Artificial and biological systems may evolve similar computational solutions despite fundamental differences in architecture and learning mechanisms -- a form of convergent evolution. We demonstrate this phenomenon through large-scale analysis of alignment between human brain activity and internal representations of over 600 AI models spanning language and vision domains, from 1.33M to 72B parameters. Analyzing 60 million alignment measurements reveals that higher-performing models spontaneously develop stronger brain alignment without explicit neural constraints, with language models showing markedly stronger correlation (r=0.89, p<7.5e-13) than vision models (r=0.53, p<2.0e-44). Crucially, longitudinal analysis demonstrates that brain alignment consistently precedes performance improvements during training, suggesting that developing brain-like representations may be a necessary stepping stone toward higher capabilities. We find systematic patterns: language models exhibit strongest alignment with limbic and integrative regions, while vision models show progressive alignment with visual cortices; deeper processing layers converge across modalities; and as representational scale increases, alignment systematically shifts from primary sensory to higher-order associative regions. These findings provide compelling evidence that optimization for task performance naturally drives AI systems toward brain-like computational strategies, offering both fundamental insights into principles of intelligent information processing and practical guidance for developing more capable AI systems.

This paper investigates whether contemporary AI architectures employing deep recursion, meta-learning, and self-referential mechanisms provide evidence of machine consciousness. Integrating philosophical history, cognitive science, and AI engineering, it situates recursive algorithms within a lineage spanning Cartesian dualism, Husserlian intentionality, Integrated Information Theory, the Global Workspace model, and enactivist perspectives. The argument proceeds through textual analysis, comparative architecture review, and synthesis of neuroscience findings on integration and prediction. Methodologically, the study combines conceptual analysis, case studies, and normative risk assessment informed by phenomenology and embodied cognition. Technical examples, including transformer self-attention, meta-cognitive agents, and neuromorphic chips, illustrate how functional self-modeling can arise without subjective experience. By distinguishing functional from phenomenal consciousness, the paper argues that symbol grounding, embodiment, and affective qualia remain unresolved barriers to attributing sentience to current AI. Ethical analysis explores risks of premature anthropomorphism versus neglect of future sentient systems; legal implications include personhood, liability, authorship, and labor impacts. Future directions include quantum architectures, embodied robotics, unsupervised world modeling, and empirical tests for non-biological phenomenality. The study reframes the "hard problem" as a graded and increasingly testable phenomenon, rather than a metaphysical impasse. It concludes that recursive self-referential design enhances capability but does not entail consciousness or justify moral status. Keywords: Recursive algorithms; self-reference; machine consciousness; AI ethics; AI consciousness

This work investigates the benefits of implementing a systematic approach to social isolation policies during epidemics. We develop a mixed integer data-driven model predictive control (MPC) scheme based on an SIHRD model which is identified from available data. The case of the spread of the SARS-CoV-2 virus (also known as COVID-19) in Mauritius is used as a reference point with data obtained during the period December 2021 to May 2022. The isolation scheme is designed with the control decision variable taking a finite set of values corresponding to the desired level of isolation. The control input is further restricted to shifting between levels only after a minimum amount of time. The simulation results validate our design, showing that the need for hospitalisation remains within the capacity of the health centres, with the number of deaths considerably reduced by raising the level of isolation for short periods of time with negligible social and economic impact. We also show that the introduction of additional isolation levels results in a smoother containment approach with a considerably reduced hospitalisation burden.

Background: In vitro endothelial cell culture is widely used to study angiogenesis. Histomicrographic images of cell networks are often analyzed manually, a process that is time-consuming and subjective. Automated tools like ImageJ (NIH) can assist, but are often slow and inaccurate. Additionally, as endothelial networks grow more complex, traditional architectural metrics may not fully reflect network maturity. To address these limitations, we developed tubuleTracker, a software tool that quantifies endothelial network architecture and maturity rapidly and objectively. Methods: Human umbilical vein endothelial cells were cultured in an extracellular matrix, and 54 images were acquired using phase contrast microscopy. Each image was analyzed manually by three independent reviewers, and by both ImageJ and tubuleTracker. Key metrics included tubule count, total length, node count, tubule area, and vessel circularity. In parallel, trained scientists rated each image for angiogenesis maturity on a 1-5 scale (1 = most mature). Results: Analysis time per image differed significantly: manual (8 min), ImageJ (58+/-4 s), and tubuleTracker (6+/-2 s) (p<0.0001). Significant differences were also found in tubule count (manual 168+/-SD, tubuleTracker 92+/-SD, ImageJ 433+/-SD), length, and node count (all p<0.0001). tubuleTracker's metrics varied significantly across angiogenesis maturity scores, including tubule count, length, node count, area, and circularity (all p<0.0001). Conclusions: tubuleTracker was faster and more consistent than both manual and ImageJ-based analysis. Vessel circularity proved especially effective in capturing angiogenesis maturity. tubuleTracker is available as free shareware for the biomedical research community.

We introduce IntFold, a controllable foundation model for general and specialized biomolecular structure prediction. Utilizing a high-performance custom attention kernel, IntFold achieves accuracy comparable to the state-of-the-art AlphaFold 3 on a comprehensive benchmark of diverse biomolecular structures, while also significantly outperforming other leading all-atom prediction approaches. The model's key innovation is its controllability, enabling downstream applications critical for drug screening and design. Through specialized adapters, it can be precisely guided to predict complex allosteric states, apply user-defined structural constraints, and estimate binding affinity. Furthermore, we present a training-free, similarity-based method for ranking predictions that improves success rates in a model-agnostic manner. This report details these advancements and shares insights from the training and development of this large-scale model.

Grid cells in the medial entorhinal cortex (MEC) are believed to path integrate speed and direction signals to activate at triangular grids of locations in an environment, thus implementing a population code for position. In parallel, place cells in the hippocampus (HC) fire at spatially confined locations, with selectivity tuned not only to allocentric position but also to environmental contexts, such as sensory cues. Although grid and place cells both encode spatial information and support memory for multiple locations, why animals maintain two such representations remains unclear. Noting that place representations seem to have other functional roles in intrinsically motivated tasks such as recalling locations from sensory cues, we propose that animals maintain grid and place representations together to support planning. Specifically, we posit that place cells auto-associate not only sensory information relayed from the MEC but also grid cell patterns, enabling recall of goal location grid patterns from sensory and motivational cues, permitting subsequent planning with only grid representations. We extend a previous theoretical framework for grid-cell-based planning and show that local transition rules can generalize to long-distance path forecasting. We further show that a planning network can sequentially update grid cell states toward the goal. During this process, intermediate grid activity can trigger place cell pattern completion, reconstructing experiences along the planned path. We demonstrate all these effects using a single-layer RNN that simultaneously models the HC-MEC loop and the planning subnetwork. We show that such recurrent mechanisms for grid cell-based planning, with goal recall driven by the place system, make several characteristic, testable predictions.

Populations experience a complex interplay of continuous and discrete processes: continuous growth and interactions are punctuated by discrete reproduction events, dispersal, and external disturbances. These dynamics can be modeled by impulsive or flow-kick systems, where continuous flows alternate with instantaneous discrete changes. To study species persistence in these systems, an invasion growth rate theory is developed for flow-kick models with state-dependent timing of kicks and auxiliary variables. The invasion growth rates are Lyapunov exponents characterizing the average per-capita growth of species when rare. Two theorems are proven to characterize permanence i.e. the extinction set is a repellor. The first theorem uses Morse decompositions of the extinction set and requires that there exists a species with a positive invasion growth rate for every invariant measure supported on a component of the Morse decomposition. The second theorem uses invasion growth rates to define invasion graphs whose vertices correspond to communities and directed edges to potential invasions. Provided the invasion graph is acyclic, permanence is fully characterized by the signs of the invasion growth rates. Invasion growth rates are also used to identify the existence of extinction-bound trajectories and attractors that lie on the extinction set. The results are illustrated with three applications: (i) a microbial serial transfer model, (ii) a spatially structured consumer-resource model, and (iii) an empirically parameterized Lotka-Volterra model. Mathematical challenges and promising biological applications are discussed.

A significant hallmark of hypertrophic cardiomyopathy (HCM) is fiber disarray, which is associated with various cardiac events such as heart failure. Quantifying fiber disarray remains critical for understanding the disease s complex pathophysiology. This study investigates the role of heterogeneous HCM-induced cellular abnormalities in the development of fiber disarray and their subsequent impact on cardiac pumping function. Fiber disarray is predicted using a stress-based law to reorient myofibers and collagen within a multiscale finite element cardiac modeling framework, MyoFE. Specifically, the model is used to quantify the distinct impacts of heterogeneous distributions of hypercontractility, hypocontractility, and fibrosis on fiber disarray development and examines their effect on functional characteristics of the heart. Our results show that heterogenous cell level abnormalities highly disrupt the normal mechanics of myocardium and lead to significant fiber disarray. The pattern of disarray varies depending on the specific perturbation, offering valuable insights into the progression of HCM. Despite the random distribution of perturbed regions within the cardiac muscle, significantly higher fiber disarray is observed near the epicardium compared to the endocardium across all perturbed left ventricle (LV) models. This regional difference in fiber disarray, irrespective of perturbation severity, aligns with previous DT-MRI studies, highlighting the role of regional myocardial mechanics in the development of fiber disarray. Furthermore, cardiac performance declined in the remodeled LVs, particularly in those with fibrosis and hypocontractility. These findings provide important insights into the structural and functional consequences of HCM and offer a framework for future investigations into therapeutic interventions targeting cardiac remodeling.

Hyperosmolarity is a key contributor to nucleus pulposus cell (NPC) apoptosis during intervertebral disc degeneration (IVDD). Aquaporin 3 (AQP3), a membrane channel protein, regulates cellular osmotic balance by transporting water and osmolytes. Although AQP3 downregulation is associated with disc degeneration, its role in apoptosis under hyperosmotic conditions remains unclear. Here, we demonstrate that hyperosmolarity induces AQP3 depletion, suppresses the PI3K/AKT/mTOR signaling pathway, and promotes mitochondrial dysfunction and ROS accumulation in NPCs. Lentiviral overexpression of AQP3 restores this pathway, attenuates oxidative damage, and reduces apoptosis, preserving disc structure in IVDD rat models. In contrast, pharmacological inhibition of AQP3 exacerbates ECM catabolism and NP tissue loss. Our findings reveal that AQP3 deficiency under hyperosmolarity contributes to NPC apoptosis via suppression of PI3K/AKT/mTOR signaling, potentially creating a pathological cycle of disc degeneration. These results highlight AQP3 as a promising therapeutic target for IVDD.

Delineating how animal behavior arises from neural activity is a foundational goal of neuroscience. However, as the computations underlying behavior unfold in networks of thousands of individual neurons across the entire brain, this presents challenges for investigating neural roles and computational mechanisms in large, densely wired mammalian brains during behavior. Transformers, the backbones of modern large language models (LLMs), have become powerful tools for neural decoding from smaller neural populations. These modern LLMs have benefited from extensive pre-training, and their sequence-to-sequence learning has been shown to generalize to novel tasks and data modalities, which may also confer advantages for neural decoding from larger, brain-wide activity recordings. Here, we present a systematic evaluation of off-the-shelf LLMs to decode behavior from brain-wide populations, termed NLP4Neuro, which we used to test LLMs on simultaneous calcium imaging and behavior recordings in larval zebrafish exposed to visual motion stimuli. Through NLP4Neuro, we found that LLMs become better at neural decoding when they use pre-trained weights learned from textual natural language data. Moreover, we found that a recent mixture-of-experts LLM, DeepSeek Coder-7b, significantly improved behavioral decoding accuracy, predicted tail movements over long timescales, and provided anatomically consistent highly interpretable readouts of neuron salience. NLP4Neuro demonstrates that LLMs are highly capable of informing brain-wide neural circuit dissection.

Analyzing network structural connectivity is crucial for understanding dynamics and functions of complex networks across disciplines. In many networks, structural connectivity is not observable, which requires to be inferred via causal inference methods. Among them, transfer entropy (TE) is one of the most broadly applied causality measure due to its model-free property. However, TE often faces the curse of dimensionality in high-dimensional probability estimation, and the relation between the inferred causal connectivity and the underlying structural connectivity remains poorly understood. Here we address these issues by proposing a pairwise time-delayed transfer entropy (PTD-TE) method. We theoretically establish a quadratic relationship between PTD-TE values and node coupling strengths, and demonstrate its immunity to dimensionality issues and broad applicability. Tests on biological neuronal networks, nonlinear physical systems, and electrophysiological data show PTD-TE achieves consistent, high-performance reconstructions. Compared to a bunch of existing approaches for network connectivity reconstruction, PTD-TE outperforms these methods across various network systems in accuracy and robustness against noise. Our framework provides a scalable, model-agnostic tool for structural connectivity inference in nonlinear real-world networks.

Teachers hold a prominent place in modern societies, particularly where education is compulsory and widely institutionalized. This ubiquity obscures an underlying question: why do societies designate certain individuals exclusively for the instruction of others? This question is especially enigmatic for dedicated teachers, who invest their labor in cultivating others' skills but do not directly participate in the productive activities for which their students are being trained. To address this puzzle, we develop a simple, mathematically tractable model of teaching and learning in a population with a shared goal. We identify a tradeoff between the size of the workforce and its collective level of expertise; and we analyze the optimal proportion of a population that should serve as teachers across a wide range of scenarios. We show that a population must exceed a critical size before it is beneficial to allocate anyone as a dedicated teacher at all. Subsequently, the peak demand for teachers is achieved at an intermediate population size, and it never surpasses one half of the population. For more complicated tasks, our analysis predicts the optimal allocation of teachers across different levels of expertise. The structure of this teacher allocation is more complex when the population size is large, in agreement with the general size-complexity hypothesis. Our account lays a foundation for understanding the adaptive advantage of dedicated teachers in both human and non-human societies.

Antibody engineering is essential for developing therapeutics and advancing biomedical research. Traditional discovery methods often rely on time-consuming and resource-intensive experimental screening. To enhance and streamline this process, we introduce a production-grade, high-throughput platform built on HelixFold3, HelixDesign-Antibody, which utilizes the high-accuracy structure prediction model, HelixFold3. The platform facilitates the large-scale generation of antibody candidate sequences and evaluates their interaction with antigens. Integrated high-performance computing (HPC) support enables high-throughput screening, addressing challenges such as fragmented toolchains and high computational demands. Validation on multiple antigens showcases the platform's ability to generate diverse and high-quality antibodies, confirming a scaling law where exploring larger sequence spaces increases the likelihood of identifying optimal binders. This platform provides a seamless, accessible solution for large-scale antibody design and is available via the antibody design page of PaddleHelix platform.

Understanding brain dynamics and functions critically depends on knowledge of the network connectivity among neurons. However, the complexity of brain structural connectivity, coupled with continuous modifications driven by synaptic plasticity, makes its direct experimental measurement particularly challenging. Conventional connectivity inference methods based on neuronal recordings often assumes a static underlying structural connectivity and requires stable statistical features of neural activities, making them unsuitable for reconstructing structural connectivity that undergoes changes. To fulfill the needs of reconstructing networks undergoing potential structural changes, we propose a unified network reconstruction framework that combines connectivity-induced change point detection (CPD) with pairwise time-delayed correlation coefficient (TDCC) method. For general neuronal networks in balanced regimes, we develop a theoretical analysis for discriminating changes in structural connectivity based on the fluctuation of neuronal voltage time series. We then demonstrate a pairwise TDCC method to reconstruct the network using spike train recordings segmented at the detected change points. We show the effectiveness of our CPD-TDCC network reconstruction using large-scale network simulations with multiple neuronal models. Crucially, our method accommodates networks with changes in both network topologies and synaptic coupling strengths while retaining accuracy even with sparsely sampled subnetwork data, achieving a critical advancement for practical applications in real experimental situations. Our CPD-TDCC framework addresses the critical gap in network reconstruction by accounting connectivity-induced changes points, potentially offering a valuable tool for studying structure and dynamics in the cortical brain.

This study explores the historical ecology of the Bavarian Forest at the threshold of modernity through the lens of a large-scale biodiversity survey conducted in 1845 across the Kingdom of Bavaria. Focusing on the Forestry Office of Zwiesel, the article analyses archival records that document the distribution of animal and tree species during a period of administrative rationalisation and early scientific systematisation. These sources include official correspondence, detailed species inventories, and early distribution maps compiled under the direction of zoologist Johann Andreas Wagner. The study highlights local and regional observations of fauna, such as the Eurasian lynx, capercaillie, and various freshwater fish, and presents new data on historical forest composition, including the presence of rare tree species and venerable specimen trees such as the "Urwaldtanne" and the "Wolframslinde". By integrating historical ecology, environmental history, and digital humanities, the article sheds light on how 19th-century state institutions, scientific actors, and local knowledge contributed to the early documentation of biodiversity. The findings also offer a basis for long-term environmental comparisons and inform current conservation efforts in the region.

This work presents a comprehensive theory of consciousness grounded in mathematical formalism and supported by clinical data analysis. The framework developed herein demonstrates that consciousness exists as a continuous, non-monotonic function across a high-dimensional neurochemical space, with dopamine serving as the primary intensity regulator and serotonin (5-HT2A) as the complexity modulator. This work offers mechanistic explanations for the full spectrum of conscious states, from deep sleep and psychosis to the ultimate collapse in neural death. The theory explains paradoxical phenomena such as prefrontal cortex hypoactivity during seizures, the evolutionary persistence of psychosis-prone individuals, and why controlled administration of classical 5-HT2A agonists shows a comparatively low incidence of serious medical events (< 0.01 % in modern clinical trials), while dopaminergic excess proves rapidly lethal. The framework is tested using 70,290 sleep nights from 242 Parkinson's disease patients, using disease severity (UPDRS) as a proxy for system integrity and medication (LEDD) as a proxy for dopaminergic input. The analysis reveals a significant LEDD x UPDRS interaction (beta=-1.7, p<.0001), confirming the model's prediction of state-dependent, non-linear dynamics.

Long-term biomolecular dynamics are critical for understanding key evolutionary transformations in molecular systems. However, capturing these processes requires extended simulation timescales that often exceed the practical limits of conventional models. To address this, shorter simulations, initialized with diverse perturbations, are commonly used to sample phase space and explore a wide range of behaviors. Recent advances have leveraged language models to infer long-term behavior from short trajectories, but methods such as long short-term memory (LSTM) networks are constrained to low-dimensional reaction coordinates, limiting their applicability to complex systems. In this work, we present nano-GPT, a novel deep learning model inspired by the GPT architecture, specifically designed to capture long-term dynamics in molecular systems with fine-grained conformational states and complex transitions. The model employs a two-pass training mechanism that incrementally replaces molecular dynamics (MD) tokens with model-generated predictions, effectively mitigating accumulation errors inherent in the training window. We validate nano-GPT on three distinct systems: a four-state model potential, the alanine dipeptide, a well-studied simple molecule, and the Fip35 WW domain, a complex biomolecular system. Our results show that nano-GPT effectively captures long-timescale dynamics by learning high-order dependencies through attention mechanism, offering a novel perspective for interpreting biomolecular processes.

Predicting drug responses using genetic and transcriptomic features is crucial for enhancing personalized medicine. In this study, we implemented an ensemble of machine learning algorithms to analyze the correlation between genetic and transcriptomic features of cancer cell lines and IC50 values, a reliable metric for drug efficacy. Our analysis involved a reduction of the feature set from an original pool of 38,977 features, demonstrating a strong linear relationship between genetic features and drug responses across various algorithms, including SVR, Linear Regression, and Ridge Regression. Notably, copy number variations (CNVs) emerged as more predictive than mutations, suggesting a significant reevaluation of biomarkers for drug response prediction. Through rigorous statistical methods, we identified a highly reduced set of 421 critical features. This set offers a novel perspective that contrasts with traditional cancer driver genes, underscoring the potential for these biomarkers in designing targeted therapies. Furthermore, our findings advocate for IC50 values as a predictable measurement of drug responses and underscore the need for more data that can represent the dimensionality of genomic data in drug response prediction. Future work will aim to expand the dataset and refine feature selection to enhance the generalizability of the predictive model in clinical settings.

The rapid growth of biomedical data, tools, and literature has created a fragmented research landscape that outpaces human expertise. While AI agents offer a solution, they typically rely on static, manually curated toolsets, limiting their ability to adapt and scale. Here, we introduce STELLA, a self-evolving AI agent designed to overcome these limitations. STELLA employs a multi-agent architecture that autonomously improves its own capabilities through two core mechanisms: an evolving Template Library for reasoning strategies and a dynamic Tool Ocean that expands as a Tool Creation Agent automatically discovers and integrates new bioinformatics tools. This allows STELLA to learn from experience. We demonstrate that STELLA achieves state-of-the-art accuracy on a suite of biomedical benchmarks, scoring approximately 26\% on Humanity's Last Exam: Biomedicine, 54\% on LAB-Bench: DBQA, and 63\% on LAB-Bench: LitQA, outperforming leading models by up to 6 percentage points. More importantly, we show that its performance systematically improves with experience; for instance, its accuracy on the Humanity's Last Exam benchmark almost doubles with increased trials. STELLA represents a significant advance towards AI Agent systems that can learn and grow, dynamically scaling their expertise to accelerate the pace of biomedical discovery.

Modern AI models, such as large language models, are usually trained once on a huge corpus of data, potentially fine-tuned for a specific task, and then deployed with fixed parameters. Their training is costly, slow, and gradual, requiring billions of repetitions. In stark contrast, animals continuously adapt to the ever-changing contingencies in their environments. This is particularly important for social species, where behavioral policies and reward outcomes may frequently change in interaction with peers. The underlying computational processes are often marked by rapid shifts in an animal's behaviour and rather sudden transitions in neuronal population activity. Such computational capacities are of growing importance for AI systems operating in the real world, like those guiding robots or autonomous vehicles, or for agentic AI interacting with humans online. Can AI learn from neuroscience? This Perspective explores this question, integrating the literature on continual and in-context learning in AI with the neuroscience of learning on behavioral tasks with shifting rules, reward probabilities, or outcomes. We will outline an agenda for how specifically insights from neuroscience may inform current developments in AI in this area, and - vice versa - what neuroscience may learn from AI, contributing to the evolving field of NeuroAI.

The basic reproduction number (R_0) is an epidemiological metric that represents the average number of new infections caused by a single infectious individual in a completely susceptible population. The methodology for calculating this metric is well-defined for numerous model types, including, most prominently, Ordinary Differential Equations (ODEs). The basic reproduction number is used in disease modeling to predict the potential of an outbreak and the transmissibility of a disease, as well as by governments to inform public health interventions and resource allocation for controlling the spread of diseases. A Petri net (PN) is a directed bipartite graph where places, transitions, arcs, and the firing of the arcs determine the dynamic behavior of the system. Petri net models have been an increasingly used tool within the epidemiology community. However, a generalized method for calculating R_0 directly from PN models has not been established. Thus, in this paper, we present a general method for calculating R_0 for Petri nets. Additionally, we show how a computational method implementing the next-generation algorithm in ODE models can also be applied to Petri net models. We also provide multiple examples of how to use this approach to calculate 0 for various SIR-type Petri net models.

Dynamic positron emission tomography (PET) and kinetic modeling are pivotal in advancing tracer development research in small animal studies. Accurate kinetic modeling requires precise input function estimation, traditionally achieved via arterial blood sampling. However, arterial cannulation in small animals like mice, involves intricate, time-consuming, and terminal procedures, precluding longitudinal studies. This work proposes a non-invasive, fully convolutional deep learning-based approach (FC-DLIF) to predict input functions directly from PET imaging, potentially eliminating the need for blood sampling in dynamic small-animal PET. The proposed FC-DLIF model includes a spatial feature extractor acting on the volumetric time frames of the PET sequence, extracting spatial features. These are subsequently further processed in a temporal feature extractor that predicts the arterial input function. The proposed approach is trained and evaluated using images and arterial blood curves from [$^{18}$F]FDG data using cross validation. Further, the model applicability is evaluated on imaging data and arterial blood curves collected using two additional radiotracers ([$^{18}$F]FDOPA, and [$^{68}$Ga]PSMA). The model was further evaluated on data truncated and shifted in time, to simulate shorter, and shifted, PET scans. The proposed FC-DLIF model reliably predicts the arterial input function with respect to mean squared error and correlation. Furthermore, the FC-DLIF model is able to predict the arterial input function even from truncated and shifted samples. The model fails to predict the AIF from samples collected using different radiotracers, as these are not represented in the training data. Our deep learning-based input function offers a non-invasive and reliable alternative to arterial blood sampling, proving robust and flexible to temporal shifts and different scan durations.

Autonomous scientific research, capable of independently conducting complex experiments and serving non-specialists, represents a long-held aspiration. Achieving it requires a fundamental paradigm shift driven by artificial intelligence (AI). While autonomous experimental systems are emerging, they remain confined to areas featuring singular objectives and well-defined, simple experimental workflows, such as chemical synthesis and catalysis. We present an AI-native autonomous laboratory, targeting highly complex scientific experiments for applications like autonomous biomolecular engineering. This system autonomously manages instrumentation, formulates experiment-specific procedures and optimization heuristics, and concurrently serves multiple user requests. Founded on a co-design philosophy of models, experiments, and instruments, the platform supports the co-evolution of AI models and the automation system. This establishes an end-to-end, multi-user autonomous laboratory that handles complex, multi-objective experiments across diverse instrumentation. Our autonomous laboratory supports fundamental nucleic acid functions-including synthesis, transcription, amplification, and sequencing. It also enables applications in fields such as disease diagnostics, drug development, and information storage. Without human intervention, it autonomously optimizes experimental performance to match state-of-the-art results achieved by human scientists. In multi-user scenarios, the platform significantly improves instrument utilization and experimental efficiency. This platform paves the way for advanced biomaterials research to overcome dependencies on experts and resource barriers, establishing a blueprint for science-as-a-service at scale.

Therapeutic antibodies require not only high-affinity target engagement, but also favorable manufacturability, stability, and safety profiles for clinical effectiveness. These properties are collectively called `developability'. To enable a computational framework for optimizing antibody sequences for favorable developability, we introduce a guided discrete diffusion model trained on natural paired heavy- and light-chain sequences from the Observed Antibody Space (OAS) and quantitative developability measurements for 246 clinical-stage antibodies. To steer generation toward biophysically viable candidates, we integrate a Soft Value-based Decoding in Diffusion (SVDD) Module that biases sampling without compromising naturalness. In unconstrained sampling, our model reproduces global features of both the natural repertoire and approved therapeutics, and under SVDD guidance we achieve significant enrichment in predicted developability scores over unguided baselines. When combined with high-throughput developability assays, this framework enables an iterative, ML-driven pipeline for designing antibodies that satisfy binding and biophysical criteria in tandem.

Recent advances in AI for science have highlighted the power of contrastive learning in bridging heterogeneous biological data modalities. Building on this paradigm, we propose HIPPO (HIerarchical Protein-Protein interaction prediction across Organisms), a hierarchical contrastive framework for protein-protein interaction(PPI) prediction, where protein sequences and their hierarchical attributes are aligned through multi-tiered biological representation matching. The proposed approach incorporates hierarchical contrastive loss functions that emulate the structured relationship among functional classes of proteins. The framework adaptively incorporates domain and family knowledge through a data-driven penalty mechanism, enforcing consistency between the learned embedding space and the intrinsic hierarchy of protein functions. Experiments on benchmark datasets demonstrate that HIPPO achieves state-of-the-art performance, outperforming existing methods and showing robustness in low-data regimes. Notably, the model demonstrates strong zero-shot transferability to other species without retraining, enabling reliable PPI prediction and functional inference even in less characterized or rare organisms where experimental data are limited. Further analysis reveals that hierarchical feature fusion is critical for capturing conserved interaction determinants, such as binding motifs and functional annotations. This work advances cross-species PPI prediction and provides a unified framework for interaction prediction in scenarios with sparse or imbalanced multi-species data.

Extracellular vesicles (EVs) are cell-derived secretions that mediate tissue homeostasis and intercellular communication through their diverse cargos, such as proteins. Distinct EV biogenesis pathways suggest specific association and co-enrichment of proteins sharing a biogenesis pathway, and non-association and co-depletion of proteins segregated into distinct pathways. Yet these associations elude conventional protein expression or co-expression measurements. Here, we propose and define pairwise protein co-enrichment (CoEn) to quantify whether a given protein is co-enriched or co-depleted with another protein relative to its overall expression. We measure CoEn, and differential CoEn (dCoEn) between a stimulus and a reference condition, of up to 240 protein pairs in EVs using antibody microarrays. We validate CoEn by modulating well-known EV biogenesis pathways, and find that dCoEn quantifies expected changes between perturbed and reference conditions while uncovering new ones; CoEn and dCoEn in three model cell lines and parental and organotropic breast cancer progeny cell lines reveals both preserved and variable CoEn that may warrant further studies. Collectively, our result suggest that CoEn reflects and illuminates cell physiology and EV biogenies, is readily measurable, and could further serve as quality control in EV biomanufacturing as well as underpin new EV biomarkers.

In the last decade, some algebraic tools have been successfully applied to phylogenetic reconstruction. These tools are mainly based on the knowledge of equations describing algebraic varieties associated to phylogenetic trees evolving under Markov processes of molecular substitution, the so called phylogenetic invariants. Although the theory involved allows to explicitly obtain these equations for all equivariant models (which include some of the most popular nucleotide substitution models), practical uses of these algebraic tools have been restricted to the case of the general Markov model. Arguably, one of the reasons for this restriction is that knowledge of linear representation theory is required before making these equations explicit. With the aim of enlarging the practical uses of algebraic phylogenetics, in this paper we prove that phylogenetic invariants for trees evolving under equivariant models can be derived from phylogenetic invariants for the general Markov model, without the need of representation theory. Our main result states that the algebraic variety corresponding to a phylogenetic tree evolving under an equivariant model is an irreducible component of the variety corresponding to the same tree under the general Markov model cut with the linear space defined by the model. We also prove that, for any equivariant model, those phylogenetic invariants that are relevant for practical uses (e.g. tree reconstruction) can be simply deduced from a single rank constraint on the matrices obtained by flattening the joint distribution at the leaves of the tree. This condition can be easily tested from singular values of the matrices and extends our results from trees to phylogenetic networks.

Conscious experience permeates our daily lives, yet general consensus on a theory of consciousness remains elusive. In the face of such difficulty, an alternative strategy is to address a more general (meta-level) version of the problem for insights into the original problem at hand. Category theory was developed for this purpose, i.e. as an axiomatic (meta-)mathematical theory for comparison of mathematical structures, and so affords a (formally) formal approach towards a theory of consciousness. In this way, category theory is used for comparison with Information Integration Theory (IIT) as a supposed axiomatic theory of consciousness, which says that every conscious state involves six axiomatic properties: the IIT axioms for consciousness. All six axioms are shown to follow from the categorical notion of a universal mapping property: a unique-existence condition for all instances in the domain of interest. Accordingly, this categorical approach affords a formal basis for further development of a (meta-)mathematical theory of consciousness, whence the slogan, ``Consciousness is a universal property.''

While cancer has traditionally been considered a genetic disease, mounting evidence indicates an important role for non-genetic (epigenetic) mechanisms. Common anti-cancer drugs have recently been observed to induce the adoption of non-genetic drug-tolerant cell states, thereby accelerating the evolution of drug resistance. This confounds conventional high-dose treatment strategies aimed at maximal tumor reduction, since high doses can simultaneously promote non-genetic resistance. In this work, we study optimal dosing of anti-cancer treatment under drug-induced cell plasticity. We show that the optimal dosing strategy steers the tumor to a fixed equilibrium composition between sensitive and tolerant cells, while precisely balancing the trade-off between cell kill and tolerance induction. The optimal equilibrium strategy ranges from applying a low dose continuously to applying the maximum dose intermittently, depending on the dynamics of tolerance induction. We finally discuss how our approach can be integrated with in vitro data to derive patient-specific treatment insights.

We develop a general modelling framework for compartmental epidemiological systems structured by continuous variables which are linked to the levels of expression of compartment-specific traits. We start by formulating an individual-based model that describes the dynamics of single individuals in terms of stochastic processes. Then we formally derive: (i) the mesoscopic counterpart of this model, which is formulated as a system of integro-differential equations for the distributions of individuals over the structuring-variable domains of the different compartments; (ii) the corresponding macroscopic model, which takes the form of a system of ordinary differential equations for the fractions of individuals in the different compartments and the mean levels of expression of the traits represented by the structuring variables. We employ a reduced version of the macroscopic model to obtain a general formula for the basic reproduction number, $\mathcal{R}_0$, in terms of key parameters and functions of the underlying microscopic model, so as to illustrate how such a modelling framework makes it possible to draw connections between fundamental individual-level processes and population-scale dynamics. Finally we apply the modelling framework to case studies based on classical compartmental epidemiological systems, for each of which we report on Monte Carlo simulations of the individual-based model as well as on analytical results and numerical solutions of the macroscopic model.

Chemical reaction networks underpin biological and physical phenomena across scales, from microbial interactions to planetary atmosphere dynamics. Bacterial communities exhibit complex competitive interactions for resources, human organs and tissues demonstrate specialized biochemical functions, and planetary atmospheres are capable of displaying diverse organic and inorganic chemical processes. Despite their complexities, comparing these networks methodically remains a challenge due to the vast underlying degrees of freedom. In biological systems, comparative genomics has been pivotal in tracing evolutionary trajectories and classifying organisms via DNA sequences. However, purely genomic classifications often fail to capture functional roles within ecological systems. Metabolic changes driven by nutrient availability highlight the need for classification schemes that integrate metabolic information. Here we introduce and apply a computational framework for a classification scheme of organisms that compares matrix representations of chemical reaction networks using the Grassmann distance, corresponding to measuring distances between the fundamental subspaces of stoichiometric matrices. Applying this framework to human gut microbiome data confirms that metabolic distances are distinct from phylogenetic distances, underscoring the limitations of genetic information in metabolic classification. Importantly, our analysis of metabolic distances reveals functional groups of organisms enriched or depleted in specific metabolic processes and shows robustness to metabolically silent genetic perturbations. The generalizability of metabolic Grassmann distances is illustrated by application to chemical reaction networks in human tissue and planetary atmospheres, highlighting its potential for advancing functional comparisons across diverse chemical reaction systems.

Neuronal circuits of the cerebral cortex are the structural basis of mammalian cognition. The same qualitative components and connectivity motifs are repeated across functionally specialized cortical areas and mammalian species, suggesting a single underlying algorithmic motif. Here, we propose a perspective on current knowledge of the cortical structure, from which we extract two core principles for computational modeling. The first principle is that cortical cell types fulfill distinct computational roles. The second principle is that cortical connectivity can be efficiently characterized by only a few canonical blueprints of connectivity between cell types. Starting with these two foundational principles, we outline a general framework for building functional and mechanistic models of cortical circuits.

Intrinsically disordered regions (IDRs) account for one-third of the human proteome and play essential biological roles. However, predicting the functions of IDRs remains a major challenge due to their lack of stable structures, rapid sequence evolution, and context-dependent behavior. Many predictors of protein function neglect or underperform on IDRs. Recent advances in computational biology and machine learning, including protein language models, alignment-free approaches, and IDR-specific methods, have revealed conserved bulk features and local motifs within IDRs that are linked to function. This review highlights emerging computational methods that map the sequence-function relationship in IDRs, outlines critical challenges in IDR function annotation, and proposes a community-driven framework to accelerate interpretable functional predictions for IDRs.

The paradigm of large language models in natural language processing (NLP) has also shown promise in modeling biological languages, including proteins, RNA, and DNA. Both the auto-regressive generation paradigm and evaluation metrics have been transferred from NLP to biological sequence modeling. However, the intrinsic structural correlations in natural and biological languages differ fundamentally. Therefore, we revisit the notion of language in biological systems to better understand how NLP successes can be effectively translated to biological domains. By treating the 3D structure of biomolecules as the semantic content of a sentence and accounting for the strong correlations between residues or bases, we highlight the importance of structural evaluation and demonstrate the applicability of the auto-regressive paradigm in biological language modeling. Code can be found at \href{this https URL}{this http URL}

Mild Cognitive Impairment (MCI) is a critical transitional stage between normal cognitive aging and dementia, making its early detection essential. This study investigates the neural mechanisms of distractor suppression in MCI patients using EEG and behavioral data during an attention-cueing Eriksen flanker task. A cohort of 56 MCIs and 26 healthy controls (HCs) performed tasks with congruent and incongruent stimuli of varying saliency levels. During these tasks, EEG data were analyzed for alpha band coherence's functional connectivity, focusing on Global Efficiency (GE), while Reaction Time (RT) and Hit Rate (HR) were also collected. Our findings reveal significant interactions between congruency, saliency, and cognitive status on GE, RT, and HR. In HCs, congruent conditions resulted in higher GE (p = 0.0114, multivariate t-distribution correction, MVT), faster RTs (p < 0.0001, MVT), and higher HRs (p < 0.0001, MVT) compared to incongruent conditions. HCs also showed increased GE in salient conditions for incongruent trials (p = 0.0406, MVT). MCIs exhibited benefits from congruent conditions with shorter RTs and higher HRs (both p < 0.0001, MVT) compared to incongruent conditions but showed reduced adaptability in GE, with no significant GE differences between conditions. These results highlight the potential of alpha band coherence and GE as early markers for cognitive impairment. By integrating GE, RT, and HR, this study provides insights into the interplay between neural efficiency, processing speed, and task accuracy. This approach offers valuable insights into cognitive load management and interference effects, indicating benefits for interventions aimed at improving attentional control and processing speed in MCIs.

Molecular machine learning has gained popularity with the advancements of geometric deep learning. In parallel, retrieval-augmented generation has become a principled approach commonly used with language models. However, the optimal integration of retrieval augmentation into molecular machine learning remains unclear. Graph neural networks stand to benefit from clever matching to understand the structural alignment of retrieved molecules to a query molecule. Neural graph matching offers a compelling solution by explicitly modeling node and edge affinities between two structural graphs while employing a noise-robust, end-to-end neural network to learn affinity metrics. We apply this approach to mass spectrum simulation and introduce MARASON, a novel model that incorporates neural graph matching to enhance a fragmentation-based neural network. Experimental results highlight the effectiveness of our design, with MARASON achieving 28% top-1 accuracy, a substantial improvement over the non-retrieval state-of-the-art accuracy of 19%. Moreover, MARASON outperforms both naive retrieval-augmented generation methods and traditional graph matching approaches. Code is publicly available at this https URL

Algorithms for machine learning-guided design, or design algorithms, use machine learning-based predictions to propose novel objects with desired property values. Given a new design task -- for example, to design novel proteins with high binding affinity to a therapeutic target -- one must choose a design algorithm and specify any hyperparameters and predictive and/or generative models involved. How can these decisions be made such that the resulting designs are successful? This paper proposes a method for design algorithm selection, which aims to select design algorithms that will produce a distribution of design labels satisfying a user-specified success criterion -- for example, that at least ten percent of designs' labels exceed a threshold. It does so by combining designs' predicted property values with held-out labeled data to reliably forecast characteristics of the label distributions produced by different design algorithms, building upon techniques from prediction-powered inference. The method is guaranteed with high probability to return design algorithms that yield successful label distributions (or the null set if none exist), if the density ratios between the design and labeled data distributions are known. We demonstrate the method's effectiveness in simulated protein and RNA design tasks, in settings with either known or estimated density ratios.

Understanding the dynamics of excitation patterns in neural fields is an important topic in neuroscience. Neural field equations are mathematical models that describe the excitation dynamics of interacting neurons to perform the theoretical analysis. Although many analyses of neural field equations focus on the effect of neuronal interactions on the flat surface, the geometric constraint of the dynamics is also an attractive topic when modeling organs such as the brain. This paper reports pattern dynamics in a neural field equation defined on spheroids as model curved surfaces. We treat spot solutions as localized patterns and discuss how the geometric properties of the curved surface change their properties. To analyze spot patterns on spheroids with small flattening, we first construct exact stationary spot solutions on the spherical surface and reveal their stability. We then extend the analysis to show the existence and stability of stationary spot solutions in the spheroidal case. One of our theoretical results is the derivation of a stability criterion for stationary spot solutions localized at poles on oblate spheroids. The criterion determines whether a spot solution remains at a pole or moves away. Finally, we conduct numerical simulations to discuss the dynamics of spot solutions with the insight of our theoretical predictions. Our results show that the dynamics of spot solutions depend on the curved surface and the coordination of neural interactions.

Living systems maintain stable internal states despite environmental fluctuations. Absolute concentration robustness (ACR) is a striking homeostatic phenomenon in which the steady-state concentration of a molecular species remains invariant to changes in total molecular supply. Although experimental studies have reported approximate-but not exact-robustness in steady-state concentrations, such behavior has often been attributed to exact ACR motifs perturbed by measurement noise or minor side reactions, rather than recognized as a structural property of the network itself. In this work, we highlight a previously underappreciated phenomenon, which we term asymptotic ACR (aACR): approximate robustness can emerge solely from the architecture of the reaction network, without requiring parameters being negligible or the presence of an exact ACR motif. We find that aACR is far more common than classical ACR, as demonstrated in systems such as the Escherichia coli EnvZ-OmpR system and MAPK signaling cascade. Furthermore, we mathematically prove that such ubiquity stems solely from network structure. Finally, we reveal a counterintuitive feature of aACR in systems with multiple conserved quantities, revealing subtle distinctions in how robustness manifests in complex biochemical networks.

Raw signal genome analysis (RSGA) has emerged as a promising approach to enable real-time genome analysis by directly analyzing raw electrical signals. However, rapid advancements in sequencing technologies make it increasingly difficult for software-based RSGA to match the throughput of raw signal generation. This paper demonstrates that while hardware acceleration techniques can significantly accelerate RSGA, the high volume of genomic data shifts the performance and energy bottleneck from computation to I/O data movement. As sequencing throughput increases, I/O overhead becomes the main contributor to both runtime and energy consumption. Therefore, there is a need to design a high-performance, energy-efficient system for RSGA that can both alleviate the data movement bottleneck and provide large acceleration capabilities. We propose MARS, a storage-centric system that leverages the heterogeneous resources within modern storage systems (e.g., storage-internal DRAM, storage controller, flash chips) alongside their large storage capacity to tackle both data movement and computational overheads of RSGA in an area-efficient and low-cost manner. MARS accelerates RSGA through a novel hardware/software co-design approach. First, MARS modifies the RSGA pipeline via two filtering mechanisms and a quantization scheme, reducing hardware demands and optimizing for in-storage execution. Second, MARS accelerates the RSGA steps directly within the storage by leveraging both Processing-Near-Memory and Processing-Using-Memory paradigms. Third, MARS orchestrates the execution of all steps to fully exploit in-storage parallelism and minimize data movement. Our evaluation shows that MARS outperforms basecalling-based software and hardware-accelerated state-of-the-art read mapping pipelines by 93x and 40x, on average across different datasets, while reducing their energy consumption by 427x and 72x.