Inference from interaction maps, such as centromere identification from genome-wide chromosome conformation capture techniques -- notably Hi-C -- can be formulated as a generic inverse problem: infer a set of parameters given a map summarizing pairwise interactions between entities through blocks of variable numbers and sizes. In this work, we introduce a data-driven approach that leverages shared structure between these maps, such as global alignment between localized patterns, while handling the variability in number and size of entities arising in real-world data. Our approach relies on a transformer architecture capable of handling such variability and a custom simulator to generate abundant, yet computationally cheap synthetic data for training. Applied to the problem of centromere localization, the method accurately recovers their genomic positions across a wide range of species of various genome sizes.
Motivation: Interpretability is not optional in biology: understanding gene regulation requires models whose learned structure can be directly interrogated, not merely accurate predictors whose internals resist mapping onto regulatory relationships. We ask whether an architecture mirroring the central dogma yields attention and gradient maps that recover known regulatory elements and networks in inspectable form. Results: Central Dogma Transformer II (CDT-II) mirrors the central dogma in its architecture -- DNA self-attention, RNA self-attention, and DNA-to-RNA cross-attention -- requiring only genomic embeddings and raw per-cell expression. On K562 CRISPR interference (CRISPRi) data with five genes held out entirely, CDT-II predicts perturbation effects (per-gene mean r = 0.84), recovers the GFI1B regulatory network (6.6-fold enrichment, P = 3.5 x 10^-17), and concentrates cross-attention on ENCODE regulatory elements including CTCF sites (mean 7.67x across 28 target genes, P < 0.001). Gradient attribution predicts consequences of perturbing therapeutic targets (mean r = 0.82). For TFRC, target of the anti-TfR1 antibody PPMX-T003, it identifies erythrocyte-structure, iron-dependent DNA-synthesis and oxidative-stress genes, matching anemia and ferroptosis reported clinically and preclinically -- without clinical data as input. CDT-II acts as an AI microscope, surfacing clinically relevant regulatory structure from perturbation experiments alone. Availability: Source code is available at https://github.com/nobusama/CDT2. Pre-computed embeddings, training data, and model weights are available at https://huggingface.co/datasets/nobusama17/CDT2-data.
Learning the dynamics of a process given sampled observations at several time points is an important but difficult task in many scientific applications. When no ground-truth trajectories are available, but one has only snapshots of data taken at discrete time steps, the problem of modelling the dynamics, and thus inferring the underlying trajectories, can be solved by multi-marginal generalisations of flow matching algorithms. This paper proposes a novel flow matching method that overcomes the limitations of existing multi-marginal trajectory inference algorithms. Our proposed method, ALI-CFM, uses a GAN-inspired adversarial loss to fit neurally parametrised interpolant curves between source and target points such that the marginal distributions at intermediate time points are close to the observed distributions. The resulting interpolants are smooth trajectories that, as we show, are unique under mild assumptions. These interpolants are subsequently marginalised by a flow matching algorithm, yielding a trained vector field for the underlying dynamics. We showcase the versatility and scalability of our method by outperforming the existing baselines on spatial transcriptomics and cell tracking datasets, while performing on par with them on single-cell trajectory prediction. Code: https://github.com/mmacosha/adversarially-learned-interpolants.
Oskar Kviman, Kirill Tamogashev, Nicola Branchini +3
Reconstructing lineages from live-imaging microscopy requires linking cell detections across time, including through cell divisions. A common approach is to construct a candidate graph and associate cell segmentations (nodes) across frames. However, these and other existing methods overlook two structural obstacles in candidate tracking graphs: (i) cell divisions entangle distinct lineage paths in the node embedding space, and (ii) edges sharing a node have near-random label agreement, so the candidate-graph topology carries no useful information for graph neural networks to aggregate. We propose the \textbf{Higher-Order Cell Tracking Transformer} (HOCT), an edge-centric architecture in which candidate cell links attend to one another under a 3D geometric prior, resolving both issues. Evaluated on the Cell Tracking Challenge and a bacteria division benchmark, HOCT achieves state-of-the-art results without deep pre-trained image encoders. Moreover, the proposed approach is easier to fine-tune, quickly reducing tracking errors by 59% with 400 annotations in a human-in-the-loop setting, outperforming LoRA fine-tuning of competing transformer baselines (6.75% improvement).