Trajectory inference is a critical problem in single-cell transcriptomics, which aims to reconstruct the dynamic process underlying a population of cells from sequencing data. Of particular interest is the reconstruction of differentiation trees. One way of doing this is by estimating the path distance between nodes -- labeled by cells -- based on cell similarities observed in the sequencing data. Recent sequencing techniques make it possible to measure two types of data: gene expression levels, and RNA velocity, a vector that quantifies variation in gene expression. The sequencing data then consist in a discrete vector field in dimension the number of genes of interest. In this article, we present a novel method for inferring differentiation trees from RNA velocity fields using a distance-based approach. In particular, we introduce a cell dissimilarity measure defined as the squared varifold distance between the integral curves of the RNA velocity field, which we show is a robust estimate of the path distance on the target differentiation tree. Upstream of the dissimilarity measure calculation, we also implement comprehensive routines for the preprocessing and integration of the RNA velocity field. Finally, we illustrate the ability of our method to recover differentiation trees with high accuracy on several simulated and real datasets, and compare these results with the state of the art.

Objective: SNP heritability estimates vary substantially across estimation strategies, yet the downstream consequences for polygenic risk score (PRS) construction remain poorly characterised. We systematically benchmarked heritability estimation configurations and assessed their propagation into downstream PRS performance. Methods: We benchmarked 86 heritability-estimation configurations spanning six tool families (GEMMA, GCTA, LDAK, DPR, LDSC, and SumHer) and ten method groups across 10 UK Biobank phenotypes, yielding 844 configuration-level estimates. Each estimate was propagated into GCTA-SBLUP and LDpred2-lassosum2 PRS frameworks and evaluated across five cross-validation folds using null, PRS-only, and full models. Eleven binary analytical contrasts were tested using Mann-Whitney U tests to identify drivers of heritability variability. Results: Heritability ranged from -0.862 to 2.735 (mean = 0.134, SD = 0.284), with 133 of 844 estimates (15.8%) being negative and concentrated in unconstrained estimation regimes. Ten of eleven analytical contrasts significantly affected heritability magnitude, with algorithm choice and GRM standardisation showing the largest effects. Despite this upstream variability, downstream PRS test performance was only weakly coupled to heritability magnitude: pooled Pearson correlations between h^2 and test AUC were r = -0.023 for GCTA-SBLUP and r = +0.014 for LDpred2-lassosum2, with both being non-significant. Conclusion: SNP heritability is best interpreted as a configuration-sensitive modelling parameter rather than a universally stable scalar input. Heritability estimates should always be reported alongside their full estimation specification, and downstream PRS performance is comparatively robust to moderate variation in the heritability input.

Protein-protein interactions (PPIs) between a virus and its host govern infection, replication, and pathogenesis. While high-throughput mapping has identified thousands of virus-host associations, much of the virus-host interactome remains uncharacterized due to the labor-intensive nature of experimental screens, the inherent difficulty in capturing transient interactions, and the limited sequence homology across divergent viral families. Here, we introduce ViraHinter, a dual-modal deep learning framework for the precise prediction of virus-host interactions and large-scale inference of interaction landscapes. ViraHinter couples a structure-generation branch with a sequence-representation branch, integrating structure-informed pair representations with ESM-derived embeddings to learn generalizable interaction rules across unseen viruses. We benchmark ViraHinter on pathogenic coronaviruses and influenza A viruses and show that it consistently outperforms RoseTTAFold2-PPI, AlphaFold 3 and RoseTTAFold2-Lite in prioritizing high-confidence candidates even under severe class imbalance and across diverse interface regimes. Notably, it successfully identifies novel functionally relevant host factors and recapitulates the structural plasticity of the complex interfaces. By intersecting predictions across multiple influenza subtypes, ViraHinter reveals 33 shared host factors, offering a roadmap for broad-spectrum antiviral discovery. ViraHinter therefore serves as a robust computational approach for studying virus-host interactions, enabling systematic screening of host factors for all known human-infecting viruses, providing new insights into the shared mechanisms of viral pathogenesis, and accelerating the discovery of novel therapeutic targets and the development of broad-spectrum antivirals.

Speech production requires the rapid coordination of a complex hierarchy of linguistic units, transforming a semantic representation into a precise sequence of articulatory movements. To unravel the neural mechanisms underlying this feat, we leverage recordings from eight 3.2 x 3.2 mm 64-microelectrode arrays implanted in the motor cortex and inferior frontal gyrus of two patients tasked to produce twenty thousand sentences. We show that a hierarchy of linguistic features are robustly encoded in most of these small cortical patches. Contrary to our expectations, instead of a clear macroscopic organization between patches, we observe a multiplexing of phonetic, syllabic and lexical representations within each cortical patch. Critically, this coding scheme dynamically changes over time to allow successive phonemes, syllables and words to be simultaneously represented without interference. Overall, these results, reminiscent of position encoding in transformers, show how small cortical patches organize the unfolding of the speech hierarchy during language production.

Convergent evolution provides powerful evidence for natural selection, yet its molecular basis is typically sought in protein-coding amino acid substitutions. Whether adaptive pressures can drive the convergent evolution of synonymous codon usage bias (CUB) to override phylogenetic history remains a fundamental question. Here, we investigate this within the rapidly radiating fern family Thelypteridaceae by establishing a comparative framework that integrates chloroplast phylogenomics with dimensionality reduction of codon usage, morphological data, and divergence time estimation. Our results reveal that chloroplast CUB patterns are strikingly incongruent with the phylogeny of this family. Instead, they partition species into distinct clusters that strongly correlate with a convergently evolved morphological trait, lamina base architecture, a key adaptation whose radiation we date to the early Neogene. This convergent molecular signal is driven by a specific subset of photosynthesis-related genes (ndhJ, psaA, and psbD), which exhibit a high density of type-specific, third-position codon substitutions. These findings demonstrate that CUB can serve as a powerful, quantifiable indicator of adaptive history, revealing a cryptic layer of molecular convergence linked to the regulation of protein synthesis. Our work providing a new framework for uncovering adaptive histories obscured by complex evolutionary processes.

Large language models (LLMs) are in the ascendancy for research in drug discovery, offering unprecedented opportunities to reshape drug research by accelerating hypothesis generation, optimizing candidate prioritization, and enabling more scalable and cost-effective drug discovery pipelines. However there is currently a lack of objective assessments of LLM performance to ascertain their advantages and limitations over traditional drug discovery platforms. To tackle this emergent problem, we have developed DrugPlayGround, a framework to evaluate and benchmark LLM performance for generating meaningful text-based descriptions of physiochemical drug characteristics, drug synergism, drug-protein interactions, and the physiological response to perturbations introduced by drug molecules. Moreover, DrugPlayGround is designed to work with domain experts to provide detailed explanations for justifying the predictions of LLMs, thereby testing LLMs for chemical and biological reasoning capabilities to push their greater use at the frontier of drug discovery at all of its stages.

Public pooled single-cell perturbation atlases are valuable resources for studying transcription factor (TF) function, but downstream re-analysis can be limited by incomplete deposited metadata and missing internal controls. Here we re-analyze the human TF Atlas dataset (GSE216481), a MORF-based pooled overexpression screen spanning 3,550 TF open reading frames and 254,519 cells, with a reproducible pipeline for quality control, MORF barcode demultiplexing, per-TF differential expression, and functional enrichment. From 77,018 cells in the pooled screen, we assign 60,997 (79.2\%) to 87 TF identities. Because the deposited barcode mapping lacks the GFP and mCherry negative controls present in the original library, we use embryoid body (EB) cells as an external baseline and remove shared batch/transduction artifacts by background subtraction. This strategy recovers TF-specific signatures for 59 of 61 testable TFs, compared with 27 detected by one-vs-rest alone, showing that robust TF-level signal can be rescued despite missing intra-pool controls. HOPX, MAZ, PAX6, FOS, and FEZF2 emerge as the strongest transcriptional remodelers, while per-TF enrichment links FEZF2 to regulation of differentiation, EGR1 to Hippo and cardiac programs, FOS to focal adhesion, and NFIC to collagen biosynthesis. Condition-level analyses reveal convergent Wnt, neurogenic, EMT, and Hippo signatures, and Harmony indicates minimal confounding batch effects across pooled replicates. Our per-TF effect sizes significantly agree with Joung et al.'s published rankings (Spearman $\rho = -0.316$, $p = 0.013$; negative because lower rank indicates stronger effect). Together, these results show that the deposited TF Atlas data can support validated TF-specific transcriptional and pathway analyses when paired with principled external controls, artifact removal, and reproducible computation.

We study high-dimensional mediation analysis in which exposures, mediators, and outcomes are all multivariate, and both exposures and mediators may be high-dimensional. We formalize this as a many (exposures)-to-many (mediators)-to-many (outcomes) (MMM) mediation analysis problem. Methodologically, MMM mediation analysis simultaneously performs variable selection for high-dimensional exposures and mediators, estimates the indirect effect matrix (i.e., the coefficient matrices linking exposure-to-mediator and mediator-to-outcome pathways), and enables prediction of multivariate outcomes. Theoretically, we show that the estimated indirect effect matrices are consistent and element-wise asymptotically normal, and we derive error bounds for the estimators. To evaluate the efficacy of the MMM mediation framework, we first investigate its finite-sample performance, including convergence properties, the behavior of the asymptotic approximations, and robustness to noise, via simulation studies. We then apply MMM mediation analysis to data from the Alzheimer's Disease Neuroimaging Initiative to study how cortical thickness of 202 brain regions may mediate the effects of 688 genome-wide significant single nucleotide polymorphisms (SNPs) (selected from approximately 1.5 million SNPs) on eleven cognitive-behavioral and diagnostic outcomes. The MMM mediation framework identifies biologically interpretable, many-to-many-to-many genetic-neural-cognitive pathways and improves downstream out-of-sample classification and prediction performance. Taken together, our results demonstrate the potential of MMM mediation analysis and highlight the value of statistical methodology for investigating complex, high-dimensional multi-layer pathways in science. The MMM package is available at this https URL.

Despite many years of research, the quest to identify neural correlates of perceptual consciousness (NCC) remains unresolved. One major obstacle lies in methodological limitations: most studies rely on non-invasive neural measures with limited spatial or temporal resolution making it difficult to disentangle proper NCCs from concurrent cognitive processes. Additionally, the relatively low sensitivity of non-invasive neural measures limits the interpretation of null findings in studies targeting proper NCCs. In this review, we discuss how human intracranial recordings can advance the search for NCCs, by offering high spatiotemporal resolution, improved signal sensitivity, and broad cortical and subcortical coverage. We review studies that have examined NCCs at the level of single neurons and populations of neurons, and evaluate their implications on the debates between cognitive and sensory theories of consciousness. Finally, we highlight the limits of current intracranial human recordings and propose future directions based on emerging technologies and novel experimental paradigms.

The extent to which different neural or artificial neural networks (models) rely on equivalent representations to support similar tasks remains a central question in neuroscience and machine learning. Prior work has typically compared systems using a single representational similarity metric, yet each captures only one facet of representational structure. To address this, we leverage a suite of representational similarity metrics-each capturing a distinct facet of representational correspondence, such as geometry, unit-level tuning, or linear decodability-and assess brain region or model separability using multiple complementary measures. Metrics that preserve geometric or tuning structure (e.g., RSA, Soft Matching) yield stronger region-based discrimination, whereas more flexible mappings such as Linear Predictivity show weaker separation. These findings suggest that geometry and tuning encode brain-region- or model-family-specific signatures, while linearly decodable information tends to be more globally shared across regions or models. To integrate these complementary representational facets, we adapt Similarity Network Fusion (SNF), a framework originally developed for multi-omics data integration. SNF produces substantially sharper regional and model family-level separation than any single metric and yields robust composite similarity profiles. Moreover, clustering cortical regions using SNF-derived similarity scores reveals a clearer hierarchical organization that aligns closely with established anatomical and functional hierarchies of the visual cortex-surpassing the correspondence achieved by individual metrics.

We continue recent attempts to put together concepts and results of Chemical Reaction Networks theory (CRNT) and Mathematical Epidemiology (ME), for solving problems of stability of positive ODEs. We provide first an elegant CRN-flavored generalization of the most cited result in ME, the Next Generation Matrix (NGM) theorem. We review next the "symbolic-numeric approach of Vassena and Stadler, which tackles bifurcation problems by viewing the characteristic polynomial of the Jacobian at fixed points as a formal polynomial in the "symbolic reactivities", and identifies its coefficients as "Child Selection minors of the stoichiometric matrix". We also review two applications of this approach using the Mathematica package Epid-CRN tools from both CRNT and ME.

Adaptive control in biological systems, such as intestinal immunity, remains poorly understood despite detailed knowledge of underlying regulatory networks. We propose an alternative framework based on stochastic martingale turnover, in which cells proliferate through mutual competition and decay without cell-type-specific regulation. Through stochastic simulations and mathematical analysis, we show that this process autonomously generates balanced population compositions associated with low decay probabilities. The compositional dynamics can be described as a random walk whose step lengths decrease in low-decay regions. Reduced decay leads to larger total population sizes and an increase in the number of compatible microscopic states, which in turn shapes the distribution of compositions under fluctuating conditions. More generally, the dynamics follow a modified Langevin equation, in which constant mass is replaced by a fitness-dependent effective mass proportional to the total population size. Thus, biological systems regulate resistance to change, not merely direction, in shaping their macroscopic behavior.

We study a size-structured population model in which individual cells grow at a rate determined by a fluctuating internal variable (e.g., gene expression levels). Many previous models of phenotypically heterogeneous populations can be viewed as special cases of this model, and it has previously been observed that the internal variable decouples from cell size under certain conditions. In this work, we generalize these results and connect them to the Feynman-Kac formula, which yields relationships between the lineage dynamics and population distribution in branching processes. To this end, we derive conditions for decoupling, both in the lineage and population ensemble. When decoupling occurs in both ensembles, the size dynamics can be transformed, via a random time change, into a growth-homogeneous process, and expectations can be evaluated through an exponential tilting procedure that follows from the Feynman-Kac formula. We further characterize weaker, ensemble-specific forms of decoupling that hold in either the lineage or the population ensemble, but not both. We provide a more general interpretation of tilted expectations in terms of the mass-weighted phenotype distribution

Decoding natural language from non-invasive EEG signals is a promising yet challenging task. However, current state-of-the-art models remain constrained by three fundamental limitations: Semantic Bias (mode collapse into generic templates), Signal Neglect (hallucination based on linguistic priors rather than neural inputs), and the BLEU Trap, where evaluation metrics are artificially inflated by high-frequency stopwords, masking a lack of true semantic fidelity. To address these challenges, we propose SemKey, a novel multi-stage framework that enforces signal-grounded generation through four decoupled semantic objectives: sentiment, topic, length, and surprisal. We redesign the interaction between the neural encoder and the Large Language Model (LLM) by injecting semantic prompts as Queries and EEG embeddings as Key-Value pairs, strictly forcing the model to attend to neural inputs. Furthermore, we move beyond standard translation metrics by adopting N-way Retrieval Accuracy and Fréchet Distance to rigorously assess diversity and alignment. Extensive experiments demonstrate that our approach effectively eliminates hallucinations on noise inputs and achieves SOTA performance on these robust protocols. Code will be released upon acceptance at this https URL.