bioinformatics teams

Abstract: Existing feature attribution methods that account for feature dependencies do not scale to high dimensions. We propose causal integrated gradients (CIG) and causal expected gradients (CEG), which extend integrated gradients to incorporate prior causal structure among input features while retaining its computational efficiency and, under conditions on the causal graph, its axiomatic guarantees. In many settings, some causal structure between features is already known, for example, that a transcription factor causally regulates a target gene's expression. Yet existing gradient-based methods cannot exploit this structure, instead crediting a feature's downstream effects over its true upstream cause, such as ranking the target gene above the transcription factor that regulates it. Our key idea is to embed this causal structure by routing the integration path along the causal graph. The method thereby decomposes each feature's attribution into a direct effect and effects mediated through its causal descendants. We evaluate CIG in three settings of increasing realism. First, on a synthetic benchmark with a known causal model, CIG's attributions best match the ground-truth causal effect from Pearl's do-calculus, matching the accuracy of causal Shapley values at a fraction of the computational cost. Second, on simulated single-cell gene expression data with a known gene regulatory network (Dyngen), CIG most accurately recovers the transcription factors driving the simulation. Third, on real interferon-$β$ stimulation data, where only an approximate causal graph is available, CIG better prioritizes the transcription factors driving the measured response than DeepSHAP and integrated gradients. Together, these results show that incorporating causal structure into gradient-based attributions recovers upstream drivers that existing methods miss, without sacrificing scalability.

Abstract: Recursive self-improvement (RSI) in scientific research aims to improve agents' research capabilities through their own experimental experience. Scientific agent swarms can combine evidence and implementations from different research directions to guide their agents' subsequent experiments. However, poor experimental results can leave unclear whether to revise a hypothesis or its implementation, while overall program scores can hide components useful to other agents. To address these challenges, we introduce SwarmRSI, a framework that evolves scientific agent swarms for recursive self-improvement. We devise Feedback-Guided Swarm Mutation to refine hypotheses and their implementations using experimental feedback from other agents. We also propose Complementary Swarm Recombination to reuse retained hypotheses and complementary program components across agents, allowing partial results to support new research. Recursive Swarm Evolution integrates both mechanisms into a feedback loop, using new experimental evidence to guide subsequent research. Experiments on OpenProblems, NatureBench and MLE-Bench Lite demonstrate SwarmRSI's state-of-the-art (SOTA) performance. Further evaluations show that accumulated research experience improves performance on held-out tasks. Biologists also reproduce its programs for follow-up biological analyses.

Abstract: Conditional generative models are increasingly used for scientific prediction beyond the direct training support. Yet scientific questions often concern whether one intervention changes the effect of another. Such interactions can be of primary interest while explaining little of the total variation, allowing models to appear accurate overall without recovering the relevant scientific effect. It remains unclear how these models learn interactions and when these successfully extrapolate to unseen conditions. We therefore study interaction recovery in flow-matching models using a physiological time-series simulator, drug dose-response data, combinatorial cell perturbations, and molecular conformer generations, where we separate recovery from hallucinated interaction structure. In the controlled setting, individual effects are learned much earlier than interactions and models hallucinate interactions where none exist. Across settings, we find qualitatively different generalization problems, with successful prediction depending on whether condition structure continues from observed to held-out targets. When it does, interactions are recoverable. If not, models can generate plausible responses while missing the interaction. We furthermore find that hallucinations increase as targets become less identifiable, and that successful interaction recovery in output space can fail under nonlinear readouts. Finally, we show that aggregate fidelity metrics can conceal whether models learn and extrapolate interactions.

Abstract: Single-cell RNA sequencing (scRNA-seq) enables cell-level analysis of biological heterogeneity, but learning effective representations from high-dimensional, unordered gene expression profiles remains challenging. Gene Expression-to-Image (GE2I) offers an effective learning strategy by arranging gene values on pixel grids for convolutional neural networks, but its underlying mechanisms remain unclear. We study GE2I on full-transcriptome data while keeping the network and training procedure fixed. Our results reveal a trade-off between spatial smoothness and gene-level fidelity. Structured mappings produce smooth, low-frequency patterns that support faster early optimization, whereas assigning multiple genes to the same pixel obscures expression differences and can reduce predictive performance. This trade-off explains why random mappings can compete with structured layouts when many genes are represented. One-to-one gene-to-pixel assignment improves prediction across the tested visual backbones even when image smoothness decreases. We further find that the benefits of pretraining and augmentation depend on the backbone and mapping. These findings provide practical guidance for pixel allocation and the transfer of vision priors to gene expression data.

Abstract: Unsupervised clustering is widely used to discover underlying group structure, after which researchers often seek to validate these groups via post-hoc hypothesis testing on the population means. However, using the same data both to form clusters and to test for a difference in means inflates the Type I error rate. Recent work in selective inference has proposed solutions when the underlying data are drawn from a multivariate Gaussian distribution with a known covariance matrix or an unknown isotropic covariance matrix. We propose a new selective test for the difference in means between two clusters that provably controls the Type I error rate under an arbitrary unknown covariance matrix. Our test statistic does not require estimating the feature covariance matrix; instead, it leverages a Monte Carlo sampling procedure over the set of orthogonal matrices. We show that this new selective test can be computed efficiently, and we derive closed-form solutions when clusters are formed using k-means or hierarchical clustering. In simulations, we demonstrate that our proposed p-value controls the selective Type I error rate and achieves substantial power, and we illustrate its application on gene expression and drug review data sets.

Abstract: We propose an anomaly detection method for high-dimensional mixed-type data that maps heterogeneous features to a common scale via standardized moment-based transformations, yielding interpretable feature-level anomaly scores. These scores are combined through a dependence-aware aggregation step to construct the Mixed-data Influence (MDI) score, accounting for correlations across features and providing a unified measure of how strongly an observation departs from the reference data distribution. By incorporating higher-order moments, the MDI can detect anomalies that arise not only from location shifts, but also from changes in variability, skewness, and other distributional characteristics. The aggregation mechanism allows our method to capture both sparse anomalies concentrated in a small number of features and weak, coordinated deviations distributed across many features. We empirically investigate the distribution and thresholding behavior of the MDI score across different sample sizes, dimensions, dependence structures, and data types. Simulation experiments and two real-data applications, to multi-omics and ESG data, evaluate finite-sample calibration, detection performance, and feature-level interpretability.

Abstract: Spatial transcriptomics jointly captures molecular state, tissue morphology, and spatial organization, yet spatial-domain methods are typically compared only at late training checkpoints, obscuring differences in convergence efficiency. We introduce MP-MNCA, a morphology-prior masked neighbor cross-attention framework that preserves the full 3,000 dimensional highly-variable-gene representation while selectively routing molecular information across spatial neighbors, with histological similarity incorporated as a continuous attention prior under a self-supervised masked neighbor-contrastive objective. Across 12 heterogeneous human dorsolateral prefrontal cortex (DLPFC) sections, MP-MNCA is evaluated against established spatial-domain baselines using both convergence trajectories and epoch-wise spatial-domain visualizations. Our results show that MP-MNCA (i) reaches coherent spatial-domain structure in substantially fewer training epochs, as reflected quantitatively by convergence curves and qualitatively by progressive spatial grids, and (ii) maintains strong clustering quality, achieving a mean peak refined ARI of 0.546 versus 0.549 for the strongest baseline (STAIG), while attaining the highest mean refined NMI of 0.657 versus 0.640. Moreover, MP-MNCA outperforms STAIG on 7 of 12 sections in ARI and 11 of 12 in NMI, demonstrating faster convergence without sacrificing spatial-domain quality.

Abstract: Recursive synthetic-data training can degrade a fitted model, but its effects on the variable-screening stage that precedes model fitting are less understood. When each generation labels data for the next, a marginal screener ranks variables against the current pseudo-label target rather than the original response. Across generations, this target drift can erode or reverse the active--inactive score margin and cause screening to discard variables that clean-label screening would retain. We call this process \emph{screening collapse}. In a Gaussian linear model with minimum-norm recursive generators, we establish finite-sample screening bounds, characterize a late-generation information-loss limit, and derive a minimax impossibility result. Screening collapse can precede and compound ordinary model collapse: omitted variables incur a covariance-weighted loss that no refit restricted to the selected variables can eliminate, while recursive labels further degrade estimation on the retained variables. We also examine two approaches to mitigating screening collapse. Fixed-fraction real-label retention preserves a clean-label component but leaves resolution fixed, whereas data accumulation can avoid screening collapse if the pooled target preserves a positive margin and the growing sample resolves it. Numerical experiments on gene-expression data support the theoretical findings.

Abstract: To evaluate whether a compact bidirectional state-space autoencoder improves joint classification of species, cell type, and disease state from single-nucleus RNA-sequencing profiles in heart failure (HF), while yielding interpretable gene attributions. Building on the dense denoising autoencoder (DAE) and MLP framework of Ruz Jurado et al., we developed scHFBiMamba, combining a bidirectional Mamba autoencoder (BiMambaAE) with an MLP head. BiMambaAE maps 16,545-gene profiles to 350-dimensional latent representations using 13.2M parameters, about 14.6-fold fewer than the dense DAE (192.9M). We compared six encoder-classifier configurations on 38,275 held-out cardiac nuclei using McNemar tests with Benjamini-Hochberg correction, and assessed nine classifiers on frozen representations. Biological relevance was evaluated by comparing SHAP-derived differentially explained genes with differentially expressed genes against curated HF-related Gene Ontology keywords. BiMambaAE+MLP achieved the highest aggregate F1: pooled macro-F1 across 13 outputs was 0.966 versus 0.957 for DAE+MLP, and the mean category macro-F1 was 0.977 versus 0.970. It significantly improved cell-type and disease-state accuracy (adjusted p=7.1e-3 and p=4.8e-6, respectively), with species F1 of 1.000. SHAP-derived differentially explained genes achieved a pathway-enrichment benchmark F1 of 0.105 versus 0.053 for differentially expressed genes. Compact bidirectional state-space autoencoders can outperform substantially larger dense autoencoders for joint cardiac transcriptomic classification while reducing parameters. scHFBiMamba enables accurate multi-task prediction and hypothesis-generating gene-level interpretation. Code: https://github.com/UgoLomoio/scHFBiMamba.

Abstract: While contrastive learning is widely used to learn deterministic representations, it does not inherently provide estimates of uncertainty. Post-hoc uncertainty estimation methods, such as the Linearized Laplace approximation (LLA), offer a way to quantify uncertainty without retraining the encoder. However, we show that directly using the LLA induced distribution over the contrastive embedding does not yield reliable pointwise uncertainty estimates for downstream tasks: embedding variance alone does not reflect whether decisions such as nearest-neighbor retrieval or cluster assignment are stable. To address this limitation, we develop a post-hoc framework based on LLA that propagates encoder uncertainty through the downstream task. We characterize the curvature of contrastive objectives and introduce positive-semidefinite repairs where needed to obtain valid local Gaussian approximations without retraining the encoder. We test the proposed approach in metagenomic binning and image classification tasks. For metagenomic binning, posterior coassignment probabilities support consensus partitions and the selection of reliable cores, leading to improvements over existing baselines. Additional image classification experiments show calibration improvements on standard benchmarks and real histopathology datasets.

Abstract: Optimal transport (OT) is widely used to align distributions and transfer labels between unpaired source and target data, but source-target composition shifts can cause rare classes to be systematically under-predicted even with high transport confidence. We identify a source of this failure in the transport marginal: under the standard uniform weighting of source points, each class has transport capacity proportional to its source frequency, which can be insufficient to meet its target demand even when separated well in the embedding space. We show that displaced mass is preferentially absorbed by high-capacity classes rather than geometrically similar classes, producing confident errors that are difficult to detect from the transport plan. Downstream read-outs, entropic smoothing, and marginal relaxation provide limited recovery, whereas matching the transport marginal to the target composition substantially improves label transfer. On single-cell data, the oracle composition-matched marginal raises macro-F1 from 0.322 to 0.623, and the best deployable estimator closes 69% of the oracle gap. Correcting the marginal also separates a coverage-dependent component of error from residual error associated with class separability, showing that transport capacity and representation geometry are distinct sources of transfer error.

Abstract: Learning how local perturbations affect a network is important for identifying which components drive or absorb a system's response. We formulate this as seed-conditioned response ranking: given a perturbation at one seed node, ranking all other nodes by response strength. This is challenging when the model is given only the interaction topology, while the mechanism governing how perturbations propagate must be learned from data. We present VQIL (Visible Quantum Interference Learning), a trainable Szegedy quantum walk for seed-conditioned ranking. Edge weights, link phases, and per-node phase rotations are optimized end-to-end by backpropagation while the walk operator remains unitary throughout training. Node scores are obtained from a geometrically discounted coherent sum of quantum-walk amplitudes, enabling quantum interference before the final squared-norm readout. Because each learned parameter is attached to a named edge or node, the trained model provides directly inspectable hypotheses about the roles of individual graph components in the propagation mechanism. On AC power-flow perturbations over six transmission grids, with electrical parameters withheld from the model, VQIL improves Spearman rank correlation from 0.147 for the untrained walk to 0.831 and outperforms an identically trained random-walk model. On gene perturbation over five protein-protein interaction networks with Perturb-seq supervision, VQIL improves rank correlation from 0.171 to 0.620, outperforming the strongest learned classical and neural baselines. These results show that trainable quantum-walk interference provides a scalable and interpretable inductive bias for learning seed-conditioned response rankings on graphs.

Abstract: Querying distributed data represented as Knowledge Graphs (KGs) via SPARQL remains a difficult task, requiring fluency in query syntax, endpoint specifications, and schema details. Knowledge Graph Question Answering (KGQA) systems address this by automatically translating natural language into SPARQL, and recent advances in Large Language Models (LLMs) have made this translation increasingly feasible. In this paper, we describe SPARQL-LLM, our open-source KGQA system, in the context of the TEXT2SPARQL 2026 challenge. In this challenge, SPARQL-LLM ranks first overall among eight competing approaches across all datasets, achieving up to 59% higher accuracy than the second-best approach and supporting multilingual question answering in English, German, and Spanish. SPARQL-LLM is publicly released at https://github.com/sib-swiss/sparql-llm and deployed in production over decentralized bioinformatics KGs at https://www.expasy.org/chat.

Abstract: Biological function in RNA is encoded across scales, from local sequence motifs to long-range structural dependencies. Conventional RNA foundation models couple parameter capacity and inference depth within a fixed architecture, prescribing a fixed computation graph for each inference. Here we present Eco-RNA, an 80M-parameter RNA foundation model that makes inference depth adjustable through learned iterative refinement. Its shared, input-conditioned Transformer core refines sequence representations through repeated application. The iteration count is selected after training and controls effective depth at fixed model parameters. We train across recurrent depths with masked reconstruction, state regularization, and a one-sided loss that anchors deeper reconstruction to a shallow reference. On the 70-assay RNAGym fitness benchmark, increasing refinement from one to four iterations raises aggregate absolute Spearman correlation from 0.242 to 0.286, with the gain retained through eight iterations. At four iterations, Eco-RNA surpasses the current SOTA Evo 2 40B on all three aggregate fitness metrics despite 500x fewer parameters. Its iteration configurations advance the compute-performance Pareto frontier among the evaluated models. It also outperforms the evaluated baselines in non-coding RNA family classification, RNA secondary-structure prediction, and chemical probing profile prediction. These results establish internal inference computation as an effective scaling dimension for RNA foundation models.

Abstract: Processing a long sequence does not guarantee that distant information remains usable. As context grows, a fixed-size memory must retain many associations, connect information across positions, and preserve relevant structure without being overwhelmed by everything it observes. These are distinct requirements: a memory may store more information without representing the relationships needed for retrieval, and it may transport those relationships without preserving the ones that matter. Thus, the challenge is not simply extending context length, but constructing a memory that remains usable as context grows. We study this problem in large-chunk test-time training (TTT) and identify two basic failures: single-step writes accumulate interference, limiting capacity, while self-associative writes cannot form cross-position bindings. We introduce Double-Take (DT), which repairs these failures with multi-step unpinned updates and cross-position mixing, and adds bidirectional change-sensitive writes for selective retention. Capacity alone leaves end-to-end recall at the $0.10$ chance floor; adding binding raises it to $0.92$. Trained only on $32\,\mathrm{kb}$ genomic contexts, DT reaches $0.927$ AUROC at $131\,\mathrm{kb}$ and $0.856$ near $1\,\mathrm{Mb}$, while transferring zero-shot from human to mouse. Together, these results identify capacity, binding, and selectivity as three requirements for usable long-range memory.

Abstract: Archetypal Analysis (AA) represents observations as convex combinations of extremal data-driven profiles, yielding interpretable low-dimensional descriptions of complex datasets. Classical AA relies on a least-squares objective, which is poorly suited to discrete observations such as binary, count, and categorical data. We introduce an efficient likelihood-based framework for AA supporting Bernoulli, Poisson, and multinomial observation models. Our optimization scheme employs local quadratic approximations of the negative log-likelihood, enabling constrained updates through sequential minimal optimization (SMO) and an active-set method. Scalability is improved by bounding the active set while preserving simplex feasibility. We further introduce a cross-validated predictive likelihood criterion for selecting the number of archetypes, providing a principled alternative to reconstruction-error heuristics and stability-based diagnostics. Synthetic experiments demonstrate computational efficiency and accurate recovery of model complexity. Applications to single-cell RNA sequencing, microbiome composition, and somatic mutation data show that the learned archetypes capture interpretable domain-specific structures while achieving competitive likelihood fits and stable solutions. Overall, the proposed framework enables efficient likelihood-based archetypal analysis of discrete data, complemented by predictive likelihood-based model selection.

Abstract: Recursive feature machines (RFMs) learn representations of data by alternating between fitting a predictor to a dataset and updating features of that predictor using the average gradient outer product (AGOP). Connections between AGOPs and feature learning in neural networks motivate linear RFMs as a simple setting for analyzing how representations evolve during training. Here, we study the dynamics and statistics of linear RFM in noisy multi-output regression with isotropic sub-Gaussian input data and targets generated by a low-rank teacher matrix of dimension $d$. We extend the known connection between linear RFM and iteratively reweighted least squares from the interpolating setting to ridge-regularized multi-output regression with noise. We show that the learned feature matrix remains close to its infinite-data ideal counterpart at every iteration. Namely, for $n$ samples, we show the error in the feature matrix decays as $O(\sqrt{d/n})$ with high probability. Experiments on real-world text and single-cell gene-expression data illustrate the features learned by this simple linear model.

Abstract: The high cost of functional molecular assays, and prevalence of missing modalities and unmatched samples in computational biology, create significant barriers to comprehensive multi-omic profiling, essential for capturing and reasoning over molecules, cells, tissues, and organisms. This work proposes a model that learns meaningful representations from multi-omics cancer data supporting the reconstruction of missing and unpaired modalities. Contrary to increasingly complex, larger models, e.g. Foundation Models (FMs), ARO prioritizes practical applicability in limited or incomplete data settings. ARO optimally reconstructs missing modalities (MSE of $0.15$ on the validation and test data in the Unmasked settings), with its learned latent embeddings enabling a downstream cancer classification task. Our findings indicate that analyzing diverse molecular layers as a single integrated system offers a reliable and cost-efficient approach, reducing dependence on large-scale experimental testing, while still supporting multi-omic exploration in limited data settings.

Abstract: We introduce a novel invariance for peptide tandem mass spectrometry data, unlocking self-supervised representation learning that improves de novo sequencing of peptides. This invariance exploits the physical relationship between precursor properties (mass and charge) and fragment-ion evidence, without requiring peptide sequence labels. We introduce dIon, which adapts the DINO framework with two latent prediction tasks, both recovering a clean teacher representation: one from a spectrum mixture, using the precursor as a selection query, and one from a partial spectrum with the precursor withheld. The first associates precursor information with fragment-ion evidence; the second prevents representational collapse onto that information alone. Mechanistic probes support both effects, and ablations show that the full objective performs best. Under identical end-to-end training, dIon initialization improves de novo peptide precision over training from scratch by 5.5 and 8.4 percentage points on the held-out MassIVE-KB and Kingdoms test sets, and by 2.3 and 4.8 percentage points with a larger supervised training corpus. The resulting models surpass fully supervised state-of-the-art de novo sequencing models on the diverse, multi-species Kingdoms corpus under the same greedy-decoding protocol. Without peptide labels, dIon learns strong native peptide-similarity geometry compared with other learned models; with limited peptide-supervised adaptation, it achieves the best retrieval and pair-discrimination performance across all representation benchmarks.

Abstract: Discovery of causal relationships in high-dimensional Gene Regulatory Networks (GRN) is computationally challenging and often difficult to interpret due to dense connections. Therefore, grouping genes together into functional modules can improve tractability and biological interpretability. However, existing cluster level causal discovery methods assume access to a predefined admissible partitions, requiring the graph over clusters to be acyclic. Constructing such partitions is therefore challenging. In this work, we introduce GO-based Clustering for Causal Discovery (GO4CD), an algorithm that uses Gene Ontology (GO) to construct biologically meaningful gene partitions at multiple levels of granularity, while favoring those more likely to be admissible for causal discovery. GO4CD groups together genes participating in a shared biological process, and propagates gene annotations through the ontology hierarchy to achieve different granularity of partitions. Furthermore, we integrate GO4CD with Causal Learning over Clusters (CLOC) algorithm and evaluate recovery of true Markov equivalence class both with an oracle of conditional independencies and on simulated gene expression data using multivariate conditional independence tests. We evaluate GO4CD on multiple E.coli regulatory subnetworks and find that it is inadmissible in 18.1% of the cases, compared with 65.3-82.3% for the semantic-similarity baselines. Our results indicate that GO4CD is substantially better suited to learning causal GRNs defined over biologically meaningful gene clusters.

Abstract: Learning population dynamics from unpaired temporal marginals is an ill-posed inverse problem that requires structural assumptions on the underlying dynamics. We introduce $\textit{Discrete Action Matching}$ (DAM), a finite-state counterpart of Action Matching based on discrete Wasserstein geometry. For a prescribed marginal path and transport geometry, we derive an action-minimization objective for its canonical minimum-kinetic-energy current. Our key observation is that the density dependence of the discrete action reduces to neighboring density ratios. Along an empirical interpolation of the snapshots, DAM first estimates these ratios and then learns an action potential. The learned fields also define a graph-supported Markov sampler. Experiments on controlled synthetic dynamics and real mouse gastrulation data evaluate marginal reconstruction and interpolation. Additional experiments approximate numerical surface-transport paths from paired samples.

Abstract: Genomic language models can write synthetic DNA that carries no record of its origin. A generation-time watermark could provide a provenance signal, if a verifier can detect it using only the DNA sequence, a key, and published detector settings, without knowing where the generated region starts, which strand it lies on, or how it was divided into six-base tokens. We embed the SynthID tournament watermark in two genomic language models, Carbon and GENERator-v2. The verifier searches both strands, every start position, and four window lengths, and corrects its decision for the whole search. In a detection cohort of 1,544 held-out prompts, it found all 3,088 marked sequences per model, unedited and after one substituted, inserted, or deleted base. For ordinary sequences, the one-sided 95% upper confidence bound on the false-positive rate was at most 0.850%; one bound for the wrong-key control reached 1.015% (Carbon, after a deletion). In a development cohort, neither model showed a detectable change in likelihood or in predefined sequence measures. Under random edits placed without reference to the detector, detection stayed complete or nearly complete up to a 2% per-base edit rate. These results show statistical detection, not biological function, secret-key security, or robustness to an editor who sees the detector.

Abstract: Background: Rapid growth of high-throughput molecular data demands systems for efficient retrieval, integration, and scalability across omics layers. Traditional file-based workflows hinder cross-modal analysis and reproducibility because of fragmented storage and ad-hoc querying. Few existing tools for genomic variation data prioritize modular multi-omics integration. We developed vcf2db, a sample-centric relational framework modeling each omics modality as a distinct but linkable component centered on biological samples. This study evaluates whether this design delivers competitive genomic retrieval while enabling extension to additional molecular layers. Results: We implemented a proof-of-concept genomic schema and ingestion pipeline for annotated VCF data using the European subset of the 1000 Genomes Project (502 samples, 25 million variants). We benchmarked it against three established VCF-oriented tools on seven retrieval tasks: coordinate filtering, annotation-driven queries, genotype extraction, and aggregation. Under controlled conditions, vcf2db performed strongly on selective queries, often outperforming other systems for coordinate and annotation filters, and remained usable for genotype retrieval. Aggregation-heavy tasks were less efficient, indicating optimization targets. We also validated modular extensibility by adding a synthetic transcriptomic layer without modifying genomic tables, linking layers via shared sample identifiers. Conclusion: vcf2db supports cross-layer retrieval directly as SQL queries anchored on shared sample identifiers, enabling integrated multi-omics access that is difficult with file-based approaches.

Abstract: We give randomized algorithms for $3$-approximate edit distance in $\widetilde{\mathcal{O}}(N^{11/6})$ time for unweighted edit distance and in $\widetilde{\mathcal{O}}(N^{40/21})$ time for arbitrary metric edit weights, where $N$ is the total input length. For non-metric costs, we prove an unconditional $Ω(N^2)$ oracle-query lower bound for every approximation factor depending only on $N$, even for symmetric weights or weights satisfying the triangle inequality (but not both). Under the Orthogonal Vectors Hypothesis, we show a similar result for constant-size alphabets. This holds even for symmetric weights over a size-$3$ alphabet or triangle-inequality weights over a size-$2$ alphabet. In contrast, for symmetric weights over a binary alphabet we show an $\widetilde{\mathcal{O}}(N^{40/21})$-time $3$-approximation algorithm.

Abstract: Ribosome profiling (Ribo-seq) measures ribosome distributions along mRNAs, but observed occupancy profiles also contain experiment-specific distortions and stochastic variability. Consequently, models that accurately predict measured profiles may reproduce technical effects rather than recover the underlying biology. We ask whether jointly modeling datasets collected under different experimental conditions can reveal shared, sequence-dependent patterns of ribosome occupancy. We introduce RiboUnmix, a probabilistic multi-dataset framework in which each expected measured profile is represented as a shared sequence-dependent signal modulated by a dataset-specific multiplicative factor. A negative-binomial observation model captures variability across replicates. We evaluate RiboUnmix on a controlled synthetic benchmark combining programmed translation kinetics, ribosome traffic, stochastic count sampling, and sequence-dependent experimental distortions. Because the underlying kinetics and distortions are known, recovery of the shared profile and dataset-specific effects can be assessed separately. Both inferred components correlate strongly with their targets, demonstrating that RiboUnmix can disentangle shared kinetic patterns from experimental effects. Across four organism-specific real-data benchmarks, RiboUnmix outperforms sequence-to-profile baselines in predicting measured profiles. Models trained independently on subsets of 114 HEK-derived datasets recover concordant shared profiles for held-out transcripts, and experiments varying the number and composition of training datasets show that the learned representation remains stable. RiboUnmix thus converts variation across experiments into evidence for reproducible sequence-dependent patterns of ribosome occupancy, supporting biological hypothesis generation from diverse Ribo-seq datasets.

Abstract: Missing data are a fundamental challenge in statistical analysis and machine learning, as the choice of imputation method substantially impacts downstream inference. In this work, we propose two hybrid imputation methods called NuclearForest and SoftForest, which combine nuclear-norm-based low-rank initialization using Singular Value Thresholding (SVT) and SoftImpute, respectively, with a non-iterative Random Forest refinement. For the SVT-based component, we further introduce an adaptive step-size rule, prove adaptive step-size bounds, and establish convergence for the corresponding zero-initialized iteration. The low-rank initialization provides a structured warm start that captures the global covariance patterns in the data, while the subsequent Random Forest step recovers residual nonlinear signals encoding local dependencies. We conduct an extensive benchmark on diverse datasets from different application domains, comparing the proposed methods with seven established imputation methods under the Missing Completely at Random (MCAR), Missing at Random (MAR), and Missing Not at Random (MNAR) mechanisms across varying missingness rates. Our results demonstrate that NuclearForest and SoftForest match or exceed the imputation fidelity of state-of-the-art iterative methods such as MissForest, while significantly reducing computational cost. In particular, they achieve speedups of approximately 5.81 times and 9.52 times over MissForest by replacing iterative cycles with a single refinement step. Our approach effectively exploits the low-rank structure of real-world tabular data and accommodates mixed-type variables, providing an efficient and robust solution for data imputation in bioinformatics, economics, and beyond.

Abstract: Count data pose a challenge for score-matching-based causal discovery: derivatives are unavailable, and simply replacing them with finite differences does not generally suffice for causal discovery. We generalize SCORE's constant-curvature criterion (Rolland et al., 2022) by conditioning on the node's value, yielding the conditional curvature score (CCS) for ordering. We also extend curvature-based parent recovery through the off-diagonal curvature score (OCS), enabling directed acyclic graph (DAG) recovery with both scores constructed from score functions for continuous data and concrete scores for counts. In the bivariate setting, zero CCS exactly characterizes a semiparametric generalized linear model (GLM) conditional form in which the conditional family need not be specified in advance, unlike in classical GLMs. For bivariate semiparametric GLM DAGs under our regularity condition, canonical-parameter nonlinearity is necessary and sufficient for identifiability. In multivariate DAGs, this nonlinearity enables DAG recovery through CCS and OCS. Our framework identifies a new class of semiparametric GLM DAGs that strictly contains the nonlinear Gaussian ANM class identified by SCORE. We introduce DISCO (DIscrete SCOre), a count-DAG recovery algorithm that estimates CCS and OCS using discrete diffusion. Experiments demonstrate accurate DAG recovery across Poisson, negative binomial, binomial, and mixed-family settings, as well as scalability to 1,000-node DAGs on a single GPU.

Abstract: Single-cell RNA-seq representation learning is fundamentally label-free: cell identities, states, and contexts are not fixed training targets, so what constitutes signal or nuisance is analysis-dependent. A single representation must therefore preserve biological identity and state, remain robust to nuisance context, and retain the gene-level variation needed for expression analysis, three demands we call the representation trilemma. To tackle this problem, we introduce scTrilemma, a latent-bottleneck VAE that routes expression-derived variation to the embedding, the decoder, or the prior rather than forcing all of it through one embedding. It gates gene tokens by expression, routes the cell representation through the decoder, and conditions the prior on unlabeled pseudo-bulk context, under a single reconstruction objective and without target annotations or auxiliary representation losses. In release-based zero-shot evaluation on successive CZ CELLxGENE Census releases, scTrilemma leads all three demands at once and preserves biological-state, differential-expression, and pathway structure across multiple disease settings. Latent interventions further show that context can be removed at almost no cost to the other demands, leaving identity against fidelity as the remaining tension. Code is publicly available at https://github.com/yunhak0/scTrilemma.

Abstract: We develop a new algorithm for counting the number of subgraphs of a network isomorphic to a given query graph (#SubgraphIsomorphism), motivated by network motif search. High-degree vertices (hubs), common in real-world networks, contribute to a combinatorial explosion in the number of subgraphs, making existing motif search algorithms intractable for motif sizes greater than $\approx 8$ on a wide variety of networks of interest. Our procedure leverages the $k$-core decomposition and a novel subtree-counting technique to quickly scan the periphery of a network. These two innovations allow our algorithm to significantly speed up its predecessors in practice, especially as most real-world networks have a relatively large periphery. We prove that #RootedSubtreeIsomorphism, a key subroutine in our algorithm, is #P-complete via a reduction from counting bipartite matchings. We provide analytic upper bounds on our algorithm's execution time, and evaluate its performance on 11 real-world networks of varying topologies.

Abstract: While attaining remarkable results for many applications, Deep Learning models are notoriously difficult to explain. This work introduces HyDI, a hybrid ensemble architecture for hierarchical multi-label classification. It combines a Deep Learning (DL) model with rule-based classifiers generated by Inductive Logic Programming (ILP). For leaf classes of the label hierarchy, the rule-based classifiers replace the DL model, leading to more transparent classification results. HyDI is applied to the Chemical Entities of Biological Interest (ChEBI) ontology, providing ILP-generated rules for 314 classes. For these classes, HyDI can generate global explanations as well as local explanations that combine visual and text-based descriptions.

Abstract: Many datasets carry an intrinsic directionality: citations point backward in time, cells differentiate along lineages, and traffic follows preferred routes. Spectral embedding methods, including most of their extensions to directed graphs, discard this information: they symmetrize the data and map it into a Euclidean space where asymmetry cannot be represented. We instead model directed data as sampled from a Finsler manifold, whose distance depends on the direction of travel, and study the kernel operator built from this asymmetric distance. Through a moment expansion of this operator, we show that its symmetric and antisymmetric parts separate geometry from direction. As the bandwidth of the kernel vanishes, the symmetric part converges to a weighted Laplacian, recovering diffusion maps in the Riemannian case, while the antisymmetric part converges to a first-order transport operator that encodes the directionality. We prove that the corresponding graph operators, built from finitely many samples, converge uniformly and almost surely to these limits. For Randers metrics, this vector field is explicit and yields an embedding algorithm recovering both the manifold structure, from the spectrum of the symmetric part, and the underlying drift. We illustrate the approach on synthetic directed graphs and point-clouds.

Abstract: Inference-time steering adapts pretrained diffusion and flow-based models to new tasks, e.g., to generate samples from a conditional distribution or samples with desired properties, without retraining. This can be formalized as sampling from a reward-tilted generative prior. As exact sampling from this distribution is intractable, guidance-based methods rely on approximations producing biased samples, and sequential Monte Carlo (SMC) methods correct for this bias using importance weights. However, while exact in the large particle limit, SMC suffers from weight degeneracy and particle collapse in practice. We propose interacting particle guidance (IPG), which replaces reweighting with transport. The particles interact through an additional drift, derived from the Feynman--Kac PDE to cancel the reweighting term, and remain unweighted. Choosing the drift in a reproducing kernel Hilbert space yields a closed-form solution that is cheap to compute, with negligible overhead compared to SMC. We demonstrate the method on Gaussian mixtures with known posteriors, and on high-dimensional image inpainting and protein structure inference tasks.

Abstract: In this thesis I develop methods for statistical inference when the distributions arising from complex biological systems are multi-modal, geometrically structured, and sometimes only defined up to a normalizing constant. I start from variational inference and, when analytic update equations are unavailable, move to black-box variational inference. To build intuition regarding inference challenges and the proposed methodologies, I introduce a novel unnormalized target density (the CoLN distribution) and reuse it as a controlled test case in the kappa. I then trace a trajectory of increasingly expressive approximations: ensembles evaluated with the multiple importance sampling ELBO (Paper A) and variational mixtures that automate component cooperation and exploration (Paper B). Because expressivity comes at a cost, I develop efficient mixture learning ideas, including Monte Carlo objective estimators to scale mixture learning more efficiently (Paper C). As a new result in the kappa, I overturn a three decades long misconception regarding the potential performance benefits of using mixtures in variational inference. Finally, I move from variational inference to flow matching, where I address the need for specialized treatment of interpolant learning in multi-marginal settings (Paper D). By combining insights from Papers A-D, I derive in Section 5.5 a new method: multi-marginal flow matching with mixtures of variational interpolants. I connect these methodological developments to biological applications, with special emphasis on three-dimensional spatial transcriptomics, where stacked tissue slices induce multi-modal dynamics across space.

Abstract: Score-based generative models generate new samples by integrating a time-dependent drift that carries Gaussian noise onto the target distribution. In practice this drift is modeled by a neural network, trained on a loss integrated over time $t$ with a weighting schedule $w(t)$. Along the backward dynamics, and for multi-modal distributions, trajectories commit to modes of the target within a narrow time window, the \textit{speciation time}. In this work, focusing on high-dimensional data, we decompose the integrated loss into its single-time contributions and analyze each at fixed signal-to-noise ratio $Λ(t)$: we show that $Λ(t)$ sets the rate at which each feature of a multimodal target - the mode directions and their relative weights - is acquired during training. Crucially, at high $Λ(t)$ all mode directions are acquired together, on a single timescale insensitive to their amplitudes, while the relative weights are not learned at all. Only near the speciation time, where $Λ(t)$ becomes of order one, do all features become learnable, each on its own timescale: the weights are acquired jointly with the directions, and the directions at rates set by their relative amplitudes. For models trained on time-integrated objectives, the learning dynamics is then governed by how much of the weighting effectively sits near the speciation time, which provides insights on $w(t)$ design choices. These results follow from an exact high-dimensional analysis of the training dynamics of unbalanced and hierarchical Gaussian mixtures. Numerical experiments on image and human genome haplotype generation recover the predicted hierarchy of learning timescales in more complex settings.

Abstract: Estimating mutual information (MI) from samples is a central objective in a variety of scientific fields. Modern neural estimators are accurate in the large-data regime, but they fall short when data is scarce, and each must be fit anew for every distribution under study. Current estimators are moreover tied to specific data types. These constraints limit their adoption in many applications where per-distribution training is impractical and sample sizes are small. We present ALICE, a foundation model that removes per-distribution training, while achieving competitive estimation accuracy. Trained exclusively on a broad family of synthetic distributions, ALICE acts as an in-context estimator of rectified-flow velocity fields: conditioned on samples of an unseen distribution, it estimates that distribution's velocity field without any explicit training. MI is then obtained through a fixed identity that integrates the squared difference between the joint and conditional fields. We validate ALICE on a standard, challenging benchmark and apply it in three domains, biology, genetics, and neuroscience, whose data the model has never seen. For the first time, we show that a single model closes the gap with neural estimators trained separately for each distribution, while natively supporting different data dimensionality and sample cardinality, enabling zero-shot MI analysis across scientific domains.

Abstract: Transformers process tokens without any inherent notion of order, making positional encoding a fundamental requirement rather than an architectural refinement. Rotary Position Embedding (RoPE) has become the default positional encoding in modern language models, yet it is heavily biased toward nearby tokens. Existing alternatives have been evaluated under different settings, leaving the literature fragmented and without a clear replacement. We bring structure to this landscape by examining a specific weakness of RoPE: its slow frequency bands, whose wavelengths exceed the training context and expose models to unseen angles during extrapolation. We therefore introduce Data aware RoPE (DaRoPE), which preserves standard RoPE on the fast bands but replaces absolute position on the slow bands with bounded coordinates learned from contextual representations. Therefore, the slow-band geometry depends on the data rather than only on positional distance. We compare representative encodings under matched conditions across synthetic tasks, symbolic music, genomics, neural signals, and language models spanning 124M to 50B parameters. Across these experiments, DaRoPE leads on non-text benchmarks, mitigates recency bias, while remaining best or on par in language modeling and length extrapolation. Moreover, the learned coordinates also make the mechanism interpretable, revealing how attention layers leverage contextual information beyond token distance. Together, these results support DaRoPE as the best overall default among the evaluated methods, when there is no domain-specific reasons to prefer another.

Abstract: Mechanisms for generating GNN explanations are crucial for building trust and mitigating biases in Graph Neural Networks (GNNs), especially in high-stakes scenarios. Most current methods optimize only for fidelity under the sparsity constraint. However, this discounts the need for interpretable explanations (those that consist of familiar motif patterns) and stable explanations (those that remain unchanged under structural perturbations). We propose a novel approach that optimizes GNN explanations across these metrics, exposing their relative weighing as a control. Experiments on various real-world datasets, including MUTAG, BA-2Motif, BAMultiShapes, and PROTEINS, suggest that our method produces higher-fidelity explanations than a state-of-the-art baseline on MUTAG and PROTEINS across all evaluated budgets, and on BA-2Motif at larger budgets, while being faster in the regime of small explanation budgets. We also explore how, given an input motif library containing standard motifs for the corresponding domain, the method can be used to determine the relative importance of those motifs in generating the explanations, and how this information can be used to further improve the quality of the output explanations. We also examine the relationship between different metrics through their induced tradeoff surface, and explore its dependence on the nature of the motif library.

Abstract: Dense associative memories have traditionally focused on storing and retrieving vector-valued patterns. Many modern machine learning problems, however, are naturally graph-structured, requiring memory mechanisms for relational patterns, graph diffusion geometries, community structures, and graph-based inductive biases. We propose a spectral dense associative memory for storage and retrieval of graph data, extending the classical vector-valued memories. Retrieval is performed through a log-sum-exp energy induced by Dirichlet energy with spectral norm distances, producing a softmax-weighted average of the stored Laplacians that remains a valid graph Laplacian. We prove exponential storage capacity and exponentially decaying retrieval error. Beyond graph retrieval, we establish theoretical guarantees for spectral quantities central to graph learning, including eigenvalues, eigenspaces, and diffusion operators. Experiments on synthetic graph data, real-world airline network, protein conformation data and wearable sensor data demonstrate robust graph retrieval while preserving the graph geometry of the data. Our framework provides a new associative memory paradigm for graph-structured data and bridges dense associative memory with modern graph learning and generative AI.

Abstract: A square is a word $xx$, where $x$ is nonempty. We show that a circular word of length $n$ contains at most $\lfloor 3n/2 \rfloor$ distinct squares of length at most $n$. The proof combines known results relating squares to circuits in Rauzy graphs. The coefficient $3/2$ agrees with the known lower bound.

Abstract: Graph neural networks (GNNs) have become a prominent approach for developing fast, topology-aware surrogates in electric power systems, supporting tasks such as power flow (PF) analysis, optimal power flow (OPF) estimation, and cascading failure analysis (CFA). Despite this growing use, formally verifying GNN-based models remains challenging, with existing methods limited in scope. We extend the neural network verification (NNV) framework to graph-structured inputs through GraphStar sets, a generalization of Star sets that captures uncertainty over both node and edge features. This extension enables the propagation of linear message-passing operations and the sound approximation of ReLU nonlinearities for GNN architectures, including graph convolutional network (GCN) and graph isomorphism network with edge features (GINE) layers. We evaluate GNNV across three power system tasks, PF, OPF, and CFA, on the IEEE-24, IEEE-39, and IEEE-118 test cases, as well as two standard graph classification benchmarks, ENZYMES and PROTEINS. Our results show that GNNV provides tighter robustness guarantees than CORA on graph classification models with ReLU-based activations and, for the first time, delivers edge-aware robustness guarantees for GINE-based PF and OPF models under joint node and edge perturbations.

Abstract: We study exact pattern matching on indeterminate strings, where a text or pattern position may represent a set of symbols rather than a single letter. Focusing on Boyer-Moore-style methods, we present new bad-character rules (BC Rules I-IV) and a new good-suffix procedure, computed by Fast_GSR_Indet_Shift, which avoids the per alignment recomputation used in BM_Indet [12] by shifting with a single preprocessed position-indexed table. We conduct a systematic experimental evaluation of sixteen algorithms, including classical bad-character adaptations (e.g., Horspool, Sunday, and Zhu-Takaoka) and hybrids that combine these bad-character rules with Fast_GSR_Indet_Shift. Across synthetic scaling experiments and a case study on the E. coli K-12 MG1655 genome, the Fast_BM_Indet hybrids consistently outperform BM_Indet and KMP_Indet [12], in some settings by up to two orders of magnitude. We also find that Zhu-Takaoka is the strongest bad-character-only adaptation on small alphabets and genomic data, while the Fast_BM_Indet variant using BC Rule I offers comparable performance, making it attractive for larger alphabets. We conclude with practical guidance on choosing among these variants for indeterminate string applications.

Abstract: Many scientific datasets, such as molecular conformational ensembles or single-cell tissue measurements, are naturally modeled as meta-distributions: distributions over probability measures on non-Euclidean domains. Existing generative methods largely assume Euclidean geometry and fail to capture this structure. We introduce Riemannian Wasserstein Entropic Flow Matching (RWEFM), a generative framework on the Wasserstein space $\mathcal{P}_2(\mathcal{M})$ of a Riemannian manifold $(\mathcal{M},g)$. RWEFM is trained by regressing a neural vector field onto Riemannian optimal transport velocities, using McCann displacement interpolations as conditional paths. We confirm theoretically that this construction leads to a valid flow matching approach on $\mathcal{P}_2(\mathcal{M})$ and introduce the Riemannian Entropic Map, a GPU-efficient approximation of the optimal transport map on manifolds. Our experiments show that by respecting the intrinsic geometry of the data, RWEFM can generate whole single-cell samples in hyperspherical latent spaces and protein conformational ensembles on the torus. As RWEFM requires only a geodesic distance and a projection operator, it is not restricted to manifolds with closed-form geometry, which we demonstrate by generating distributions on a general triangulated mesh.

Abstract: Scientific investigations into microbial natural products (NPs) present significant challenges for novices, largely due to the complexity of microbial systems, biochemical diversity, technical skill requirements, and the demands of bioinformatics and data analysis processes. To address these issues, we introduce ChatT2, a large language model (LLM)-based agent that is specifically tailored to the unique characteristics of bacterial type II polyketides. These polyketides form a structurally distinct and therapeutically important NP family. ChatT2 was developed within an autonomous multiagent framework composed of a mentor, an executor, and an evaluator, each with defined responsibilities. The mentor acts as an intermediary between ChatT2 and the user, utilizing chain-of-thought prompting to refine the intent of the user. Under the guidance of the mentor, the executor synthesizes multimodal information via retrieval-augmented generation techniques and seamlessly integrates bioinformatics and cheminformatics tools. The evaluator ultimately assesses the output of the executor to ensure the richness and accuracy of the retrieved information. Our research highlights how ChatT2, designed with this multiagent framework, addresses the challenges faced by general LLMs in terms of understanding limited, specialized corpora and complex biological information and provides both experts and novices with a valuable tool for exploring various NPs of interest. The ChatT2 webserver can be accessed at https://chatt2.site/#/chat.

Abstract: Translocations are genome rearrangement operations that exchange prefixes of two chromosomes. We study the non-uniform non-contiguous translocation distance problem, where every string produced during the computation remains available for reuse. Given an initial set of strings $A$ and a target set $B$, the objective is to produce all strings in $B$ using as few translocations as possible. We present the first polynomial-time approximation algorithm for this problem. For a single target string of length $n$, we obtain an $O(\log n)$-approximation, and we extend the result to arbitrary finite target sets with an $O(\log N)$-approximation, where $N$ is the total length of the targets not already present in the initial set. This resolves the approximability question for the non-uniform non-contiguous case left open by Constantin and Popa (TCS 2025).

Abstract: Intrinsically disordered proteins (IDPs) differ from folded proteins in that they are dynamic, lack a stable three-dimensional conformation, and have low sequence similarity between similar proteins. The conformational heterogeneity of IDPs - while beneficial for their diverse functions - limits the use of traditional experimental tools to determine their conformation. The experimental difficulty, along with low sequence similarity, results in data scarcity, and makes it difficult to classify/detect IDPs that are similar or dissimilar, a task relevant to understand biology and evolution. We address this challenge using Multi-task ProtBERT (MT-ProtBERT), a multi-task extension of ProtBERT tailored for low-data regimes. MT-ProtBERT integrates Dynamic Window Masking, a Multi-Scale 1D Convolutional classifier (MS-Conv1D), and auxiliary objectives that jointly optimize masked language modeling and biochemistry-informed tasks. We evaluate this framework on two tasks under limited data: (i) phosphorylation site prediction (S/T/Y) in short sequences and small datasets, and (ii) protein compaction prediction on two small datasets (684 and 530 sequences), including sequences comparable in length to typical disordered regions. MT-ProtBERT consistently outperforms PARROT, an RNN-based IDP-specific model, across all tasks. These results demonstrate that combining self-supervised and biochemistry-informed tasks, and multi-scale learning enables robust modeling of unstructured proteins under data scarcity.

Abstract: High-dimensional count data are common in scientific applications, but most diffusion and flow models are designed for continuous or categorical data, and generation often requires many sequential model evaluations. We propose Count Flow Map, a generative model that learns finite-time transitions directly in count space for one- or few-step generation. Our model directly learns stochastic transitions over finite time intervals, using Poisson births and Binomial deaths to preserve nonnegative integer counts without a predefined maximum. These transition models are trained to match the underlying local birth--death dynamics and to maintain consistency across step sizes. We characterize the connection between local dynamics and finite-time transition consistency and derive a bound on the generation error. After validating Count Flow Map in several simulations, including a high-dimensional, high-count setting, we apply it to single-cell drug perturbation prediction and neural population forecasting, where it captures perturbation responses and supports forecasts of high-activity events with only one or a few model evaluations. Together, these experiments demonstrate that Count Flow Map enables high-quality generation directly in count space across inference budgets, from one-step to few-step generation, using a single trained model.

Abstract: Best match graphs (BMGs) were introduced in mathematical phylogenetics to describe the concept of closest relatives for related genes (leaves of rooted tree) in different organisms (defining leaf colors). We generalize this concept here to leaf-colored rooted networks, where least common ancestors are in general neither unique nor comparable. We characterize BMGs of rooted networks as those vertex-colored digraphs that are properly colored and satisfy an easy-to-check condition that we call the sicor-in-hub property. BMGs can be recognized in linear time and an explaining network can be constructed in quadratic time. Analogous results are obtained for reciprocal best match graphs (RBMGs), where an edge $\{x,y\}$ corresponds to pairs of vertices with different color that are mutually closest relatives.

Abstract: Collaborative research projects in life sciences increasingly need to integrate private, embargoed consortium data with public reference databases in order to reach statistically meaningful interpretations. The Resource Description Framework (RDF) is well suited to this task: it facilitates the integration of heterogeneous data sources, and allows researchers to keep data and their documentation as metadata in the same place, provided the knowledge graph itself remains private during the time course of the project. Nevertheless, the development and long-term maintenance of a scientific knowledge graph remains a challenging, labour-intensive endeavour owing to the state of constant flux of most public resources. To tackle this challenge, we present kgsteward, a Python command-line tool that builds and maintains knowledge graphs inside RDF stores from a single, version-controlled configuration file. kgsteward supports multiple triplestores, keeps the local graph up-to-date with its external sources possibly already in RDF, or transformed into it on the fly, and uses SPARQL 1.1 UPDATE commands to amend further imported RDF on the fly. It can also validate the resulting graph with SPARQL queries that double as usage examples for both human users and AI agents. kgsteward has already been used in several collaborative projects at the SIB Swiss Institute of Bioinformatics, and we demonstrate its applicability in two real-world international research projects: one that builds a library of plant extracts with chemical analyses and associated bio-activities, and a second that reconciles public reference resources for human metabolic-network reconstruction.

Abstract: Graph foundation models (GFMs) aim to learn transferable representations across severely heterogeneous graph domains. However, severe domain shifts in topology, graph scale, and feature semantics impede the construction of a unified, domain-agnostic representation space. To address this, we propose SCGFM-ART, a structure-centric GFM framework that aligns arbitrary graphs onto a shared relational atlas via Amortized Relational Transport (ART). The relational atlas serves as a universal coordinate system defined by a finite set of relational landmarks (bases), while ART directly predicts reusable, end-to-end graph-to-base transport plans, bypassing costly runtime Gromov-Wasserstein optimizations. Under this formulation, SCGFM-ART decomposes a graph into a unified representation: globally via its relational response coordinates relative to the atlas, and locally via its node-to-role structural correspondences. These correspondences project disparate node attributes into a canonical role space, resolving structural and semantic heterogeneity within a singular alignment interface. Rigorously modeling graphs and atlas bases as finite measured relational spaces, we establish coordinate fidelity bounds, prove stability under predicted transport plans, and derive an amortized coverage bound that guarantees our learning objective tightly surrogates ideal relational coverage. Benchmarked across 14 cross-domain graph- and node-level classification tasks, SCGFM-ART achieves state-of-the-art transferability, securing superior average ranks of 2.29 and 1.14, respectively. Topological perturbation analyses demonstrate that node-role transport retains fine-grained structural nuances beyond global coordinates. On real-world benchmarks, the amortized formulation yields 44.2 to 85.1 times faster frozen target-domain inference by avoiding iterative alignment at test time.

Abstract: Gromov--Wasserstein optimal transport (GW-OT) extends classical optimal transport by introducing structure-aware transport cost. This is particularly relevant for spatial transcriptomics, where dynamical reconstruction should preserve tissue structure in addition to matching expression patterns. While static formulations have been widely used for such structure-aware alignment, a general dynamic formulation for reconstructing continuous trajectories is still missing. We introduce Travelling Pair Dynamical Alignment and Trajectory Estimation (TP-DATE), a theoretical and computational framework to generalize GW-OT dynamically in a simulation-free manner. We formulate a broad class of static and dynamic Quadratic-form OT (QOT) through path actions and prove the static dynamic equivalence. We further develop travelling-pair flow matching, which allows interacting conditional paths and marginalizes their interactions into a single vector field. On synthetic and real spatial transcriptomics data, TP-DATE better preserves spatial structure and improves continuous 3D dynamics reconstruction.

Abstract: Liver cancer is a complex disease responsible for a high number of deaths across the globe each year, making automated solutions for liver cancer classification urgent. The most common form of liver cancer is hepatocellular carcinoma (HCC), accounting for over 90% of liver cancer cases. There is a distinct lack of publicly available HCC datasets utilizing genomic data, which is necessary for training artificial intelligence (AI) models for automated HCC classification. This study proposes constructing a multi-stage HCC dataset using XGBoost and Semi-Supervised learning on three separate datasets of genomic biomarkers, utilizing their existing labels in the Semi-Supervised learning process to label the proposed dataset. The proposed dataset consists of 770 patient samples in total, categorized into five classes that represent normal tissue alongside different stages of HCC. Each sample in the dataset consists of 11,150 different gene expression levels. The XGBoost model demonstrated a final classification accuracy of 96.5% during the Semi-Supervised learning process.

Abstract: Message-passing Graph Neural Networks (GNNs) iteratively propagate and aggregate local neighborhood information followed by global readout to learn graph representations. However, their discriminative power is upper-bounded by the Weisfeiler--Lehman (1-WL) graph isomorphism test. This prevents GNNs from distinguishing certain non-isomorphic graphs with identical local neighborhood structures, often leading to similar graph representations. Unified Topological Signatures (UTS) capture compact, multi-scale representation of global graph topology derived from persistent homology. We introduce two complementary UTS signatures: Graph_UTS- a static signature of the input graph topology, and Embedding_UTS- a dynamic signature of the evolving embedding topology. They encode structural information inaccessible to 1-WL-based message-passing GNNs, yet their capabilities are explored solely for post-hoc embedding-space analysis. We integrate UTS into GNN training across three architectural interventions: (i) UTS-Aug: augmenting with standard readout feature that encodes graph's true topology; (ii) UTS-Reg: topological regularizer that constrains representation collapse; (iii) UTS-Pool: topology-guided pooling that retains structurally critical nodes. We further leverage UTS as a layer-wise diagnostic to quantify oversmoothing during GNN training. Theoretically, we show that integrating UTS into GNN optimization strictly extends GNN expressivity beyond the 1-WL hierarchy. Experiments on three graph classification benchmarks show consistent benefits: Graph-UTS, Dual-UTS, and UTS-Pool improve accuracy across all three datasets, Embedding-UTS provides smaller but similarly consistent gains, and UTS-Reg's benefit varies across graph domains. Accuracy improves by up to 5.8% with Graph-UTS augmentation, by up to 1.9% with UTS-Reg, and achieves comparable performance to TOGL with UTS-Pool.

Abstract: Hidden Semi-Markov Models (HSMMs) are fundamental probabilistic models widely adopted across diverse domains, from computational biology to finance and signal processing. The Viterbi algorithm decodes the most likely state sequence given an HSMM and can be applied iteratively for ab initio model learning. However, existing Viterbi implementations remain sequential, and GPU-accelerated solutions are entirely absent, making HSMM decoding impractical for large-scale workloads. We present a tensor-based formulation of the Viterbi algorithm for HSMMs, restructuring the inner loops into tensor operations that naturally map onto SIMD units and massively parallel architectures. Building on this formulation, we provide optimized implementations spanning single- and multi-core CPUs, and, for the first time, GPU. Experimental evaluation demonstrates speedups of up to 14x on a single core, over 200x with multi-core, and over 570x on GPU over the state-of-the-art sequential baseline, establishing a new performance baseline for large-scale HSMM decoding.

Abstract: Single-cell foundation models (scFMs) increasingly rely on large-scale transcriptomic pretraining, yet expanding pretraining data can yield diminishing gains while substantially increasing computational cost. Our data scaling analyses showed that incorporating biological knowledge, including cell-level text annotation and gene-level regulatory information, provided additional scaling dimension than simply increasing data size. Motivated by this observation, we present scKITE, a simple yet effective scFM that integrates cell-annotation and gene-regulatory supervision into a shared transcriptomic Transformer encoder through lightweight auxiliary decoders. These decoders are used only during pretraining and subsequently discarded, yielding a general-purpose encoder enriched with biological knowledge for downstream applications. With only 179,067 pretraining samples, i.e., less than 0.5\% of those used by previous strong scFMs, scKITE outperformed these models across diverse downstream tasks, highlighting knowledge-enhanced pretraining as a promising paradigm for biologically grounded scFMs.

Abstract: We study weighted edit distance between two strings of total length $n$, where edit costs are induced by an arbitrary metric. For equal-length inputs, Kuszmaul (2019) gave an $O(n^δ)$-approximation with $\widetilde{O}(n^{2-δ})$ running time for every fixed $0 < δ< 1$. We give the first constant-factor approximation for weighted edit distance over arbitrary metrics in strongly subquadratic running time. For every $0 < \varepsilon \le 1$, our randomized algorithm runs in $\widetilde{O}(n^{7/4}/\varepsilon^8)$ time and returns a $(3+\varepsilon)$-approximation with probability at least $1-n^{-10}$. The algorithm allows unequal input lengths and places no bound on the ratio between edit costs.

Abstract: Accurate cell segmentation remains a major bottleneck in subcellular spatial transcriptomics (SST), in which morphological images and spatially resolved RNA transcripts are used to partition tissues into individual cellular instances. As segmentation serves as the foundation for constructing cell-level representations, boundary errors can lead to incorrect transcript assignments and compromise downstream analyses. However, reliable ground-truth boundaries are unavailable because they must be inferred from incomplete morphological and transcript signals. Furthermore, manual annotation of a large number of cells is time-consuming. Agreement among complementary segmentation methods provides a practical surrogate for identifying well-supported and ambiguous regions, but explicit consensus construction requires executing multiple computationally intensive pipelines. In this study, we propose MARC (Morphology-Aware Regression of Consensus), a framework that predicts a multi-method consensus-support map for SST segmentation. MARC is trained with leave-one-method-out consensus pseudo-targets and a Foreground-Union Consensus Loss that focuses supervision on candidate and consensus foreground. We evaluated MARC on 4,642 held-out tiles from Xenium kidney tissue, achieving a mean Dice score of 0.90, a mean intersection-over-union of 0.82, and a mean cell-level Spearman correlation of 0.79 against explicitly computed cross-method consensus maps. We demonstrate that the predicted consensus maps localise weakly supported regions while preserving consensus-based rankings and identifying low-consensus cells for manual review. These results show that MARC closely approximates explicit cross-method consensus without multi-method inference and therefore has the potential to facilitate robust, consensus-aware evaluation of cell segmentation in large-scale SST studies.

Abstract: Classical-to-quantum I/O is a critical bottleneck for data-intensive quantum workloads. Quantum Oracle Sketching (QOS) has been proposed to address this problem. We identify its practical requirements, including the representation of data as a probability distribution over oracle addresses, the relation between sample count, approximation error, and update cost, and the coherence and runtime support required for online execution. To study QOS on current quantum computing devices, we develop an offline realization that compiles sample blocks into empirical phase oracles and evaluate it using DNA fingerprinting. The application converges with relatively few samples, while exact phase fusion combines repeated updates to the same address. However, the compiled circuits remain too deep for current quantum computing devices. Practical QOS therefore requires lower depth oracle synthesis and interactive quantum runtimes.

Abstract: Acidophilic proteins that remain stable and functional under highly acidic conditions, are important for industrial biocatalysis, acid-related bioprocessing, and the discovery of acid-stable enzymes. However, their identification relies heavily on time-consuming experimental screening methods. With the rapid growth of protein sequence databases, the need for computational identification methods that are both accurate and efficient has become stronger. The emergence of protein language models (PLMs) has significantly improved the sequence representation of downstream biological prediction tasks. This paper proposes MI-PEFT, a mixture-of-experts integrated parameter-efficient fine-tuning framework. Built on the ESM C-600M backbone, the framework incorporates LoRA-based PEFT methods and a DeepSeekMoE-based classification head to resolve the limitations of PEFT and significantly improve computational efficiency. Notably, this task is characterized by a significant class imbalance in the dataset, making high specificity particularly challenging. The experimental results demonstrate that MI-PEFT on PLMs, especially {\text{C}}^{\text{3}}\text{A}, serves as an efficient tool for identifying acidophilic proteins and a constrained pathway that helps resolve class-imbalance by preserving the pretrained representations.

Abstract: Many scientific graphs attach several variables to each node, so a single scalar edge weight cannot describe direction-dependent interactions. We model each edge by a symmetric positive-definite (SPD) matrix and infer a posterior over matrix-valued graph geometries, which we call the Bayesian matrix-valued graph (BMVG). We ask how these interactions reconfigure across contexts: how large the change is and which multivariate directions strengthen or weaken. The geodesic distance induced by the affine-invariant Riemannian metric (AIRM) quantifies deformation magnitude and generalized eigenvalues resolve its signed directions.Against fused graphical lasso, Bayesian multiple-GGM, and common principal components, BMVG is competitive on global precision recovery while retaining identifiable matrix-valued edge structure and accurately recovering edge-level deformation directions. In controlled known-truth experiments, it resolves structural change with increasing sample size, including orientation changes that leave ordinary eigenvalues unchanged. In one year of Bay Area weather data, the geometry of 12-hour change reconfigures spatial coupling about as much as whole seasons differ. In TCGA-BRCA, estrogen-receptor (ER)-associated reconfiguration concentrates on specific gene-module pairs and persists under graph-scaffold sparsification and removal of subgroup mean differences. These results establish posterior matrix-valued edge geometry as a unified framework for quantifying and interpreting context-dependent multivariate reconfiguration.

Abstract: Automated prediction of Enzyme Commission (EC) numbers plays a central role in functional annotation and computational drug discovery. However, standard multi-label machine learning pipelines frequently rely on default decision thresholds (t=0.50), assuming balanced prior distributions across target heads. In this study, we present a systematic empirical diagnostic of uncalibrated fixed decision boundaries operating under severe class imbalance across N = 14,096 annotated compounds categorized into six primary EC classes (EC1-EC6). Our results highlight a pronounced Accuracy Paradox: while the multi-label system achieves a deceivingly high mean accuracy of 77.16%, the macro F1-score (0.3976) and macro recall (0.3872) reveal severe predictive breakdown. Majority target classes suffer from hyper-sensitivity and over-prediction, whereas minority classes exhibit sharp recall decay, culminating in a total decision boundary collapse for EC6 (Recall = 0.00%) despite underlying discriminative power (ROC-AUC = 0.5857). Feature correlation analysis further reveals high linear redundancy among topological indices relative to fingerprint density metrics. Ultimately, this diagnostic study demonstrates that standard point predictions mask critical errors in bioinformatics workflows. We establish target-specific threshold optimization and post-hoc conformal calibration as essential, open-source post-processing safeguards for reliable applied machine learning and deep learning architectures.