Understanding how social behavior influences epidemic dynamics has become a central focus in mathematical epidemiology. In particular, \textit{behavioral homophily} (the tendency of individuals to associate with similar others) and \textit{conformity} (the adjustment of individual behavior to group norms) are key mechanisms in shaping transmission patterns. In this work, we investigate the combined impact of these behavioral processes on the susceptible-infected-susceptible (SIS) dynamics on networks with large, densely connected groups, modeled as cliques. Each individual has an intrinsic behavioral preference, but their expressed behavior within a group is modulated by its composition, reflecting conformity dynamics. Using the approximate master equations (AME) framework, we characterize the interplay between behavioral heterogeneity, group structure, and epidemic localization. Our results reveal that behavioral homophily amplifies the effects of conformity in large groups, enabling minority behaviors to persist as well as substantially shifting epidemic thresholds and spreading regimes.

Understanding how network function constrains neural connectivity is a central challenge in neuroscience. An influential approach is to train neural networks with gradient descent on cognitive tasks and characterize the resulting connectivity. A key limitation is that the resulting structure depends on the details of the training procedure. Here we propose a complementary normative approach based on the maximum entropy principle for network connectivity, independent of any particular learning algorithm. We describe connectivity as a probability distribution over single-neuron weights, express task requirements as constraints on this distribution, and determine the unique distribution maximizing Shannon entropy subject to these constraints. A weight scale parameter controls the balance between randomness and task-induced structure. We apply this framework to context-dependent input-selection tasks in 2-layer feed-forward networks, and show that maximum entropy inference becomes analytically tractable by mapping nonlinear networks onto gain-modulated linear models. Starting from an a priori homogeneous distribution, we find that maximizing entropy under task constraints leads to the emergence of populations of neurons, each defined by its pattern of contextual gain modulation. Increasing the number of contexts drives a transition from context-specialized to unspecialized, random populations. Increasing the weight scale drives a parallel transition from structured to random stimulus selectivity. Strikingly, this maximum entropy connectivity matches both qualitatively and quantitatively the structure of networks trained with gradient descent across different learning regimes. Our results suggest that the interplay between task constraints and entropy maximization provides a fundamental principle for understanding the relationship between structure and function in neural networks.

Autocatalysis lies at the heart of many (bio)chemical processes and is key to processes leading up to the origin of life. Two seemingly very different formalisms have emerged that define autocatalysis. Kauffman introduced collective autocatalysis to describe systems of molecules that mutually catalyze each other's formation, emphasizing the self-sustaining character of autocatalytic systems. This view is mathematically formalized in the theory of Reflexively Autocatalytic and Food-generated sets (RAF). In parallel, stoichiometric autocatalysis emerged from the theory of Chemical Reaction Networks (CRN), focusing on the net-productive, self-amplifying character of autocatalytic subnetworks. These two frameworks have coexisted independently in the literature, since RAF theory considers each reaction as explicitly catalyzed, while the CRN approach often excludes explicitly catalyzed reactions altogether. Nevertheless, both frameworks describe reaction networks and thus admit a common mathematical representation in terms of stoichiometric matrices. We highlight this connection and show that the two formalisms are less disparate than they might appear. To illustrate this point we prove that, under mild and general conditions, any RAF is stoichiometrically autocatalytic.

Wearable sensing technology capable of point-of-care, continuous and non-invasive analysis of exosomes in biofluid such as tears and sweat is an essential part for future personalized medicine. Major detection and identification methods of cell secreted Extracellular Vesicles (EVs) often require labeling and are time-consuming, resulting in low efficiency in EV mechanism research and disease diagnosis. While the label-free Surface-enhanced Raman spectroscopy (SERS) has been combined with deep learning model for EV identification in blood, their application to non-invasive detection of EVs in tears and sweat are missing. Here, we filled this gap by developing an artificial intelligence (AI)-assisted Surface-enhanced Raman spectroscopy (SERS) method based on salt-induced nanoparticle aggregation for fast EV identification in tears and sweat with high accuracy. Significantly, our label-free detection and AI differentiation of EVs from 6 cell lines (HepG2, Hela, 143B, LO-2, BMSC, H8) achieved the identification of EVs in tear fluids from 7 different disease sources with accuracies >92%. Our results showed that this platform can not only distinguish EVs from multiple cell sources but also generate highly reproducible and selective EV signals in tear fluids without a need for chemical labeling or separation steps. Molecular dynamics simulations revealed that silver atoms (Ag) form electrostatic interactions with oxygen atoms of multiple amino acid residues in proteins, suggesting a high affinity. This strategy realizes ultra-sensitive and anti-interference detection of EVs, providing a new idea for the rapid diagnosis of clinical diseases.

Nucleotide sequences constitute the fundamental genetic basis of biological systems, rendering viral genomic analysis critical for biomedical advancement. Despite progress in biological foundation models, specifically nucleotide foundation models (NFMs), the field lacks a unified standard for viral genomics to facilitate community development and enforce biosecurity constraints. To address this, we introduce ViroBench, the first comprehensive and large-scale benchmark specifically designed for NFMs in viral settings. ViroBench evaluates models across two critical dimensions: biological understanding and latent biosecurity risk, covering 18 diverse scenarios within 4 task types. Extensive evaluation of 66 NFMs across diverse architectures yields three critical conclusions. Firstly, NFMs exhibit a performance degradation in biological understanding under phylogenetic and temporal shifts, indicating weak extrapolation capabilities. Secondly, generation tasks reveal a decoupling between statistical likelihood and biological functional validity, posing latent biosecurity risks. Thirdly, controlled ablation studies reveal that taxonomic diversity in pretraining data outweighs parameter scale. Specifically, a lightweight baseline trained on diverse data achieves a 67.5% performance gain over its original model. Overall, ViroBench provides interpretable, diagnostic evaluations and a reproducible measurement framework for future research on viral nucleotide foundation models. The datasets and code are publicly available at https://github.com/QIANJINYDX/ViroBench.

Fastest arrival events, where the first among many diffusing particles reaches a target, are central in triggering signal initiation in molecular stochastic systems. Classical approaches to simulate such events rely on full trajectory generation of all particles, leading to prohibitive computational costs in the large particle number regime. In this work, we present a general simulation framework for efficiently generating order statistics of arrival times by exploiting asymptotic first-passage distributions. This framework applies to diffusion processes in bounded domains with localized absorbing targets, for which short-time first-passage asymptotics are available, such as Brownian motion in dimensions one, two, and three. Starting with the case of instantaneous emission, we derive and implement a recursive inverse transform algorithm to simulate the first $k$ arrivals without tracking particle trajectories. We extend this algorithm to time-dependent emission profiles via an iterative approach, enabling the simulation of extreme statistics in systems with temporal injection, ranging from rapid to prolonged emission. Additionally, we provide asymptotic estimates of the mean fastest arrival time. To conclude, the present acceleration algorithm which bypasses Brownian simulations of trajectories can be used for spatial reaction networks, rare event detection, or diffusion-controlled activation.

Understanding the statistics of level crossings in stochastic processes is crucial across many scientific disciplines. The traditional Kac-Rice formula gives the mean rate of level crossings and has found broad use. However, that mean rate captures only a coarse summary of the crossing process. It depends entirely on local properties of the stochastic process at a given instant and is therefore blind to the correlation structure of the process over time. To understand whether crossing events, such as neuronal spikes, tend to cluster in time, spread apart, or exhibit more complex temporal organization, one must go beyond the mean rate and study higher-order crossing statistics. Here we go beyond the mean by deriving the exact analytical formulae for the variance and Fano factor of arbitrary level crossings in smooth stationary Gaussian processes. Our exact solution reveals how the full temporal correlation structure dictates whether crossings cluster or become regular. In systems with oscillatory correlations, such as a stochastic damped harmonic oscillator, a recent crossing suppresses an immediate subsequent one, producing sub-Poissonian statistics. However, as damping increases and oscillations disappear, a large and slow excursion above the threshold can produce multiple closely spaced crossings, yielding super-Poissonian statistics. In purely relaxational, non-oscillatory systems, such as a mean-reverting process driven by Ornstein-Uhlenbeck noise, the competition between the timescales of the driving noise and system relaxation produces a richer landscape, including reentrant transitions between sub- and super-Poissonian statistics as the threshold level is varied. Taken together, the exact variance and Fano factor derived here complement the Kac-Rice mean rate, enabling more robust parameter estimation and model selection across any setting where Gaussian processes are used.

Multicellular self-organization drives development in biological organisms, yet a comprehensive theory is lacking as basic properties of cells can complicate common approaches. Framing such properties by dynamic graphs led to new theoretical propositions for multicellular self-organization in Escherichia coli. Here, corresponding ideas are developed from biologically-general first principles. The resulting perspective could aid both experimental and computational approaches to multicellular biology as well as efforts to control and engineer it.

Although obtaining deep brain activity from non-invasive scalp electroencephalography (sEEG) is crucial for neuroscience and clinical diagnosis, directly generating high-fidelity intracranial electroencephalography (iEEG) signals remains a largely unexplored field, limiting our understanding of deep brain dynamics. Current research primarily focuses on traditional signal processing or source localization methods, which struggle to capture the complex waveforms and random characteristics of iEEG. To address this critical challenge, this paper introduces NeuroFlowNet, a novel cross-modal generative framework whose core contribution lies in the first-ever reconstruction of iEEG signals from the entire deep temporal lobe region using sEEG signals. NeuroFlowNet is built on Conditional Normalizing Flow (CNF), which directly models complex conditional probability distributions through reversible transformations, thereby explicitly capturing the randomness of brain signals and fundamentally avoiding the pattern collapse issues common in existing generative models. Additionally, the model integrates a multi-scale architecture and self-attention mechanisms to robustly capture fine-grained temporal details and long-range dependencies. Validation results on a publicly available synchronized sEEG-iEEG dataset demonstrate NeuroFlowNet's effectiveness in terms of temporal waveform fidelity, spectral feature reproduction, and functional connectivity restoration. This study establishes a more reliable and scalable new paradigm for non-invasive analysis of deep brain dynamics. The code of this study is available in https://github.com/hdy6438/NeuroFlowNet

Understanding how the brain integrates motor suppression with motivational processes remains a fundamental question in neuroscience. The rostral Pedunculopontine nucleus, a brainstem structure involved in motor control, has been shown to induce transient motor arrest upon optogenetic or electrical stimulation. However, our current understanding of its potential role in linking motor suppression with motivational or reinforcement-related processes is still insufficient. To further explore the effects induced by PPN stimulations and infer the potential mechanism underlying its role involved in both motor and emotional regulation, we developed a fully automated, low-cost system combining real-time animal tracking with closed-loop optogenetic stimulation, using the OpenMV Cam H7 Plus and embedded neural network models. The system autonomously detects the rat's position and triggers optical stimulation upon entry into a predefined region of interest, enabling unbiased, unsupervised behavioral assays. Optogenetic activation of CaMKIIa-expressing neurons in the rostral PPN reliably induced transient motor arrest. When motor arrest was spatially paired with a defined region of interest, rats developed a robust place preference after limited training. These results suggest that rostral PPN activation can couple motor inhibition with reinforcement-related behavioral circuitry. Together, our work provides both a technical framework for scalable closed-loop neuroscience experiments and preliminary evidence that the rostral PPN may participate in coordinating motor suppression with motivational processes.

Identifying enzymes that catalyze target biochemical reactions is a key step in computational enzyme discovery and biocatalyst design. Recent representation-learning methods formulate this problem as enzyme--reaction matching, where paired enzymes and reactions are embedded into a shared space. However, most existing approaches primarily rely on pairwise enzyme--reaction supervision and make limited use of the relationships within reaction sets or enzyme families. This work introduces a multi-alignment contrastive learning framework for biochemical retrieval. The framework jointly models cross-domain compatibility between enzymes and reactions and within-domain relationships induced by functional annotations. In addition, a Gromov--Wasserstein-inspired regularization objective encourages geometric consistency between the learned enzyme and reaction representation spaces. By combining pairwise catalytic supervision with higher-order relational alignment, the model captures both direct enzyme--reaction associations and broader functional organization. We evaluate the approach on enzyme virtual screening and bidirectional enzyme--reaction retrieval tasks. Experiments on EnzymeMap show improved early-recognition performance under BEDROC and enrichment-factor metrics compared with strong contrastive baselines. On ReactZyme, the method achieves consistent gains across time-based, enzyme-similarity, and reaction-similarity splits, demonstrating robustness to unseen enzymes and unseen reactions. Ablation studies further indicate that within-domain alignment, functional supervision, and the geometric regularization term each contribute to the observed improvements. These results suggest that modeling multiple forms of alignment can improve contrastive retrieval models for enzyme discovery, reaction annotation, and related computational biology applications.

Molecular representation learning methods typically tokenize molecules as individual atoms or use rigid, rule-based fragment decompositions, limiting their ability to capture meaningful chemical substructure context. We introduce FragmentNet, a graph-to-sequence model built around a novel adaptive, learned tokenizer that decomposes molecular graphs into chemically valid fragments of adjustable granularity, complemented by chemically aware spatial positional encodings that preserve molecular topology in the resulting sequence. Extending masked pre-training strategies from natural language processing to the molecular domain, we mask and reconstruct molecules at the level of chemically meaningful fragments rather than individual atoms. Evaluating across multiple property prediction benchmarks, we find that pre-training at fragment granularity leads to improved downstream performance on the majority of tasks, demonstrating that tokenization granularity is an important design choice for molecular representation learning.

This paper presents a novel neural network architecture for the purpose of pervasive visualisation of a 3D human upper limb musculoskeletal system model. Bringing simulation capabilities to resource-poor systems like mobile devices is of growing interest across many research fields, to widen applicability of methods and results. Until recently, this goal was thought to be out of reach for realistic continuum-mechanical simulations of musculoskeletal systems, due to prohibitive computational cost. Within this work we use a sparse grid surrogate to capture the surface deformation of the m.~biceps brachii in order to train a deep learning model, used for real-time visualisation of the same muscle. Both these surrogate models take 5 muscle activation levels as input and output Cartesian coordinate vectors for each mesh node on the muscle's surface. Thus, the neural network architecture features a significantly lower input than output dimension. 5 muscle activation levels were sufficient to achieve an average error of 0.97 +/- 0.16 mm, or 0.57 +/- 0.10 % for the 2809 mesh node positions of the biceps. The model achieved evaluation times of 9.88 ms per predicted deformation state on CPU only and 3.48 ms with GPU-support, leading to theoretical frame rates of 101 fps and 287 fps respectively. Deep learning surrogates thus provide a way to make continuum-mechanical simulations accessible for visual real-time applications.

The use of artificial intelligence to enable precision medicine and decision support systems through the analysis of pathology images has the potential to revolutionize the diagnosis and treatment of cancer. Such applications will depend on models' abilities to capture the diverse patterns observed in pathology images. To address this challenge, we present Virchow, a foundation model for computational pathology. Using self-supervised learning empowered by the DINOv2 algorithm, Virchow is a vision transformer model with 632 million parameters trained on 1.5 million hematoxylin and eosin stained whole slide images from diverse tissue and specimen types, which is orders of magnitude more data than previous works. The Virchow model enables the development of a pan-cancer detection system with 0.949 overall specimen-level AUC across 17 different cancer types, while also achieving 0.937 AUC on 7 rare cancer types. The Virchow model sets the state-of-the-art on the internal and external image tile level benchmarks and slide level biomarker prediction tasks. The gains in performance highlight the importance of training on massive pathology image datasets, suggesting scaling up the data and network architecture can improve the accuracy for many high-impact computational pathology applications where limited amounts of training data are available.

This article presents an operationalized solution to the mind-body problem which relies on rigorously defined theoretical reasoning rather than philosophical argument. We identify a specific operation which is a necessary property of all healthy human conscious individuals -- specifically the operation of self-certainty, or the capacity of healthy conscious humans to "know" with certainty that they are conscious. This operation is shown to be inconsistent with the properties possible in any meaningful definition of a physical system. This inconsistency is demonstrated by proving a "no-go" theorem for any physical system capable of human logical reasoning, if this reasoning is required to be both sound and consistent. The proof of this theorem is both general -- it applies to any function whereby evidence affects the state of some physical system -- and recursive, since any physical process subserving a function of this type is shown to imply another such function. Thus for at least one aspect of human consciousness, the mind-body problem is now conclusively resolved.

Despite the increasing scale of genome language models (gLMs), their ability to decode the function of regulatory sequences remains unclear. gLM pretraining relies on sequence reconstruction, which may struggle due to the noisy, rapidly evolving nature of regulatory DNA. Self-supervised contrastive approaches provide a promising alternative. Inspired by language-image architectures like CLIP, we introduce contrastive promoter-protein pretraining (C3P). By learning to align promoters to their corresponding proteins, we leverage the rich representations of proteins learned by protein language models as supervisory signal for the learning of promoter representations. After training on 88 million bacterial promoter-protein pairs, we evaluate the predictive power of C3P-learned promoter representations for inference of curated regulatory annotations, finding multi-fold improvement over leading gLMs. We also introduce zero-shot co-regulated gene retrieval, the ability to find co-regulated genes in a genome using no experimental data. We find that compared to a randomly initialized baseline, C3P training consistently provides significant zero-shot performance gains, unlike gLMs. Scaling analysis reveals the potential for further improvement as well as the efficiency of C3P, which achieved strong performance at a fraction of the training cost of leading gLMs. In addition to demonstrating that C3P training is effective for learning representations of bacterial regulatory sequences, our strong zero-shot co-regulated gene retrieval performance suggests the possibility of decoding gene regulation for millions of bacteria from their genomes alone.

Spiking neural networks (SNNs) can be used for implementing cost-efficient artificial intelligence computing or mechanistic modelling of experimentally observed neural data. In the latter, fitting neural data with recurrent SNNs (RSNNs) remains a challenge. Importantly, given that neuronal network oscillations are known to play important roles in neural functions, fitting specific RSNN oscillation frequencies with neural firing rates has yet to be fully explored. In this work, we extended our previous application of genetic algorithm (GA), specifically non-dominated sorting GA (NSGA-III), on sensitive Izhikevich neuron-based RSNNs by optimising their connectivity parameters to target emergent neuronal (sub)population firing rates and network oscillation frequencies. We evaluated this, via RMSEs on a Pareto frontier, on spontaneously active simulated RSNN model and low-activation brain organoid, followed by a simulated RSNN model with transient decision dynamics. In all cases, the models comprised spontaneously firing cortical excitatory and inhibitory neurons. We showed that NSGA-III could readily optimise for multiple network firing rates and dominant network oscillation frequencies, and for the decision-making model, for activity patterns in different time epochs. Notably, dominant oscillation frequencies were found to be more parameter sensitive, but firing rates were more robustly met. We also identified low-activity regime for decision-making. Overall, we have successfully demonstrated the implementation of multi-objective GA optimisation on RSNNs' and brain organoid's neural firing rates and oscillations.

We develop a novel cloud-function formalism describing the dynamical relationship between sensory-information processing in large-scale brain networks (supraliminal processing) and the content of the mental representation of an observed object. The formalism combines elements of neural field theory for large-scale neural activity with the spatial characteristics of perceived objects and their embedding in the environment from the first-person perspective. The cloud function is characterized by two key features: (i) its spatial structure inherits properties of the perceived physical object, and (ii) its temporal evolution is governed by regularities reflecting intrinsic properties of large-scale neural activity. The governing equation for the cloud function is based on a neural-field model with polynomial nonlinearities and global phase-shift invariance of neural-pattern oscillations. Its structure may be interpreted as a Schrodinger-type equation with a nonlinear non-Hermitian Hamiltonian supplemented by terms analogous to those of the Lotka-Volterra model. The proposed approach is applied to the change-of-mind phenomenon in decision-making, in which an initial choice may be revised during its execution. Changes of mind are explained as arising from the interplay between fast preconscious sensory processing and slower conscious comparison of alternatives, consistent with neurophysiological evidence for continuous post-decisional evidence accumulation. The necessity of incorporating cloud-function self-interaction is also discussed.

Spatial and temporal resource constraints are critical for both biological and artificial intelligent systems. Here we define differentiable cost terms for breadth, depth, and time within a recurrent convolutional neural network conceived as a finite subset of an infinite lattice. We optimize these costs jointly with task errors via backpropagation. We set different pressures on breadth, depth, and time, which leads to diverse computational graphs emerging organically through training. We find that all three resources can be traded off against each other to achieve a given level of accuracy. Networks grow in all three dimensions with task complexity and spontaneously take more recurrent steps when inputs are occluded. Surprisingly, time used by the model correlates with human reaction times in an object recognition task. Our framework provides a normative account of how resource constraints shape neural architectures, connecting to questions about brain design in neuroscience, and may help illuminate the diversity of neural solutions found in nature.

Isotopically non-stationary metabolic flux analysis (INST $^{13}$C-MFA) provides unique insights into cellular physiology but is typically limited by low throughput and high experimental costs. Here, we present a miniaturized and automated workflow that integrates transient isotope labeling experiments with advanced computational modeling to enable parallel INST $^{13}$C-MFA at microliter scale. The approach is demonstrated for an evolved $Corynebacterium~glutamicum$ strain capable of efficient growth on ethanol, a substrate for which isotopically stationary $^{13}$C-MFA is inherently limited due to low labeling diversity. Using robotic liquid handling, rapid hot isopropanol quenching, and LC-QToF-MS-based analytics, highly informative datasets were generated from parallel 48-well experiments with different ethanol tracers. Multi-dataset INST $^{13}$C-MFA unlocked joint estimation of intracellular fluxes and metabolite pool sizes and significantly improved flux precision compared to single-dataset analyses. While net fluxes were robust across datasets, pool size estimates exhibited variability and did not converge under joint inference, highlighting a fundamental methodological difference to single-dataset INST $^{13}$C-MFA. The resulting multi-dataset flux map reveals a central role of the glyoxylate shunt during growth on ethanol, consistent with metabolic adaption to C2-based substrate utilization. Overall, this work demonstrates that automated multi-dataset INST $^{13}$C-MFA is technically feasible and provides high-quality flux analysis at a fraction of the cost of conventional lab-scale bioreactor-based approaches. The presented workflow establishes a scalable framework for high-throughput quantitative fluxomics in microbial biotechnology and supports integration into iterative strain engineering and biofoundry pipelines.

Integrating multimodal datasets in clinical oncology is frequently hindered by high dimensionality and blockwise missingness, where entire data sources are unavailable for specific patient subsets. Standard survival models often struggle with these gaps, leading to biased results or patient exclusion. We introduce Multimodality Stacking with Blockwise missing values (MSB), a late-fusion framework for survival analysis that independently models modality-specific features before aggregating predictions via a cross-validated stacking meta-learner. MSB was validated on the PIONeeR study (n=443 patients, 378 biomarkers across eight heterogeneous sources) to predict progression-free survival in advanced non-small cell lung cancer patients receiving immunotherapy. MSB yielded higher predictive performance (C-index) than baseline algorithms. Improvements varied by baseline strength: linear models showed a 15.9% increase (p<0.001 for the Wilcoxon signed-rank test), random survival forests gained 5.4% (p=0.002), and gradient boosting methods improved by 2.1% (p=0.030). Beyond discrimination, MSB reduced the generalization gap (train-test difference in 5 folds cross-validation repeated 3 times: 0.055 vs 0.380 for linear models). Permutation importance analysis identified routine laboratory markers, clinical features, and PD-L1 expression as primary predictive drivers. Missing block indicators showed negligible importance, suggesting the model learned from biomarker values rather than data availability patterns. MSB provides a statistically validated framework for multimodal survival prediction with blockwise missingness. By enabling systematic biomarker evaluation without requiring complete data, MSB offers a practical tool for predictive modeling in biomedical research, pending external validation. Implementation is available at https://github.com/MohamedBoussena/MSB under Inria license.

An agent must act on the situation before it, learn what it cannot yet represent, and model other agents well enough to coordinate. These faculties are usually realized by separate mechanisms, yet they share a failure mode: the situation can exceed what the agent can currently represent, and the honest response is then a principled refusal that says what was missing. We develop a small cognitive architecture in which these limits arise from a single quantity. An Interpretation-Decision Unit (IDU) interprets a content vector through a family of regimes - local representational frames with private bases - and decides which actions it licenses; a scalar residual of the content against the active regimes' representational scope drives the unit. Low residual with a clean licensing emits an action; otherwise the unit re-interprets, attempts a description-length-justified expansion, or halts with a typed, witnessed terminal. We prove the unit is total and deterministic: for any content and fixed configuration it halts in finitely many bounded-cost steps with a unique terminal witness, so abstention carries its cause by construction. By binding the architecture's open parameters without changing its mechanics, the same residual-against-scope constraint recovers three documented phenomena at three scopes: the typology of not-knowing (typed abstention); a forced misunderstanding between agents, localized to one shared concept and invisible to the agent committing it (bounded empathy); and prerequisite dependence in learning derived from a bounded focus window rather than posited (developmental prerequisites). Each instantiation is worked for a natural and an artificial agent and states a falsifiable prediction, so one constraint can model limits in both human and machine cognition. The account contributes a unification and a notion of accountable abstention, typed and witnessed by construction.

Retinal imaging provides a non-invasive window into systemic microvascular health and has emerged as a potential biomarker for systemic diseases. However, whether retinal features encode biologically meaningful systemic signals that can be reliably interpreted using explainable artificial intelligence (XAI) remains unclear. An explainable multi-task deep learning framework was developed to investigate associations between retinal microvascular features and systemic abnormalities in Type 2 Diabetes Mellitus. A total of 11,011 fundus images from 2,719 individuals were analysed using a shared neural network with task-specific heads for glycaemic status, kidney abnormality, and multi-system involvement. Model interpretability was evaluated using Gradient-weighted Class Activation Mapping (Grad-CAM), anatomical masking, and vessel alignment analysis. The framework demonstrated task-dependent predictive performance, with the best discrimination observed for kidney abnormality (AUC up to 0.63), whereas glycaemic status prediction showed limited performance (AUC = 0.49-0.61). Explainability analyses consistently localized model attention to retinal vessels and peripapillary regions. Masking experiments showed that occlusion of vascular regions caused the greatest performance decline, indicating that retinal vessels were the primary predictive source. Different architectures exhibited heterogeneous attention patterns, suggesting multiple representational pathways for systemic signal encoding. This pilot study demonstrates that retinal microvascular features contain measurable signals associated with systemic abnormalities, particularly microvascular damage. By integrating multi-task learning with quantitative XAI validation, this framework advances retinal imaging toward interpretable digital biomarkers for systemic risk stratification in diabetes.

Background: Type 2 diabetes mellitus (T2DM) is increasingly recognised as a systemic disease characterised by coordinated dysfunction across metabolic, renal, lipid, and inflammatory pathways. Existing clinical assessments often fail to capture this multi-dimensional burden. Methods: We conducted a retrospective study of 1,195 patients using routinely collected laboratory biomarkers. System-level abnormality indices were constructed to quantify organ-specific dysfunction, and multi-system involvement was defined as abnormalities in two or more systems. Supervised machine learning models, including logistic regression, random forest, and gradient boosting, were trained to predict multi-system dysregulation. Model interpretability was achieved using SHapley Additive exPlanations (SHAP). Results: The gradient boosting model demonstrated near-perfect discrimination (AUC = 1.000), significantly outperforming logistic regression (AUC = 0.925). Feature attribution analysis revealed that hyperglycaemia, renal impairment, dyslipidaemia, and inflammation were the dominant drivers of multi-system risk. Dose-response relationships observed in partial dependence analyses further supported the biological plausibility of model predictions. Conclusion: This study presents an interpretable, data-driven framework for quantifying systemic disease burden in T2DM. By linking routine biomarkers to multi-organ dysfunction, our approach provides both predictive accuracy and mechanistic insight, offering potential for improved risk stratification and precision medicine in diabetes care. The data and code used in this study are openly available on GitHub at: https://github.com/MiniHanWang/Type-2-Diabetes-1.git

Untargeted metabolomics generates large volumes of tandem mass spectrometry (MS/MS) data and computational annotations that can reveal molecular mechanisms across organisms and environments. Public reuse has improved through harmonized repository metadata and access infrastructures such as Pan-ReDU, and through metabolomics knowledge graphs such as ENPKG and METRIN-KG. Yet the analytical layer remains fragmented: spectra, features, workflow outputs, annotations, confidence evidence, and contextual metadata are still scattered across repositories and tabular artifacts. We present MetaboKG, an analysis-centric knowledge graph framework for engineering reusable metabolomics knowledge from public repositories, metadata, and GNPS molecular network results. MetaboKG contributes a transformation workflow that preserves links between repository exports, analytical files, spectra, features, and annotation results; a semantic model grounded in PROV-O and SIO and aligned with the Mass Spectrometry ontology (MS), ChEBI, NCBITaxon, ENVO, and NCIT to represent provenance, analytical evidence, metadata attributes, and controlled vocabulary terms; and a Universal Annotation Identifier strategy extending the Universal Spectrum Identifier (USI) with workflow-specific components for late binding, incremental ingestion, and post hoc linkage across analyses. We demonstrate MetaboKG at the public-repository scale on 680 GNPS molecular networking results and evaluate it through competency questions covering biochemical enrichment, environmental specificity, and cross instrument analytical variation. Results show that graph-based integration supports traceable annotation reuse and reproducible SPARQL exploration of biochemical relationships that remain fragmented across repository-native resources.

Language models are typically trained to predict the next token in a sequence. Here, we explore an alternative predictive principle from reinforcement learning: Successor Representations (SRs), which model the expected discounted distribution of future states rather than the immediate next state. We transfer this framework to natural language and train neural networks to predict future word distributions across multiple temporal horizons, thereby learning representations of long-range transition structure. We train a deep residual neural network on WikiText-103 (103 million tokens; 20,000-word vocabulary) and optimize successor representations as probability distributions using KL divergence. Without explicit linguistic supervision, structured language representations emerge spontaneously. After training, the learned space develops a clear geometric organization with respect to part-of-speech (POS) categories: nouns, verbs, and adjectives become separable and recoverable through unsupervised clustering. This organization depends systematically on predictive horizon, with short horizons producing the strongest syntactic structure and longer horizons increasingly integrating broader contextual and semantic information. At finer resolutions, additional interpretable lexical substructure emerges, revealing coherent subclasses within major word categories. These findings suggest that syntactic categories need not be explicitly encoded but may arise as a consequence of predictive sequence learning. To our knowledge, this work provides the first systematic application of successor representations to natural language and establishes a conceptual bridge between reinforcement learning, linguistics, and cognitive neuroscience.

Biological systems exhibit marked molecular asymmetry, with proteins based predominantly on L-amino acids and nucleic acids and carbohydrates largely composed of D-sugars. Explanations for homochirality include asymmetric photochemistry, autocatalytic amplification, stochastic symmetry breaking and mineral-surface stereoselectivity, but these mechanisms only partially address the influence of finite geometry and collective spatial interactions on stereochemical stabilization. Inspired by recent developments in condensed-matter physics, we investigated whether coherent chirality could emerge from the interplay among nonlinear stereochemical amplification, stochastic fluctuations and boundary-dependent spatial constraints. We developed a reaction-diffusion simulation in which local stereochemical populations evolved within finite two-dimensional domains under spatial coupling and weak geometrical bias fields. Our model combined bistable autocatalytic dynamics, nearest-neighbor interactions and suppression of locally inconsistent stereochemical configurations in order to quantify temporal evolution of enantiomeric excess, same-handed neighbor agreement and radial stereochemical organization under varying interaction strengths and fluctuation amplitudes. Our results showed progressive formation of chiral domains, segregation of opposite-handed regions and geometry-dependent modulation of local stereochemical organization. Spatial coupling increased local coherence and modified persistence of mixed stereochemical states, while finite boundaries influenced radial organization and anisotropic stabilization of molecular populations. Potential applications include geometrically controlled asymmetric synthesis, confined stereoselective catalytic systems, adaptive chiral materials and characterization of heterogeneous stereochemical distributions in microstructured reaction environments.

Long non-coding RNAs (lncRNAs) are emerging regulatory molecules implicated in chronic disease pathogenesis, including Type 2 Diabetes Mellitus (T2D). We investigated ten literature reported lncRNAs associated with T2D: MALAT1, MEG3, MIAT, ANRIL, GAS5, KCNQ1OT1, H19, BCYRN1, XIST, and HOTAIR across two independent population-based RNA-seq cohorts. Single-omics approaches provide an incomplete view of disease biology, therefore, an integrative multi-feature framework was developed, extracting expression, secondary-structure, and sequence features for each lncRNA. Eight machine learning (ML) classifiers were evaluated under stratified k-fold, leave-one-out cross-validation (LOOCV), and repeated hold-out schemes to ensure robust performance estimation. SHAP analysis was applied for subject-level association interpretation. In one cohort, GAS5 and XIST expression features, along with GAS5, MEG3, and ANRIL sequence features, were found to be associated with T2D, while MALAT1 expression and KCNQ1OT1, ANRIL, and MEG3 sequence features were found to be associated in the second cohort. MEG3 was identified by SHAP as the dominant lncRNA in both cohorts. ML results were consistent with established statistical methods while additionally providing population- and subject-level disease association profiles linked to specific molecular feature types. The proposed framework advances mechanistic understanding of T2D and supports lncRNA-based precision medicine.

Achieving advanced machine intelligence remains a central challenge in AI research, often approached through scaling neural architectures and generative models. However, biological systems offer a broader repertoire of strategies for adaptive, goal-directed behavior - strategies that emerged long before nervous systems evolved. This paper advocates a genuinely life-inspired approach to machine intelligence, drawing on principles from biology that enable robustness, autonomy, and open-ended problem-solving across scales. We frame intelligence as flexible problem-solving, following William James, and develop the concept of "cognitive light cones" to characterize the continuum of intelligence in living systems and machines. We argue that biological evolution has discovered a scalable recipe for intelligence - and the progressive expansion of organisms' "cognitive light cone", predictive and control capacities. To explain how this is possible, we distill five design principles - multiscale autonomy, growth through self-assemblage of active components, continuous reconstruction of capabilities, exploitation of physical and embodied constraints, and pervasive signaling enabling self-organization and top-down control from goals - that underpin life's ability to navigate creatively diverse problem spaces. We discuss how these principles contrast with current AI paradigms and outline pathways for integrating them into future autonomous, embodied, and resilient artificial systems.

Evaluating true metacognition in Large Language Models (LLMs) is difficult due to biases and heuristics. This paper presents a framework to measure and enhance LLM metacognition while controlling for these biases. A measurement method using the $d'_{\rm type2}$ metric is established to isolate metacognitive ability. The Evolution Strategy for Metacognitive Alignment (ESMA) is proposed, demonstrating robust generalization across unseen datasets, languages, and newly acquired knowledge. Finally, parameter analysis reveals that these improvements are driven by a sparse set of parameters, offering new pathways for targeted metacognitive optimization.