Microbial genomes and metagenomes contain millions of proteins whose enzymatic functions remain unknown, the enzyme dark matter. While deep learning has improved protein function prediction, most methods are black boxes relying on sequence or structural similarity, limiting discovery of novel catalytic activities. The ESMC-6B protein language model and its sparse autoencoder with a 16,384-dimensional codebook of interpretable biological concepts, each annotated by GPT-5, creates a new opportunity: using these features directly as semantic signatures for enzyme function. Here, we show that ESMC-SAE features enable accurate and interpretable enzyme commission (EC) number prediction without task-specific training or GPU-intensive computation. On a balanced benchmark of 4,868 microbial SwissProt enzymes across 161 EC3 subclasses, ESMC-SAE binary features achieve 78.9% top-1 and 88.5% top-5 accuracy, 37.6% higher than 3-mer baselines (57.3%). In leave-one-EC3-class-out evaluation simulating discovery of novel enzyme classes, SAE features recover the EC1 superclass in 47.7% of cases (3.3x random, 14.3%), versus 26.6% for sequence methods. Discriminative features correspond to mechanistically interpretable concepts: catalytic triad geometry for hydrolases, NAD(P)H-binding Rossmann folds for oxidoreductases, phosphate-binding P-loops for transferases. We also survey the ESM Atlas of 7.7 million clusters and identify 169,859 dark enzyme-like candidates across all major microbial phyla. Our results establish a paradigm for enzyme function discovery in microbial dark matter: interpretable by design, scalable without GPU clusters, and applicable to the billions of proteins in the ESM Atlas.

Circulating-tumour DNA (ctDNA) carries evidence of drug resistance months before imaging shows it, but the earliest evidence lives below the assay's limit of detection (LoD): a nascent subclone is detected only intermittently, producing a flickering sequence of faint detects and non-detects. Commercial liquid biopsies treat each draw as an independent snapshot and a non-detect as nothing. We argue a non-detect is a left-censored observation, and the pattern of non-detects and faint detects over time carries actionable evidence of growth before any single value is trustworthy. We introduce Span, a censored-Poisson Bayesian latent-growth change-point detector that models the binary detection process, accumulates a sequential generalised-likelihood-ratio statistic for an upward change-point in the per-variant detection rate, and raises a competing-risks alarm with calibrated false-alarm control. Span has no learned weights, so there is nothing to overfit. On a synthetic cohort of HR+/HER2- metastatic breast cancer on first-line CDK4/6-inhibitor plus endocrine therapy, at a matched 10% false-alarm rate, Span roughly doubles the fraction of impending progressions caught three months ahead (indolent regime: 25% vs 11% for the snapshot), with a falsifiable dose-response: large for indolent emergence, vanishing for fast emergence. A value-trajectory baseline performs identically to the snapshot, isolating the gain to the censored detection model. The survival backbone matches a Cox baseline on real breast-cancer data (GBSG-2, n=686; C-index 0.67 vs 0.68), and on a real longitudinal cohort with clean biomarkers (PBC2, n=312) the same pipeline correctly declines to win, a falsifiable boundary test confirming the mechanism is regime-specific. All ctDNA trajectories are synthetic.

De novo peptide sequencing from tandem mass spectrometry is pivotal in proteomics, enabling identification of novel peptides without reference databases. While recent Transformer-based encoder-decoder models have achieved remarkable performance, we uncover a critical pathology in their inference dynamics. Through comprehensive feature scaling experiments, we demonstrate that existing auto-regressive peptide decoders tend to over-rely on generated-sequence priors while progressively under-utilizing fine-grained physical evidence from the input mass spectrum. This phenomenon leads to suboptimal results, where generated peptide sequences are biologically plausible yet not faithful to the input spectrum. To rectify this, we propose MemNovo, a training-free and plug-and-play mechanism that re-balances peptide and spectral contributions at inference time. MemNovo alleviates the information bottleneck by establishing a persistent spectral memory bank and injecting retrieved features directly into the final decoding stage via an ultra-conservative residual connection. Theoretical analysis confirms that this mechanism restores the mutual information between the decoder state and the raw spectrum. Extensive experiments on the Nine Species benchmark with two representative baselines, Casanovo and InstaNovo, demonstrate that MemNovo consistently improves both amino acid precision and peptide precision, achieving up to 39.1% relative improvement in peptide precision for Casanovo and up to 3.9% for InstaNovo, with negligible computational overhead.

Multispecies spatial data arise in many applications where interactions between different entities are central to system behaviour, including biomedical imaging, geospatial analysis, and species ecology. Despite their importance, relatively few quantitative tools exist to capture such interactions. In this work, we propose magnitude-based features for the analysis of multispecies spatial data. Magnitude is a real-valued invariant of finite metric spaces that can be interpreted as an effective number of points, incorporating both spatial configuration and scale. We develop global and local magnitude feature vectors and demonstrate their utility on synthetic tumour microenvironment data, and in tissue microarray data from human colorectal cancer samples. Locally, the method identifies distinct neighbourhood types and reveals spatial heterogeneity; in the model, this includes radial patterns associated with different qualitative outcomes of the simulations, while in the real-world data it reflects the importance of tertiary lymphoid structure-like interactions between B and T cell populations. Globally, the approach recovers known classifications of long-term simulation outcomes across parameter regimes in synthetic data, and suggests important roles for CD4+ T cells and CD163+ macrophages in distinguishing patients with favourable Crohn's like reactions from unfavourable diffuse immune infiltration. Together, these results suggest that magnitude-based features provide a powerful and flexible tool for the analysis of multispecies spatial data.

Synthetic random heteropolymers (RHPs), consisting of a predefined set of monomers, offer an approach toward the design of protein-like materials. These RHPs, if designed appropriately, can mimic protein behavior and function. As such, there is a need for computational tools to efficiently guide RHP design. We bridge this gap by developing DeepRHP, a modified variational autoencoder (VAE) model under a semi-supervised framework. By equipping a classical VAE with an additional feature-based VAE, DeepRHP forces the latent space to capture structures of critical chemical features as well as individual RHP sequence patterns. In this sense, our method is versatile by allowing any relevant features to be incorporated in a hybrid manner. We demonstrate the effectiveness of DeepRHP by suggesting potential monomer compositions that stabilize membrane proteins (e.g. Aquaporin Z) in non-native environments and cross-validating our prediction with published results. The concordance between our model and true RHP function suggests strong potential in utilizing hybrid autoencoder architectures to guide RHP design for proteins and other biological compounds.

Compositional data -- vectors encoding relative proportions -- arise across scientific domains, including ecology, geochemistry, and genomics. The features in these data often come with known hierarchical structure (e.g., taxonomies, phylogenies, ontologies), yet existing methods either ignore this structure, discard the intrinsic Aitchison geometry, are designed for binary trees, or yield incomplete coordinate systems. We describe PolyILR, a canonical orthonormal decomposition of the Aitchison tangent space aligned with any tree topology. Our construction defines a weighted local geometry at each internal node capturing full branching structure, then lifts these to a global orthonormal basis where every coordinate corresponds to a specific tree location. On microbiome and single-cell benchmarks, PolyILR yields stable, interpretable features and enables inference at multiscale tree resolution. We also establish a novel theoretical connection to softmax classifiers, suggesting possible applications to probabilistic modeling.

Biotic communities vary continuously across space, yet biome maps impose categorical boundaries that compress this variation, particularly at ecotones where transitional communities are ecologically distinct. Could Earth observation (EO) foundation models, which encode spectral, spatial, and temporal information with dense embeddings, convert discrete biome maps into continuous representations that better capture ecological variation? Here, we fit a linear classifier on Clay v1.5 satellite image embeddings to predict biome labels from a categorical map. The softmax output yields a continuous probability vector whose dimensions correspond to named biome classes. We evaluate this approach using six Brazilian biomes, 1.3 million embeddings, and 10,015 withheld forest inventory plots spanning 4,672 plant species. The continuous biome representation outperforms discrete biome labels for predicting species occurrence (mean per-species AUC 0.618 vs. 0.570 across 10 spatial cross-validation folds). Decomposing this gain shows that continuity in the graded probability output, rather than label reassignment, accounts for the improvement; the pattern holds across all distances from biome boundaries. The raw 1024-dimensional embedding remains the strongest predictor we tested (mean AUC 0.646 vs. 0.618), but the continuous representation recovers most of the embedding's gain over discrete labels. This simple approach provides a probabilistic replacement for categorical map labels, preserving their meaning while encoding graded variation that discrete maps suppress.

Accurate prediction of absorption, distribution, metabolism, and excretion (ADME) properties is critical to drug discovery, but remains challenging because ADME endpoints are noisy, interdependent, and often data-limited. We propose a molecular graph-transformer pretraining framework that combines chemistry-specific self-supervision with contrastive mutual information machine learning (cMIM). Our method encodes molecular graphs into latent variables, reconstructs SMILES strings from the graph-derived latent codes, and augments the contrastive objective with domain-specific self-supervised chemistry tasks. Rather than treating these tasks as auxiliary regularizers with separately tuned loss weights, we formulate reconstruction, contrastive discrimination, and chemistry-specific supervision as unit-weighted log-probability factors in a single probabilistic latent-variable objective. For fine-tuning, we propose a multi-task GNN readout architecture with task-specific multilayer perceptron heads, preserving shared representation learning while mitigating negative transfer and improving the modeling of heterogeneous, nonlinear task relationships. Across Biogen, ExpansionRX, and ChEMBL-MT, the resulting Contrastive KERMT pretraining improves over the KERMT baseline by 7.6%, 9.9%, and 9.5% respectively (averaged over significantly-improved endpoints). Adding ADME-adjacent molecules to the pretraining corpus further improves transfer, and the contrastive component sharpens chemically meaningful latent neighborhoods.

While long treated as empirical fits, Hill functions have been postulated to be the universal Hopfield barrier for sharpness of input-output responses by Martinez-Corral, Nam, DePace, and Gunawardena. A Hopfield barrier is a fundamental limit on how well biological systems can process information without expending energy. Their case rested on numerical findings for Hill coefficients $4$ and $6$. We give a precise formulation and proof of this: measuring sharpness by the supremum of the derivative in semi-log scale, any rational function $r(x)=(\alpha_0+\alpha_1 x+ \cdots +\alpha_n x^n)/(\beta_0 + \beta_1 x+ \cdots + \beta_n x^n)$ with real coefficients $0\leq \alpha_i\leq \beta_i$ has sharpness at most $n/4$, with equality if and only if $r$ is a Hill function with Hill coefficient $n$.

Neural recordings are often interpreted as local measurements, yet the signal at any one sensor can also reflect structured activity distributed across the broader network. This raises a basic question: to what extent does an electrode's signal reflect local versus distributed information in the underlying system? More specifically, how much of an electrode's activity is carried by its immediate neighborhood, and how much is embedded more broadly across the array? We address this with a Spatially Masked Regression (SMR) framework that reconstructs each electrode's timeseries from the remaining electrodes while excluding a configurable neighborhood around the target. By progressively increasing this mask, spatial locality becomes an experimental control for quantifying how much predictive information survives after nearby channels are withheld. We apply SMR to intracranial EEG with heterogeneous electrode coverage and to scalp EEG with standardized montages over sensorimotor cortex. Using distance correlation between original and reconstructed signals, we find strong within-subject reconstruction in both modalities, substantial residual predictability even when local neighbors are excluded, and markedly stronger cross-subject transfer in EEG than in iEEG. Masking shows that nearby electrodes contribute strongly to reconstruction but do not account for all of it, indicating that individual channels reflect both local redundancy and broader distributed structure. Surrogates that preserve selected marginal or spectral properties while disrupting phase structure or temporal ordering substantially reduce performance, supporting the conclusion that SMR depends on structured temporal and cross-channel organization rather than on marginal statistics alone. These results position SMR as an interpretable framework for quantifying the balance between local and distributed information in recordings.

Health digital twins (HDTs) promise patient-specific modeling and decision support but current approaches remain structurally fragmented: monolithic models that address a single organ or task lack cross-scale fidelity, while system-level twins lack generalizable architectural frameworks. We propose OmniBioTwin, a System-of-Twinned-Systems (SoTS) framework that organizes HDTs as modular computational entities coupled through explicit interaction operators within a multi-layer network architecture. The framework comprises seven coordinated layers - spanning data integration, autonomous twin modeling, cross-scale coupling, temporal synchronization, and human-in-the-loop decision support. We demonstrate OmniBioTwin by instantiating a multiscale twin for glucagon-like peptide-1 (GLP-1) signaling pathways in Alzheimer's disease, illustrating how molecular, cellular, and organ-level twins can be composed and coupled within a unified system.

Inferring cellular trajectories from destructive snapshots is complicated by the challenges of stochasticity and non-conservative mass dynamics such as cell proliferation and apoptosis. Existing unbalanced Optimal Transport (OT) methods treat mass as a continuous fluid, performing inference at the population level. However, this macroscopic view often fails to capture the discrete, jump-like nature of birth-death events at single-cell resolution, which is essential for understanding lineage branching and fate decisions. We present Unbalanced Schrödinger Bridge (USB), a simulation-free framework for learning underlying dynamics that effectively integrates both stochastic and unbalanced effects which also models the discrete, jump-like birth-death dynamics at single-cell resolution. Theoretically, USB provides a tractable solution to the Branching Schrödinger Bridge (BSB) problem, offering a rigorous microscopic interpretation where individual cells undergo both Brownian motion and discrete birth-death jumps. Technically, the method implements an efficient solver by introducing a simulation-free training objective that effectively scales to high-dimensional omics data. Empirically, we demonstrate on both simulated and real-world datasets that USB not only achieves trajectory reconstruction performance better than or comparable to deterministic baselines but also uniquely enables realistic discrete simulation of birth-death dynamics at single-cell resolution.