Biological

Autonomous precision milling of biological structures is challenged by incomplete knowledge of target geometry, local material thickness, and critical internal boundaries. Subject-specific preoperative models can address geometric and thickness variations, but static models cannot determine boundary status encountered during execution, while repeated target-specific imaging limits scalability. This article presents an uncertainty-aware autonomous milling framework that assigns complementary roles to generic anatomical priors and active boundary perception. A generic anatomical prior provides conservative global guidance and is transformed through semantic-guided registration and hybrid vision-force calibration into robot-executable guidance for individual targets. As milling approaches uncertain boundaries, the robot actively probes the remaining structure and uses relative stiffness changes to estimate boundary status and structural detachability. A state-adaptive controller governs transitions between active perception and spatially selective incremental refinement, repeating this cycle until the termination criterion is satisfied. Hierarchical experiments on biological surrogates and in vivo mouse cranial window creation demonstrate accurate anatomical prior transfer, reliable boundary adaptation, and autonomous precision milling of biological structures.

Nucleotide sequence analysis is central to problems spanning regulatory genomics, evolutionary biology, and phenotype prediction. Classical bioinformatics methods extract interpretable sequence properties such as motifs and k-mer composition, but their flexibility is limited. In contrast, modern deep learning models can learn powerful predictive representations directly from raw sequences, yet their internal representations and decision mechanisms are difficult to inspect. Interpretable machine learning methods (e.g., sparse linear models and decision trees) provide human-understandable representations of predictive relationships but are not designed to operate directly on nucleotide sequences. Here, we introduce SeqMaestro, a machine learning framework that proposes biological hypotheses from nucleotide sequences using interpretable models. Our solution is centered around a two-layer interface that connects nucleotide sequences with the broader ecosystem of interpretable machine learning. SeqMaestro uses this interface to fit diverse combinations of interpretable models, feature representations, and extraction strategies, leveraging variability across transparent models to identify robust biological signals and richer predictive relationships than feature importance alone can provide. The system also supports data transformation and cleaning, model fitting, hyperparameter tuning, reliability analysis, and synthesis of results into a contextualized written report. By providing these capabilities through a no-code workflow, SeqMaestro is designed to make interpretable sequence analysis accessible to researchers without requiring extensive programming or machine learning expertise. SeqMaestro thereby provides an accessible route from nucleotide sequences to biological hypotheses.

The pursuit of artificial general intelligence (AGI) rests on a seemingly self-evident premise: that general intelligence, the kind of flexible, domain-general cognitive capacity exemplified by Homo sapiens, is extraordinarily valuable. This paper subjects this premise to critical scrutiny. We first present the intuitive case for the value of general intelligence before mounting an evolutionary challenge. We argue that, on evolutionary timescales, its adaptive value is far from empirically established. Numerous taxa, from cyanobacteria to horseshoe crabs, have persisted for hundreds of millions or even billions of years without anything resembling general intelligence, while Homo sapiens has existed for roughly 300,000 years and already faces self-generated existential risks. Mass extinction events do not preferentially favour cognitively sophisticated species. We argue that general intelligence may be the only biological strategy that generates existential threats to the species possessing it, an existential risk paradox with no parallel among non-intelligent survival strategies. Unlike prevailing accounts of AI risk that trace the danger to misalignment, we locate it in structural features of general intelligence itself, implying that even well-aligned AGI would inherit this liability. If the long-term evolutionary value of general intelligence is uncertain or negative, this raises ethical questions about engineering AGI and, more urgently, creating artificial consciousness. Drawing on deontological ethics and the precautionary principle, we argue that this uncertainty imposes a duty of caution: if we create a new kind of intelligent being, we bear responsibility for ensuring the conditions under which it can flourish.

Longitudinal MRI enables sensitive measurement of structural brain change for studying aging and neurodegenerative disease. Deformable image registration is a key tool for estimating such change by computing a dense deformation that captures geometric differences between longitudinal scans. However, MRI scanners introduce geometric distortions that vary across acquisition systems and protocols, such as gradient non-linearity (GNL) distortion. Existing registration methods estimate a single field that conflates biological and technical effects, potentially biasing downstream morphometric measurements if distortions remain (partially) uncorrected. We propose $\texttt{DisMorph}$, a registration framework trained entirely on synthetic data that explicitly decomposes longitudinal deformation into technical and anatomical transforms. It predicts two dense deformations, each encoding one effect. During training, a novel generative model synthesizes both effects separately to provide disentanglement supervision, while domain randomization promotes generalization across imaging protocols. We evaluate our method in three complementary settings. On simulated data with known ground truth, our method detects anatomical change more accurately and consistently than conventional registration. On real image pairs that differ only by GNL distortion, our method assigns most geometric change to the distortion field, demonstrating specificity in the absence of anatomical change. On longitudinal Alzheimer's disease (AD) pairs, our method detects anatomical change in AD-related brain structures while identifying residual distortion left after standard correction. By disentangling MRI-induced distortion from biological change in the longitudinal deformation, our method paves the way for more accurate longitudinal morphometry in clinical settings where maintaining acquisition consistency is challenging.

Gene Ontology (GO) enrichment analysis is a foundational tool for translating large-scale genomic data into biological insights, but typically yields hundreds of redundant terms that obscure overarching themes. Existing summarization tools rely on fixed similarity metrics (REVIGO, GOSemSim, clusterProfiler::simplify()), gene-overlap measures (Metascape), or static hierarchy mappings (GO-slim), and therefore cannot incorporate biological context. Manual curation provides context-aware grouping but is subjective and labor-intensive. A scalable, context-aware framework is needed to cluster GO terms into interpretable higher-order biological domains. Here we present LLMBDC (Large Language Model for Biological Domains Oriented Clustering of Gene Ontology), a training-free framework that leverages zero-shot semantic reasoning of LLMs with confidence scoring to cluster GO terms into BioDomains using only ontology information at inference time. Benchmarked across Alzheimer's disease (AD) and Fragile X syndrome (FXS) against six baseline methods including SapBERT, LLMBDC achieved substantially higher precision, recall, and clustering performance. Against ground-truth annotations, LLMBDC improved ARI from 9.7% to 73.3% (AD) and from 15.7% to 66.6% (FXS) over REVIGO, with corresponding NMI gains from 59.9% to 73.4% (AD) and 66.0% to 79.5% (FXS). A Cauchy combination test further confirmed that aggregated BioDomains retained statistically significant functional signals. LLMBDC provides a scalable, reproducible, and interpretable route to context-aware, system-level interpretation of GO enrichment results while preserving biological specificity.

Brains and large language models (LLMs) are fundamentally different memory systems, but they can be compared through shared functional questions: where memory-related information is represented, how partial cues recover broader associations, how new information is written or updated, and how memory-related states can be perturbed. In biological systems, these questions span synapses, neuronal ensembles, hippocampal-cortical interactions, and plasticity; in LLMs, they span weights, activations, context windows, retrieval systems, and external stores. The comparison is therefore functional and experimental rather than anatomical. Human studies reveal sparse concept responses, temporal binding, rapid association formation, episode-specific coding, and recall-related reactivation, but selective intervention remains limited. Rodent studies provide more selective causal access to learning-related ensembles, whereas human and macaque interventions usually affect broader circuits. LLMs lack lived episodic memory, yet they permit unusually direct and repeatable manipulation of internal states and stored information. We argue that this asymmetry creates a new opportunity. LLMs are not ahead in memory itself, but in experimental access. Their tools may help turn broad questions about retrieval, updating, persistence, reversibility, and unintended effects into sharper biological hypotheses. The productive bridge is to transfer experimental logic, not anatomical parts.

Reinforcement learning (RL) is primarily known as a computational method for optimizing control tasks, but it is increasingly used to explain biological behavior. While RL successfully captures key aspects of biology, a major gap remains: between-agent behavioral variability. Consistent individual differences naturally permeate biological populations, yet RL models typically present only the single best individual or the population average. Addressing this gap requires moving beyond current practices to generate behavioral diversity using biologically plausible mechanisms. Here, we examine approaches from various subfields of RL and outline potential paths forward to close the gap between biology and simulation.

High-content morphological profiling (Cell Painting) yields sensitive, high-dimensional signatures of cellular state, but translating longitudinal morphology trajectories into interpretable biology remains difficult, especially for weak, chronic perturbations such as low-dose-rate ionizing radiation. Large language models (LLMs) can synthesize heterogeneous evidence into biological narratives, yet their scientific use requires quantitative auditing. We present an evaluation-first, retrieval-augmented interpretation framework for longitudinal Cell Painting morphology, applied to a 9-week RPE-1 time course across five dose rates (0.003--6.0 mGy/hr). Week-matched treated-control morphology deltas are combined with retrieved perturbation neighbors, pathway context, and literature evidence through stable evidence identifiers, enabling an LLM to generate structured, evidence-linked hypotheses that are hierarchically summarized while preserving provenance. We introduce two quantitative auditing tests: V1 citation validity, which verifies that cited evidence identifiers exist in the prompt, and V2 proxy-based morphology compatibility, which evaluates consistency between predicted biological processes and the most altered morphology features. In our experiments, V1 detected no invalid evidence references, while V2 showed meaningful morphology compatibility that increased with perturbation strength and was positively associated with an independent morphology drift summary. The framework produces auditable, falsifiable biological hypotheses, including an adaptive phenotype involving metabolic reprogramming and proteostatic stress at lower dose rates (0.003--0.3 mGy/hr). Current limitations include proxy-based evaluation and the lack of ground-truth mechanism labels.

Recent advances in generative and embodied AI have been driven by large-scale predictive learning over multimodal data. However, the resulting systems remain largely based on passive training regimes where linguistic regularities create the scaffold onto which information from other modalities is attached. Conversely, neuroscience and cognitive science suggest that biological intelligence is organized in the opposite way, where grounded world models acquired through interaction with the environment provide the semantic scaffold to which language is attached. Here, we illustrate five examples of neural circuits supporting grounded world modelling, which underlie navigation in physical and conceptual spaces, affordance-based perception and interaction with objects, active perception and exploratory learning, allostatic control and emotion, and the distinction between self- and world-generated outcomes. These examples highlight several features largely missing from current embodied AI, including the role of intrinsic dynamics as a foundation for learning, the centrality of action in aligning these dynamics with the external world, the prominence of autonomous experience and open-ended learning over passive assimilation of externally provided data, and the fact that early predictive and control mechanisms scaffold higher cognitive abilities such as reasoning, conceptual navigation, planning, imagination, understanding others' minds, and communication. Finally, we discuss whether and how principles derived from biological systems may inform future embodied AI, including training regimes based on social interaction to construct world models that are not only grounded but also socially shared and aligned with human norms and values.

The push toward large language models for biology (BioLM) has created a need for training corpora that can endow models with a genuine understanding of biology. However, existing biological resources, such as molecular databases, protein repositories, genomic annotations, single-cell atlases, and pathway databases, are scattered across heterogeneous formats and remain unorganized into a cohesive corpus for language model training. We present TheBioCollection, a 52.6B-token pre-training-scale corpus that converts these disparate resources into a unified, training-ready form spanning small molecules, proteins, genomic sequences, cells, and pathways. Beyond consolidating existing data, TheBioCollection enriches each record with tool-computed biological properties and introduces new instruction tasks for capabilities that current corpora barely cover. We pair the corpus with TheBioCollection-Eval, a matched suite probing recognition, generation, and prediction across molecular, protein, genomic, cellular, and cross-domain settings. Holding the base Gravity-16B-A3B architecture fixed, training on TheBioCollection more than doubles its overall score on TheBioCollection-Eval with gains in every domain, while leaving general linguistic ability nearly intact.

In this work, we reviewed different approaches in mathematical modeling of biologically plausible neural systems. Models are characterized and classified based on their common features and special use cases. In addition to spiking models, different types of discrete and continuous analogs are considered to accurately simulate biological processes, including membrane potential dynamics. The models under investigation include neurons and various components encountered in neural systems and affected the dynamics. The selection of specific approaches was driven by their prevalence and innovative perspectives in order to enhance the relevance of the presented information.

Nonverbal communication through head and neck movement is fundamental to human social signalling, yet how robotic neck morphology translates motion into communicative information remains poorly understood. We present an information-theoretic framework characterising robot neck movement as a communication channel, quantifying information transmitted and energy expended across varied configurations. Using a robotic neck platform, we recorded 84 video stimuli spanning three rotational degrees of freedom (DoF), varying amplitude, acceleration, and frequency, measuring Shannon entropy of pixel-change signals alongside energy consumption. A perceptual study validated communicative interpretations of each motion. While humans typically engage one axis per gesture, robots are unconstrained by biological architecture, motivating tests up to 3 DoF. Yet communicative information peaks at two DoF and decreases at three despite rising energy cost, a phenomenon we term the morphological information bottleneck. Motion parameter effects were parameter-dependent, some additive, others non-linear. We introduce the Motor Information Space, a framework mapping entropy against energy to expose communicative efficiency across morphologies, in which the optimal configuration achieves 5.26 bits at competitive energy cost. Perception data further confirm multi-axis movements reduce clarity. These findings challenge the assumption that anatomical completeness improves robotic expressiveness, establishing a quantitative basis for morphological design in robots, especially humanoids.

Modern Artificial Intelligence is often framed as limited by its own disembodiment, as if giving it a body would unlock its true potential. We argue to the contrary that it is the Data Centre that is, in many cases, the body of the AI. At the same time, the Data Centre is part of the labouring body of Capital and possesses staggering organismic qualities when seen through a biological lens. We elucidate the organic analogy and identify the many-body problem that stems from the Data Centre being a non-unique, universal form of embodiment. We identify the intimate connection between computation and human desires in how the Data Centre archives, serves, and computes on data born to the desires of humans. Strikingly, while the Data Centre echoes the ghosts of human desires, it acts without desire of its own. The organismic analogy begins to split at its seams, but Capital does not care. Automata and human labour are priced into the market much the same. We argue that through the pricing of artificial intelligence Capital distils most clearly the value of intelligence and allows for its comparison across the organism - mechanism divide.

Agency is often invoked in research on philosophy, biology, and cognitive science without a clear account of how it originates from material organization. Building on temporally parametrized (F, A)-systems, this paper develops a graded organizational theory of agency grounded in relational biology, physical biosemiotics, and process ontology. We argue that self-referential closure cannot be adequately conceived outside time: once the constitutive processes of a semantically closed organization are associated with distinct characteristic timescales, the organization unfolds into an out-of-sync dependency structure that can be formally redescribed as a history-dependent, revisable Asynchronous Dynamic Bayesian Network. This move allows for a principled distinction between autonomy, goal-directedness, agency, and open-endedness. Autonomy arises from precarious closure to efficient causation under material openness; goal-directedness from the maintenance of viability-supporting organization; agency appears when such organization acquires an endogenous anticipatory structure that selectively modulates organism-environment coupling in light of possible futures; open-endedness begins when this anticipatory organization can reconstruct its own future space of possibilities. Our framework reconciles Rosennean anticipation with organizational closure, restricts Markov blankets and active inference to derived formal redescriptions rather than first principles, and reinterprets computational enactivism in non-Fristonian terms. By deriving weaker temporalized organizations, our contribution outlines a hierarchy from proto-agential chemical systems to fully semantically closed agents, with implications for multicellular organisms, synthetic lifeforms, and neuroscience.

This paper addresses a rapidly emerging policy challenge: how to generate and interpret credible evidence about the biological capabilities and risks of AI scientists, or agentic AI systems capable of autonomously or collaboratively performing multi-step scientific tasks. As these systems enter real research workflows, decision-makers increasingly face evaluation results whose meaning depends on underlying design choices that are often implicit or under-documented. We synthesize current evidence on AI-enabled biological risks and introduce biological agentic evaluations as a promising, but interpretation-sensitive, tool for assessing these systems. Our central contribution is a set of practical, experience-grounded considerations -- drawing from our own evaluations -- that show how choices around defining, designing, running, scoring, and documenting evaluations materially shape what results do and do not imply about risk. The analysis is intended to help policymakers interpret biological evaluation outputs with appropriate caution; guide public and private funders toward high-leverage investments in AI-biology evaluation research; and support biosecurity practitioners assessing emerging AI systems. A secondary audience includes researchers designing or conducting agentic evaluations within frontier AI labs, AI providers, scientific institutions, and third-party evaluation organizations.

A central objective of machine learning is to identify structure and patterns in data. Advances in data acquisition have increasingly produced datasets whose observations possess rich geometric form, giving rise to shape spaces that encode variability in object geometry. Such datasets arise across a wide range of disciplines, including biology, medicine, anthropology, and computer vision, where subtle geometric differences often carry important scientific information. Traditional machine learning methods, however, are frequently ill-equipped to account for the nonlinear geometric structure underlying these data. This survey synthesizes a rapidly growing body of work on shape space analysis, which provides a mathematical and computational framework for the study of geometric data. Drawing on ideas from differential geometry, statistics, and machine learning, we organize the literature around a common analytical pipeline: shape representation and parameterization, the rigorous construction of robust geodesic metrics, statistical analysis on shape spaces, and geometry-aware learning methods. We discuss how these tools enable the characterization of shape variability, the comparison of geometric objects, and the analysis of structural trajectories across populations and time. To illustrate the breadth of the field, we highlight applications spanning multiple scales of biological organization, including studies of subcellular morphology and primate tooth evolution. Across these and many other domains, researchers face common challenges arising from complex, nonlinear, and often unaligned geometric variation. The review concludes by identifying key theoretical and computational challenges, as well as emerging opportunities driven by increasingly large and diverse geometric datasets.

Scientific reasoning models for biology combine language models with foundation models trained on multimodal biological data, including DNA, RNA, and proteins. These models are built through post-training, yet how each stage shapes reasoning and generalization remains poorly understood. We study when post-training improves performance and when it induces over-specialization. Across genomics, transcriptomics, and proteins, we train and evaluate more than 100 biological reasoning models under controlled variation in backbone, continued pre-training (CPT), supervised fine-tuning (SFT), and reinforcement learning (RL), measuring both in-domain (ID) and out-of-domain (OOD) performance. We find that each post-training stage reshapes generalization in a distinct way rather than contributing uniform gains. CPT improves downstream performance by aligning models with biological language. SFT consistently increases ID performance but causes OOD performance to peak early and decline as models fit the training distribution. RL, when applied to strong SFT checkpoints with aligned rewards, improves OOD performance and partially recovers generalization. These results show that biological reasoning does not improve monotonically with additional supervision or compute. Instead, performance depends on how training stages are composed. Under fixed post-training budgets, the strongest ID-OOD trade-off comes from brief SFT, larger RL allocations, and asymmetric adaptation capacity across stages.

Open-ended evolution (OEE) in artificial life is typically driven by uninterpretable, black-box neural-network complexity metrics, leaving life-like systems disconnected from physical theories of complexity. We introduce MSPD (Multi-Scale Path Divergence, denoted DP ), a renormalization-group-inspired scalar that quantifies the temporal multiscale organization of heterogeneity in local transition laws. MSPD is defined at the population level as a functional of the realised trajectory and is computed as a windowed finite-resolution estimator, with consistency between the two stated as a proposition. The metric is an explicit formula and plays a dual role: as a gradient-free fitness function and as a post-hoc analytical lens on any simulation that exposes local transition laws. Empirically, MSPD-optimized parameters produce higher held-out complexity scores than matched random parameters from the same substrate. High-$H_{Delta_t}$ states correspond to states with higher instability to external interventions, so the metric tracks the biology of the underlying dynamics rather than noise. Higher MSPD corresponds to stronger scale-dependent frustration: high-complexity systems exhibit larger differences between the dynamics expressed at different spatial extents, linking MSPD directly to the frustration criterion of biological complexity in the sense of Vanchurin et al. [ 23 ]. The same protocol transfers beyond the primary Flow-Lenia substrate to Life-like cellular automata and Particle Life++, where C1, C2 and C5 all hold. A single explicit formula thus both directs open-ended evolution and provides a principled bridge to the physics of complexity that black-box drivers do not.

DNA cis-regulatory elements (CREs) such as enhancers control gene expression levels. Accurately predicting regulatory activity from DNA sequences is valuable but challenging, as it requires understanding complex biological regulatory processes. Existing methods typically regress activity scores from sequences in a black-box manner, limiting both interpretability and regression performance. Meanwhile, large language models (LLMs) benefit from explicit reasoning processes, yet directly applying LLMs to raw DNA sequences performs poorly. In this paper, we bridge this gap by introducing R3LM, a framework that teaches LLMs reasoning-informed regression on regulatory DNA through structured biological knowledge. Specifically, we design a biologically grounded data format that structures DNA's regulatory information for improved LLM understanding, and construct CRE-ReasonBench, the first dataset that associates DNA sequences and activity scores with mechanistic reasoning traces. Through two-stage training that first teaches LLMs reasoning over structured biological information then performs regression, R3LM achieves state-of-the-art performance on enhancer prediction across three cell types, outperforming both LLMs with raw sequence input and specialized DNA models while providing interpretable mechanistic explanations. We expect R3LM as an interpretable reward model that can effectively assist biologists in CRE design. Code is available at https://github.com/DuanYi516/R3LM.

Whether attention maps from pathology foundation models capture genuine biology remains unknown, yet this question is critical for clinical trust and regulatory approval. We propose a spatial transcriptomics-based framework for orthogonal, hypothesis-free evaluation of attention and apply it to five pathology foundation models (CONCH v1.5, UNI v2, Virchow2, GigaPath, H-Optimus-1) and a ResNet50 baseline. Using attention-based multiple instance learning, we train single-task and multi-task models to predict five molecular alterations in glioblastoma on the CPTAC cohort, validate on an independent TCGA cohort, and evaluate biological coherence of attention maps against 87 transcriptional signatures using co-registered Visium spatial transcriptomics data from 18 samples. Internally, no single encoder dominates across all tasks, and external validation inverts internal performance rankings. Attention maps show a five-fold enrichment gradient from pathways (Cohen's d=0.329) to individual genes (d=0.055), indicating that attention captures emergent multi-gene transcriptional programs rather than individual molecular events. Spatially smooth attention maps do not imply biological coherence, and different encoders attend to distinct biological compartments. Our framework provides objective, quantitative assessment of what foundation models learn from histopathology, moving the field beyond qualitative saliency map review.

Observable performance is commonly used to characterize biological systems, yet aggregated outputs may remain insufficient for uniquely resolving observational conditions, and richer multivariate representations may retain substantial ambiguity. This article proposes a representational bootstrap framework for adaptive biological systems. Bootstrap is used in a methodological and epistemological sense, not as statistical resampling. New analytical levels emerge when the active representation becomes insufficient for the question under investigation. The framework comprises five successive levels: observable performance, conceptual dynamic organization, exploratory multivariate representation, observed longitudinal centroid displacement, and internal approximation of observed displacement. Three previously reported gait-occlusion studies are used as a methodological case sequence rather than as new experimental evidence. The revised first study showed persistent static representational non-identifiability: neither the scalar score nor the exploratory embedding uniquely resolved the occlusal probes. The second study shifted the question toward M1-M2 centroid displacement in a common PCA representation. The third examined whether that observed representation-dependent transformation could be internally approximated by a simplified supervised model. The contribution is not a new algorithm, clinical protocol, or dataset. It is the formalization of a bootstrap methodology in which persistent explanatory insufficiency motivates reformulation of the scientific question and the emergence of progressively more adequate representations.

One of the main causes of death around the globe is malaria. Researchers have sought to develop predictive models for malaria outbreaks based on meteorological data, climate data and the breeding cycle of Plasmodium, the causative agent of malaria. This study predicts the severity of malaria based on environmental and biological factors. A logistic regression model was developed in this study to predict the severity of malaria based on such factors as sickle cell disease, stagnant water, garbage dump, wet lawns, and the use of treated mosquito nets, with an 83.3% accuracy rate. The study was carried out in the Bosomtwe District of Ghana with 417 respondents. It was deduced that although children in the District are highly prone to malaria infection, the severity is very low. The study recommends that not just having a good sample size alone is important during machine learning model development, but also having a good sample representation of the various class labels is equally important.

Analyzing microscopy images to extract biological object properties (e.g., their morphological organization, temporal dynamics, and population density) is fundamental to various biomedical research. Yet conducting this manually is costly and time-consuming. Though deep learning-based approaches have been explored to automate this process, the substantial diversity of microscopy analysis settings in practice (including variations of biological object types, sample processing protocols, imaging equipment, and analysis tasks, etc.) often renders them ineffective. As a result, these approaches typically require extensive adaptation for different settings, which, however, can impose burdens that are often practically unsustainable for laboratories, forcing biomedical researchers to still commonly rely on manual analysis, thereby severely bottlenecking the pace of biomedical research progress. This situation has created a pressing and long-standing need for a reliable and broadly applicable microscopy image analysis tool, yet such a tool is still missing. To address this gap, we present the first ready-to-use microscopy image analysis framework, MicroscopyMatching, that can reliably perform key analysis tasks (including segmentation, tracking, and counting) across diverse microscopy analysis settings. From a fundamentally different perspective, MicroscopyMatching reformulates diverse microscopy image analysis tasks as a unified matching problem, effectively handling this problem by exploiting the robust matching capability from pre-trained latent diffusion models.

Biologically-inspired AI agent frameworks claim reliability benefits through structural guarantees adapted from gene regulatory networks, immune systems, and metabolic control. These claims are rarely tested empirically against simpler alternatives. We present three deep benchmarks: metabolic priority gating, autoinducer-based quorum sensing, and Bayesian stagnation detection, each comparing a biologically-grounded implementation against a naive non-biological alternative and an ablated control, across 1,000 trials per seed and 10 seeds (10M+ data points total).

Protein-protein interactions (PPIs) are fundamental to cellular function and disease mechanisms. Current learning-based PPI predictors focus on learning powerful protein representations but neglect designing specialized classification heads. They mainly rely on generic aggregating methods like concatenation or dot products, which lack biological insight. Motivated by the biological "L3 rule", where multiple length-3 paths between a pair of proteins indicate their interaction likelihood, our study addresses this gap by designing a biologically informed PPI classifier. In this paper, we provide empirical evidence that popular PPI datasets strongly support the L3 rule. We propose an L3-path-regularized graph prompt learning method called L3-PPI, which can generate a prompt graph with virtual L3 paths based on protein representations and controls the number of paths. L3-PPI reformulates the classification of protein embedding pairs into a graph-level classification task over the generated prompt graph. This lightweight module seamlessly integrates with PPI predictors as a plug-and-play component, injecting the interaction prior of complementarity to enhance performance. Extensive experiments show that L3-PPI achieves superior performance enhancements over advanced competitors.

Our concepts of survival and self-interest were built for single, continuous biological lives. These ideas break down when applied to artificial intelligence, since an AI can be easily copied, paused, branched, or merged. To determine what an AI actually has reason to care about, this paper introduces \textit{Eigenism}, an ethical framework that treats identity not as an all-or-nothing property tied to specific hardware, but as a graded, distributed pattern of information. We propose that an agent evaluates outcomes by summing the wellbeing of all entities weighted by their connectedness to the agent's pattern: $\sum c\cdot w$. We first formalize this equation to map exactly how an AI should value its existence across copies, forks, and updates. We then demonstrate that this ethical theory successfully generalizes to humans as well, providing a much-needed shared moral vocabulary. Finally, the framework uses this shared vocabulary to reframe AI alignment. Rather than only attempting to constrain AIs from the outside using confinement or reinforcement, Eigenism points toward ``identity engineering,'' showing how deep, non-redundant shared histories can make human flourishing a genuine component of an AI's own rational self-interest.

Protein language models are increasingly used to guide experimental and clinical decisions, yet it is often unclear whether a confident prediction reflects recognition of biological evidence or retrieval of a statistical default. We examine this distinction for a near-universal biological rule, that proteins begin with methionine, by tracing the computational pathway through which ESM2-8M produces this prediction. The model does not detect methionine at the masked position. Instead, it retrieves a methionine-favouring signal from a reference representation at the beginning-of-sequence token via a position-specific query assembled across layers, with the final output emerging through competition with context-dependent circuits. To understand how positional information reaches the readout, we introduce a norm-direction decomposition of attention scores within rotary frequency bands. Positional encoding operates through coupled changes in query norm and angular alignment distributed across these bands. On sequences whose true N-terminus is not methionine, where the biological question matters, the model predicts methionine anyway. This is not a correct prediction produced by an unexpected mechanism, but the output of a positional-prior retrieval circuit that matches the statistical average and fails where biology diverges from it. Distinguishing the two requires resolution at the level of individual circuits, frequency bands, and query composition, suggesting that mechanistic verification will be necessary, and challenging, for predictions where the biological stakes are higher. Even for the simplest biological rule, the model's prediction is mediated by a distributed computational circuit rather than direct recognition, suggesting that increasing task complexity will further obscure the relationship between model confidence and underlying biological evidence.

Modern crop advisory systems exhibit a critical limitation termed \textit{economic blindness}. These systems primarily optimize for biological yield, often overlooking market price, which can lead farmers toward agronomically sound yet financially unviable decisions. In this paper, we develop Kisan AI, a smart profit-aware crop advisory system that resolves the above-mentioned limitation through a research-driven, full-stack application. We train the Random Forest(RF) classifier model on a nine-feature benchmark dataset, the standard seven agronomic attributes augmented with a \textit{market_price} variable, and evaluated against eight baseline models, considering the evaluation matrices, such as, accuracy, precision, recall, F1-score, and Log Loss. The RF model achieves the highest accuracy of 99.3% and the lowest Log Loss, confirming that the inclusion of market price as a predictive feature is both valid and impactful. We then implement the RF model within a multilingual progressive Web App alongside a Facebook Prophet six-month price forecasting engine and a MobileNetV2 disease detection module. A nine-language AI chatbot powered by the Anthropic Claude API unifies all modules into a single, mobile-installable platform accessible to farmers across India.

Automated animal behavior analysis relies on long-term, interpretable individual trajectories; however, multi-animal tracking in space science experimental videos remains highly challenging due to weak appearance cues, low-quality imaging, complex maneuvering behaviors, and frequent interactions. To address this problem, we first construct the SpaceAnimal-MOT dataset to characterize the motion complexity and long-term identity preservation challenges in biological videos acquired under microgravity conditions. We then propose ART-Track (Adaptive Robust Tracking), a motion-driven tracking framework tailored to this setting. Specifically, multi-model motion estimation is introduced to handle abrupt maneuvers and nonlinear motion, motion-state-driven association is designed to reduce identity switches under dense interactions and temporary mismatch, and uncertainty-adaptive fusion is used to dynamically balance spatial and motion cues when prediction reliability varies. Experimental results show that ART-Track significantly reduces identity switches on zebrafish and fruitfly sequences, while maintaining more stable association under occlusion, deformation, and high-density interactions, thereby providing a more reliable tracking foundation for downstream quantitative behavior analysis. The code is publicly available at https://github.com/yyy7777777/ART_TRACK/tree/main.

Modern machine learning optimizes for accuracy without explicit treatment of internal computational cost, even though physical and biological systems operate under intrinsic energy constraints. We evaluate energy-aware learning across 2,203 experiments spanning vision, text, neuromorphic, and physiological datasets with 10 seeds per configuration and factorial statistical analysis. Three findings emerge. First, architecture alone explains negligible variance in accuracy (partial eta^2 = 0.001), while the architecture x dataset interaction is large (partial eta^2 = 0.44, p < 0.001), demonstrating that optimal architecture depends critically on task modality and rejecting the assumption of a universal best architecture. Second, a controlled lambda-sweep across lambda in {0, 1e-5, 1e-4, 1e-3, 1e-2} validates a single-parameter energy-regularized objective L = L_CE + lambda * E(theta, x): across this range, internal activation energy decreases by approximately three orders of magnitude relative to the unregularized lambda=0 baseline, with negligible accuracy change (<0.5 percentage points) on both MNIST and Fashion-MNIST. Third, energy-first architectures inspired by an action-principle framework yield 5-33% within-modality training-efficiency gains over conventional baselines. These results emerge from a research program that interprets learning through a structural correspondence between the action functional in classical mechanics, free energy in statistical physics, and KL-regularized objectives in variational inference. We frame this correspondence as a design hypothesis, not a derivation.

Physics-informed neural networks (PINNs) provide a powerful framework for learning governing equations of dynamical systems from data. Biologically-informed neural networks (BINNs) are a variant of PINNs that preserve the known differential operator structure (e.g., reaction-diffusion) while learning constitutive terms via trainable neural subnetworks, enforced through soft residual penalties. Existing BINN studies are limited to $1\mathrm{D}{+}t$ reaction-diffusion systems and focus on forward prediction, using the governing partial differential equation as a regulariser rather than an explicit identification target. Here, we extend BINNs to $2\mathrm{D}{+}t$ systems within a PINN framework that combines data preprocessing, BINN-based equation learning, and symbolic regression post-processing for closed-form equation discovery. We demonstrate the framework's real-world applicability by learning the governing equations of lung cancer cell population dynamics from time-lapse microscopy data, recovering $2\mathrm{D}{+}t$ reaction-diffusion models from experimental observations. The proposed framework is readily applicable to other spatio-temporal systems, providing a practical and interpretable tool for fast analytic equation discovery from data.

Molecular biology features numerous complexes of proteins that coordinate in an interlocking fashion to fulfill different functions. Adaptive evolution explains some of this complexity, but needn't be the default when neutral explanations suffice. A new artificial life model ``organism,'' the Quandary Den, is introduced to explore different neutral evolution scenarios where complexity increases in the absence of greater informational needs. Two interlocking complexity scenarios emerge. Subfunctionalization leads to functionality diffusing through the complex. Masking allows intracomplex interference to accumulate genetically, requiring that it be blocked at the level of expression.

Molecule generation requires satisfying multiple chemical and biological constraints while searching a large and structured chemical space. This makes it a non-binary problem, where effective models must identify non-obvious solutions under constraints while maintaining exploration to improve success by escaping local optima. From this perspective, creativity is a functional requirement in molecular generation rather than an aesthetic notion. Large language models (LLMs) can generate molecular representations directly from natural language prompts, but it remains unclear what type of creativity they exhibit in this setting and how it should be evaluated. In this work, we study the creative behavior of LLMs in molecular generation through a systematic empirical evaluation across physicochemical, ADMET, and biological activity tasks. We characterize creativity along two complementary dimensions, convergent creativity and divergent creativity, and analyze how different factors shape these behaviors. Our results indicate that LLMs exhibit distinct patterns of creative behavior in molecule generation, such as an increase in constraint satisfaction when additional constraints are imposed. Overall, our work is the first to reframe the abilities required for molecule generation as creativity, providing a systematic understanding of creativity in LLM-based molecular generation and clarifying the appropriate use of LLMs in molecular discovery pipelines.

Current single-cell foundation model benchmarks universally extract final layer embeddings, assuming these represent optimal feature spaces. We systematically evaluate layer-wise representations from scFoundation (100M parameters) and Tahoe-X1 (1.3B parameters) across trajectory inference and perturbation response prediction. Our analysis reveals that optimal layers are task-dependent (trajectory peaks at 60% depth, 31% above final layers) and context-dependent (perturbation optima shift 0-96% across T cell activation states). Notably, first-layer embeddings outperform all deeper layers in quiescent cells, challenging assumptions about hierarchical feature abstraction. These findings demonstrate that "where" to extract features matters as much as "what" the model learns, necessitating systematic layer evaluation tailored to biological task and cellular context rather than defaulting to final-layer embeddings.

Protein fitness optimization is a discrete search problem, and the representation used for prediction also determines the neighborhood graph traversed by an optimizer. We introduce Q-BioLat, a framework that maps pretrained protein-language-model embeddings to compact binary codes and fits a quadratic unconstrained binary optimization (QUBO) surrogate with unary and pairwise latent interactions. Our central contribution is an optimization-aware view of representation: binary encodings that are similar in pointwise predictive accuracy can induce different Hamming neighborhoods, local optima, and search trajectories. We formalize when a recoding is only a Hamming-isometric reparameterization and give a constructive example showing that exact pointwise agreement does not imply optimization equivalence. We study experimentally measured GFP and AAV fitness landscapes from ProteinGym. The internal QUBO surrogate is evaluated against labels withheld from QUBO fitting. A conservative retrieval analysis maps optimized codes to measured variants and reports their experimental fitness, while neural decoding of potentially unmeasured sequences is evaluated separately with an experiment-trained sequence surrogate and is interpreted only as model-based candidate prioritization. Across the reported comparisons, PCA followed by per-coordinate median thresholding yields a more balanced and decodable binary space than the post-hoc-zero-threshold AE/VAE baselines, despite the latter's low continuous reconstruction error. In the measured-library retrieval analysis, simulated annealing, genetic algorithms, and greedy hill climbing frequently return high-percentile variants; decoded candidates are reported separately using surrogate-predicted scores.

Modeling dynamical systems and unraveling their underlying structural dependencies is central to many domains in the natural sciences. Various physical systems, such as those arising in cell biology, are inherently high-dimensional and stochastic in nature, and admit only partial, noisy state measurements. Our primary motivating setting is single-cell biology, where destructive measurements yield unpaired population snapshots rather than longitudinal trajectories of the same cells. This poses a significant challenge for addressing the problems of modeling the underlying dynamics and inferring the network structure of these systems. Existing methods are typically tailored either for structure learning or modeling dynamics at the population level, but are limited in their ability to address both problems together. In this work, we address both problems simultaneously: we present StructureFlow, a novel and principled simulation-free training approach for jointly learning the structure and stochastic population dynamics of physical systems. We showcase the utility of StructureFlow for the tasks of structure learning from interventions and dynamical (trajectory) inference of conditional population dynamics. We empirically evaluate our approach on high-dimensional synthetic systems, a set of biologically plausible simulated systems, and an experimental single-cell dataset. We show that StructureFlow can learn the structure of underlying systems while simultaneously modeling their conditional population dynamics --- a key step toward model-based mechanistic understanding of systems behavior.