that treats text embeddings as semantic illumination for feature modulation, thereby improving semantic consistency in LMIS. TIRNet introduces two key blocks integrated at each decoder stage: (1) the Retinex-inspired Text Modulation Block (RTMB), which employs positive and negative illumination maps to enhance text-relevant foreground features and suppress background interference; and (2) the Consistent Detail Compensation Block (CDCB), which selectively recovers high-frequency details via a consistency-gated mechanism conditioned on illumination reliability. Furthermore, we propose a Multi-Scale Illumination Supervision Loss (MSIS-Loss), comprising a Region-Grounded Contrastive Loss (RGC-Loss) that enforces cross-modal similarity to be concentrated in text-relevant foreground regions and suppressed in background regions, and a Background Suppression Loss (BS-Loss) that provides pixel-level supervision for negative illumination maps, jointly ensuring a precise cross-modal alignment at each decoder stage. Extensive experiments on the MosMedData+ and QaTa-COV19 datasets demonstrate that TIRNet achieves state-of-the-art performance in LMIS. The code is available at: https://github.com/anaanaa/TIRNet.
Pretrained biological language models expose per-token probability distributions through masked-token prediction, providing the likelihood interface central to sequence design, variant scoring, and mechanistic interpretation. Yet these distributions are learned from broad unlabeled corpora and are not naturally conditioned on task-specific biological contexts such as interaction partners, cellular environments, or therapeutic interventions. Existing contextual matching methods often distort this interface through pooled embeddings, contrastive latent spaces, or task-specific prediction heads. We introduce LOGICA (Logit-space Contrastive Alignment), a framework for context-conditioned prediction that performs contrastive learning directly in output-logit space. Using gated cross-modal adapters compatible with each model's native token head, LOGICA preserves the pretrained likelihood interface and converts contextualized token log-likelihoods into matching scores. Alignment is defined through context-sensitive token probabilities rather than proximity in a shared embedding space, enabling learning from sparse paired data across models with distinct vocabularies, without a shared tokenizer or decoder. LOGICA is particularly effective for mutation-local variant ranking, where comparisons reduce to context-conditioned likelihoods of mutant tokens at perturbed sites. Across protein--ligand binding, TCR--peptide activity, and drug-conditioned resistance prediction, LOGICA improves over prior state-of-the-art methods, including matched latent-contrastive and conditional MLM baselines, while retaining a token-level interface for interpretation and generation. On held-out-gene single-mutation drug-resistance prediction, LOGICA improves AUC from near-random latent-space baselines of $\sim$0.55 to $\sim$0.65.
Clustering is fundamental to scRNA-seq analysis, serving as a cornerstone for identifying cell populations and resolving tissue heterogeneity. However, existing methods focus on mining numerical statistical patterns, suffering from semantic agnosticism by neglecting the intrinsic biological functions encoded by genes. While Large Language Models (LLMs) offer promising semantic capabilities, their direct adaptation to cell clustering is hindered by the structural mismatch between generative pre-training objectives and discriminative downstream tasks. To bridge this gap, we propose scLLM-DSC, a novel LLM-Knowledge Enhanced Cross-Modal Deep Structural Clustering framework. Diverging from data-driven paradigms, scLLM-DSC establishes a semantically-grounded representation by synergizing two views: a Knowledge-Driven Semantic View derived from NCBI gene priors and contextualized Cell2Sentence embeddings, and a Structure-Aware Topological View extracted via a graph-guided encoder. Crucially, we introduce a cross-modal contrastive alignment mechanism to enforce consistency between biological semantics and transcriptomic features within a unified latent space. Extensive benchmarks demonstrate that scLLM-DSC significantly outperforms eleven state-of-the-art baselines in clustering accuracy.
Radiology report generation (RRG) has emerged as a promising approach to alleviate radiologists' workload and reduce human errors by automatically generating diagnostic reports from medical images. A key challenge in RRG is achieving fine-grained alignment between complex visual features and the hierarchical structure of long-form radiology reports. Although recent methods have improved image-text representation learning, they often treat reports as flat sequences, overlooking their structured sections and semantic hierarchies. This simplification hinders precise cross-modal alignment and weakens RRG accuracy. To address this challenge, we propose RIHA (Report-Image Hierarchical Alignment Transformer), a novel end-to-end framework that performs multi-level alignment between radiological images and their corresponding reports across paragraph, sentence, and word levels. This hierarchical alignment enables more precise cross-modal mapping, essential for capturing the nuanced semantics embedded in clinical narratives. Specifically, RIHA introduces a Visual Feature Pyramid (VFP) to extract multi-scale visual features and a Text Feature Pyramid (TFP) to represent multi-granularity textual structures. These components are integrated through a Cross-modal Hierarchical Alignment (CHA) module, leveraging optimal transport to effectively align visual and textual features across various levels. Furthermore, we incorporate Relative Positional Encoding (RPE) into the decoder to model spatial and semantic relationships among tokens, enhancing the token-level alignment between visual features and generated text. Extensive experiments on two benchmark chest X-ray datasets, IU-Xray and MIMIC-CXR, demonstrate that RIHA outperforms existing state-of-the-art models in both natural language generation and clinical efficacy metrics.
Brain encoding models not only serve to decipher how visual stimuli are transformed into neural responses, but also represent a critical step toward visual prostheses that restore vision for patients with severe vision disorders. Brain encoding involves two fundamental steps: achieving faithful reconstruction of neural responses and establishing cross-modal alignment between visual stimuli and neural responses. To this end, we propose ViBE, a novel brain encoding framework for generating magnetoencephalography (MEG) and electroencephalography (EEG) signals from visual stimuli. Specifically, we first design a spatio-temporal convolutional variational autoencoder (TSC-VAE) that captures the spatio-temporal characteristics of M/EEG signals for effective neural response reconstruction. To bridge the modality gap between visual features and neural representations, we employ Q-Former to map CLIP image embeddings to the TSC-VAE latent space, producing neural proxy embeddings. For comprehensive cross-modal alignment, we combine mean squared error (MSE) loss for point-wise feature matching with sliced Wasserstein distance (SWD) for probability distribution alignment between the neural proxy embeddings and TSC-VAE latent embeddings. We conduct extensive experiments on the THINGS-EEG2 and THINGS-MEG datasets, demonstrating the effectiveness of our approach in generating high-quality M/EEG signals from visual stimuli.