Papers

Neural ordinary differential equations (NODEs) and universal differential equations (UDEs) provide flexible and popular frameworks for learning interpretable dynamical systems from noisy time-series data. However, training these models remains challenging, and versatile methods that robustly handle sparse and noisy data as well as partially observed models are lacking. To address this, we introduce curriculum multiple shooting (CMS), a general-purpose training strategy for fitting ordinary differential equation (ODE) models to time-series data by integrating curriculum learning with multiple shooting. Across twelve benchmarks spanning simulated and real data, and covering NODEs, UDEs, and mechanistic ODEs, CMS accelerates and stabilises training convergence, outperforms state-of-the-art training strategies, and ranks among the best methods in generalisation. Finally, we discuss possible explanations for the strong performance of CMS in light of contemporary theories of what makes training on time-series challenging.

Distinguishing True Progression (TP) from Pseudo-Progression (PsP) after chemoradiotherapy remains a major diagnostic challenge in GBM, as both entities present near-identical appearances on conventional contrast-enhanced post-treatment MRI. This distinction carries substantial clinical weight, since TP and PsP demand divergent management yet cannot be reliably separated on routine imaging alone. We investigated whether radiomic features derived from a parsimonious, voxel-wise pharmacokinetic model of dynamic contrast-enhanced (DCE) MRI, combined with MGMT status, could discriminate between the two. The cohort comprised 82 adults with IDH-wildtype GBM who developed a new contrast-enhancing lesion within six months of chemoradiotherapy; classification (53 TP, 29 PsP) was established by histopathology where available (n=52) and modified RANO criteria otherwise (n=30). At every voxel, contrast-concentration time courses were fitted to five candidate pharmacokinetic models, and the best fit was retained by AIC minimisation, yielding parsimonious Ktrans, Ve, Vp, and taui maps adapting to local heterogeneity rather than a single fixed model across the tumour. Following segmentation, 1,073 radiomic descriptors were extracted and reduced via Mann-Whitney U filtering and Elastic Net, then used to train five classifiers across four feature configurations. A Random Forest classifier combining parsimonious DCE-MRI radiomics with MGMT status achieved the best discrimination (mean AUC 0.89, sensitivity 0.93, specificity 0.76, F1 0.90), outperforming features without MGMT (0.84), a T1-post-contrast baseline (0.72), and a single-model extended-Tofts analysis (0.68). Shape and textural descriptors of the Ktrans map, with tumour volume, were the strongest predictors, MGMT contributing a smaller, independent effect. Allowing the model to vary voxel-wise improves non-invasive discrimination.

Respiration provides a continuously available window into physiological state and behavior. However, monitoring it outside controlled settings remains challenging because a wearable system must capture small body deformations while remaining comfortable, low power, and robust to changes in posture and motion. We present a compact non-invasive respiratory sensing system based on a force-sensitive resistor (FSR) embedded in an abdominal belt and integrated with a custom Bluetooth Low Energy acquisition board. The system combines a simple piezoresistive readout with a mechanical holder designed to transfer abdominal expansion to the sensor without analog amplification. We evaluate the complete sensing pipeline across multiple breathing patterns and body positions. In stationary settings, the recorded signals exhibit consistent amplitude changes and recurring peak-to-peak timing across breathing maneuvers; under light movement, these variations remain visible despite motion-induced baseline shifts. We further design a five-phase stress-induction protocol and collect respiratory recordings from 12 participants. Using interpretable time-domain features and standard classifiers, we examine whether the acquired signals distinguish relaxation from stress-induction phases. In this preliminary experiment, the best-performing model achieves 88.0% test accuracy, indicating that the extracted respiratory features distinguish stress-induced phases from relaxation phases in this dataset. Overall, our results show that the proposed platform enables real-time respiratory monitoring across diverse daily-life scenarios and captures respiratory changes that distinguish stress-induction from relaxation phases, supporting its potential for affective-computing applications.

Base-rate neglect is usually treated as one mistake: giving the prior too little weight. But turning co-occurrences into a judgment means correcting for two base rates, not one – the prior (how common the outcome is) and the cue's own frequency. Under-correcting the prior is classical base-rate neglect; under-correcting the cue is the cue-density effect, long studied but not usually framed as base-rate neglect's cue-side analogue. We write both corrections as two weights in one Bayesian equation. Response format fixes which weight a study can measure: a graded rating carries the cue-frequency weight in full; a forced choice between two outcomes cancels it and measures a companion weight in odds space instead, the same correction as it acts on the posterior odds rather than on the judged magnitude. The cancellation is exact, so a same-cue choice carries no information about the cue-frequency weight, not even its direction; a choice between two cues rather than two outcomes keeps the term and identifies the weight, and differing cue frequencies is necessary and sufficient for a choice to see it. The same weight appears in six standard learning-and-memory models, some as an exact identity and some only as a limiting or constructed correspondence; when an experiment keeps only the four cells of a cue x outcome contingency table, every model family rich enough to fit them projects onto one scalar coordinate, which alone cannot separate the accounts free to sit anywhere along it. The two neglects should be separately identifiable: an experimenter can move the regressor driving one weight without moving the regressor driving the other – a two-coefficient separation a one-parameter account cannot produce. This paper lays out the framework and the rating experiment that tests the coefficient separation; a companion paper fits the two weights to an existing colour-flavour dataset.

Transcutaneous spinal cord stimulation (tSCS) modulates spinal sensorimotor circuits primarily through activation of afferent networks. While prior work has emphasized locomotor performance and spinal excitability, how tSCS affects conscious proprioceptive perception and the extent to which such effects parallel changes in locomotor control remain unclear. We investigated the acute and training-related effects of tSCS on ankle proprioception and gait in unimpaired adults (n = 14), with an independent control group (n = 14) completing identical proprioceptive training without stimulation. Proprioception was quantified using a bilateral robotic assessment of dynamic ankle localization ability (Crisscross), gross motor output using maximum dorsiflexion strength, and gait during normal and tandem treadmill walking using spatiotemporal, trunk-sway, and mediolateral center-of-mass (CoM) excursion measures. Acute tSCS increased ankle proprioceptive error (p < 0.001) while dorsiflexion strength was unchanged (p = 0.30). Gait shifted toward a modestly more constrained locomotor pattern, characterized by reduced step width and ML CoM excursion (p < 0.05). With continued training under stimulation, proprioceptive error decreased and, unlike the control group, the tSCS group showed progressive improvement that persisted after stimulation ended. Sagittal-plane gait measures recovered toward or beyond baseline, whereas mediolateral measures remained constrained, revealing a direction-dependent reorganization of locomotor control. Together, these findings show that tSCS influences multiple aspects of the sensorimotor control loop, disrupting conscious proprioception while reshaping locomotor behavior, and that the nervous system can adapt to altered afferent input through training.

Proteins occupy heterogeneous free-energy landscapes in which high-entropy ensembles converge toward compact, low-energy basins with multiple sub-states. Molecular dynamics can access these landscapes at atomic resolution, but exhaustive sampling remains computationally demanding. Meanwhile, most quantum approaches target only single optimal structures, leaving full ensemble energetic heterogeneity unexplored. We introduce a residue-level, gate-based quantum circuit framework for coarse-graining protein thermodynamics. Each amino acid is represented as a two-state qubit (stabilised vs. excited solvation state) based on residue solvation energetics. A structure-informed entanglement block then encodes covalent and non-covalent contacts using parameterised controlled gates, embedding correlations across the residue-interaction network. Sampling the circuit ($\sim 10^6$ measurements) yields binary thermodynamic microstates used to compute protein energy distributions, residue-level statistical couplings, energetic sensitivities, and information gains relative to total free energy. We showcase the framework on the benchmark Trp-cage miniprotein 1L2Y (TC5b) and 9GDL, a disulfide-stabilised Trp-cage-fortified exenatide chimera. For 1L2Y, the circuit reproduces a structured, folding-funnel-like energy distribution. Comparative analysis with 9GDL reveals shifts in global energy distributions and residue-level stability profiles. Coupling and information-theoretic analyses localise residues associated with ensemble reorganisation, while multi-body couplings show the circuit resolves both direct and indirect statistical correlations. This framework expands quantum protein modelling beyond single-structure optimisation toward ensemble-level characterisation, capturing key features of rugged energy landscapes to guide protein design, mutation mapping, and allosteric pathway identification.

Hierarchical predictive coding proposes a compelling hypothesis of brain computation, suggesting that the cortex builds layered predictions to minimize surprise. Yet most models rely on error-coding neurons or generative modeling of unclear biological plausibility. Here, we examine a biologically plausible framework in which the functional goals of predictive coding emerge from local contrastive learning and simple activity cancellation. Building on recent machine learning advances, we present a recurrent variant of the Forward-Forward (FF) algorithm with an inverted objective that increases activity for negative data. This setup yields predictive representations across layers, capturing hallmark features of cortical computation such as top-down modulation and surprise signaling. Our results suggest that key principles of predictive coding can emerge from simple, local learning rules, offering a new bridge between neuroscience and machine learning.

Oligonucleotide melting temperature is a fundamental determinant of nucleic acid hybridization and underpins the design of molecular diagnostics, polymerase chain reaction assays, and many other biotechnology applications. However, accurately predicting melting behavior remains difficult because it depends not only on sequence composition, but also on experimental conditions and chemical modifications commonly used in modern assay design. Existing thermodynamic models rely on fixed parameterizations that are often difficult to extend across diverse reaction environments and nucleotide chemistries. Here we show that a condition-aware nucleotide language model can accurately predict oligonucleotide melting behavior across diverse experimental conditions and both unmodified and chemically modified oligonucleotides. By combining contextual sequence representations with explicit information describing the reaction environment, the framework achieves sub-degree prediction accuracy and reduces prediction error for locked nucleic acid-modified oligonucleotides by up to 25% relative to nearest-neighbor thermodynamic approaches. The model also more accurately captures the thermal effects introduced by nucleotide modification and maintains strong performance on independent benchmark datasets spanning experimental conditions substantially different from those represented during training. Our results demonstrate that learned sequence representations can complement classical thermodynamic models by capturing context-dependent effects that are difficult to encode using fixed parameter tables alone. More broadly, this work provides a scalable framework for predicting oligonucleotide melting behavior across diverse chemistries and assay conditions, supporting more reliable molecular assay design.

Excitable and oscillatory responses are widespread in cell signaling, but how these arise in the same system is unclear. We propose a minimal model of a saddle node bifurcation on an invariant circle, where slow fluctuations modulate transitions between excitable and oscillatory states, and noise drives excitability. Fitting the model to cell signaling data from embryonic stem cells reveals that these cells operate close to the bifurcation. Proximity to the bifurcation allows the cell to tune different dynamic states, suggesting a general principle for versatile cell signaling.

Photosensitivity is a neurological condition in which the brain generates epileptiform activity in response to visual stimuli. The standardized clinical diagnosis procedure, named Intermitent Photic Stimulation (IPS), involves exposing patients to a white flashing light at different frequencies to provoke this reaction. However, clinical neurophysiologists report that this protocol is insufficient, leading to underdiagnosis. VR-IPS is a flexible visual stimulation tool that extends conventional flashing-light stimulation by incorporating configurable color lights, static and oscillatory motion patterns, and photoprovocative videos. The system comprises a stimulation module that can run on Virtual Reality headsets or on standard monitors, together with a control module that allows clinicians to create, select, and configure visual stimulus, while controlling the whole stimulation procedure.

Objective: Routine third-trimester examination yields fetal biometry, maternal, Doppler and fetal-cardiac measurements, acquired at clinical discretion and therefore often incomplete. We show that these four measurement blocks are close to mutually uninformative, and that this single property determines what a representation of them can impute, what it can audit, and what fetal size alone cannot indicate. Methods: A linear-Gaussian factor model (K = 8 by parallel analysis, VARIMAX-rotated) was fitted to 25 measurements in four blocks from 977 fetuses (169 SGA, 61 severe; 77 LGA). Posterior precision sums contributions from observed measurements only, so missing values are marginalized rather than imputed. Data quality was screened using the standardized residual between each measurement and its reconstruction. Results: Predicting any one block from the other three gives an out-of-fold R2 of 0.023. The representation is a continuous growth spectrum with no cluster structure (Hartigan dip p = 0.99, gap statistic k = 1, three-cluster silhouette 0.07) ordering fetuses by birthweight centile (Spearman rho = 0.55). Among 169 SGA fetuses the haemodynamic redistribution axis separated the 25 adverse outcomes (AUC 0.70, 0.585-0.808) where measured size did not (0.60, 0.451-0.738). With Doppler censored, the marginalized interval covered held-out measurements in 97% and 93% of cases against nominal 95% and 90%. The reconstruction residual flagged 38 of 977 records, 36 confirmed transcription errors in the registry. Conclusion: Marginalizing missing measurements yields a representation whose uncertainty reflects the available data, and whose reconstruction residual doubles as a data-quality screen. Because the blocks are nearly independent, confirmed flags are within-block errors, and a synthetic benchmark gives the coupling needed before cross-block detection becomes available.

Learning from Electronic Health Records (EHRs) has gained significant attention due to its potential to improve clinical prediction. However, effective learning remains challenging because EHRs encode heterogeneous, temporally ordered clinical interactions. In particular, EHRs contain: (i) heterogeneous clinical entities, including patients, visits, diagnoses, prescriptions, and procedures, together with their heterogeneous interactions, (ii) longitudinal patient trajectories across hospital visits and (iii) shared statistical dependencies across related clinical prediction tasks. Existing EHR learning methods capture only a subset of these properties. To bridge this gap, we propose Multi-task Graph transformer for Heterogeneous Temporal EHRs (MiGHT-EHR), which jointly models all three within a unified representation learning method. MiGHT-EHR constructs a heterogeneous graph from EHRs in which nodes represent clinical entities and edges connect statistically associated entities identified via normalized point-wise mutual information. Across MIMIC-III and MIMIC-IV datasets, MiGHT-EHR outperforms state-of-the-art methods on average across four tasks: drug recommendation, prediction of length-of-stay, mortality, and readmission, with particularly strong improvements in mortality and readmission prediction. Furthermore, a post-hoc analysis of the learned representations reveals that patient neighborhoods are organized by clinical outcomes, salient medical concepts are recoverable as linear directions in the representation space, and task probabilities are well calibrated. Collectively, these findings demonstrate that MiGHT-EHR representations support diverse prediction tasks while preserving clinically interpretable structure.

The pruning of network connections is key to brain function but, despite its importance, there exist few biologically-plausible pruning rules with demonstrated good performance. In this work we evaluate noise-prune, a recently introduced unsupervised local pruning rule for recurrent networks that uses noisy fluctuations to determine the importance of connections. Noise-prune has previously only been empirically tested on random networks without a specific computational function. We show that noise-prune preserves task-performance in task-trained recurrent neural networks, greatly outperforming a strategy that only uses the magnitude of connections and performing on par with or exceeding a non-local strategy that uses second-order information. Rather than deterministically removing connections that fall below a certain threshold importance, noise-prune samples connections to preserve based on their importance and strengthens retained connections to preserve average synaptic strength. We show that this sampling and rescaling is essential to good performance, but that the optimal empirical degree of rescaling is lower than that predicted by the original theoretical argument. Our work thus validates noise-prune as a biologically-plausible pruning rule for functional recurrent network architectures and characterizes its optimal parameter settings.

Insomnia disorder is defined at the syndrome level, yet similar complaints can arise from different abnormalities in sleep regulation, state transition, state stabilization, spatial recruitment, architectural sequencing, and state perception. We propose a multiaxial dynamical framework whose principal contribution is organizational: a candidate profile is specified by the dynamical operation that fails, the sleep stage or boundary at which it fails, and its causal status. Objective sleep duration, age, circadian phase, comorbidity, medication exposure, and night-to-night variability are modifier/covariate dimensions rather than additional mechanistic classes. A local Landau-Ginzburg formalism, adopted from prior cortical and sleep-dynamics work, supplies a phenomenological language for nested hypotheses. Its relaxational form applies only to boundary-local dynamics under an approximate gradient description; non-gradient escape requires an action or quasipotential treatment, and whole-night REM-NREM sequencing requires reactive or oscillatory dynamics. Routine polysomnography usually identifies effective combinations rather than curvature, escape action, bias, noise, and relaxation separately. The strongest boundary-level evidence concerns sleep onset, where published results are consistent with bifurcation-like or bistable dynamics but do not yet exclude a driven smooth transition produced by the homeostatic-circadian ramp. The remaining operation classes are hypothesis-generating extensions. The taxonomy is judged by pragmatic utility, including improved communication, stratification, and prediction; the scalar-field implementation and specific dynamical profiles are separately falsifiable. The framework is a phenomenological organizing model rather than a new diagnosis, validated biomarker, or treatment-selection system.

The life sciences and health research have started to benefit from artificial intelligence, which raises ethical concerns that are real but, we argue, not special. Any science should be governed by values that rest on how the human brain is built and socialised rather than anything distinct to artificial intelligence. Importantly, the human brain has a different, much less costly computational architecture than these machines. This is achieved through the orchestration of a global neuronal workspace, and through reward best described not as a quantity to be maximised but as a continuous cycle of wanting, liking and satiety. As such, this creates the deep tension running through the ethics of the human person, between the universality of ethical judgement and the diversity of morals. The brain networks of the global workspace and emotion are universally shared, but the diversity of content is shaped by epigenetic appropriation of the particulars of the physical, social and cultural world, which makes every person unique. Still, if we were to build machines on these principles rather than the present unaffordable reward maximisers, the question of their governance would change from restraint to upbringing. We set out the institutions such a future would require, together with the questions that remain open.

Generalized dissimilarity models (GDMs) have emerged as a valuable tool for formal statistical analysis of biodiversity. In particular, beta diversity, measured using dissimilarity measures, e.g., the Bray-Curtis dissimilarity in our case, provides a statistical summary of the difference in species composition between sites. It also provides novel data for spatial and spatio-temporal modeling as it resides over the product space of one space-time pair and a second space-time pair. In earlier work we developed the spatial generalized dissimilarity mixed model (spGDMM) to remedy some of the stochastic issues concerned with the foundational GDM in the literature. Here, we extend that work to include dynamics. We find much richer modeling opportunities as we consider beta diversity with regard to change in time as well as space. We illustrate with a dataset from the Cape Floristic Region (CFR) in South Africa.

Background. Genetic factors, including single-nucleotide polymorphisms (SNPs), may modulate disease course and therapeutic efficacy in patients with inflammatory bowel disease (IBD). Aim. We investigated the association between four SNPs in cytokine genes and clinical phenotype as well as the response to molecular-targeted drugs in patients with IBD. Materials and Methods. A total of 197 IBD patients (142 Crohn's disease [CD], 55 ulcerative colitis [UC]) undergoing targeted treatment were enrolled. The SNPs analyzed were TNF-alpha rs1800629 (-308 G>A), TGF-beta rs1800471 (codon 10 C>T), IL-6 rs1800795 (-174 G>C), and IL-10 rs1800896 (-1082 G>A). Biochemical response at 12 months (T12) was defined as CRP <5.0 mg/L and fecal calprotectin <250 microg/g at T12, in the absence of ongoing corticosteroid therapy. Results. The IL-6 rs1800795 C allele was significantly associated with a younger age at diagnosis (p=0.049), while the TNF-alpha rs1800629 A allele was more frequently observed in patients with CD than UC (p=0.036). Among 134 patients included in the per-protocol analysis, 41.0% achieved biochemical remission at T12. The IL-10 rs1800896 variant allele was associated with remission (OR 2.15, 95% CI 1.03-4.44; p=0.041), and the association remained significant in multivariable analysis (adjusted OR 4.15, 95% CI 1.49-11.56; p=0.007). Conclusions. Genotyping of cytokine-related SNPs may help identify patients with distinct disease phenotypes and support personalized treatment strategies in IBD.

Genomic foundation models are increasingly reused as frozen feature extractors for downstream sequence prediction, offering a compute-efficient alternative to full fine-tuning. However, it remains unclear when biological information encoded by these models is accessible without task-specific adaptation. We present a representation-accessibility analysis of frozen genomic language models across regulatory, epigenetic, promoter, splice-site, and variant-effect prediction tasks. We evaluate DNABERT-2, Nucleotide Transformer, HyenaDNA, GENERATOR-v2, and Omni-DNA under unified frozen-probing protocols, while separating diagnostic readout analyses from validation-selected checks. Our results reveal a consistent task-dependent pattern: frozen probes recover 95-100 % of fine-tuned performance on promoter tasks, but average splice-site recovery drops to 60-88 %. Frozen embeddings are also competitive on broad Genomic Benchmark tasks such as coding-region and species-discrimination classification, but show larger gaps on some regulatory and OCR tasks. Layer-wise probing, in-silico mutagenesis, variant-effect prediction, and embedding geometry show that local biological signal is partially present in frozen representations, but is not always accessible through final pooled embeddings.

Parameter identification from observations of dynamical systems is a fundamental problem in population biology. Mechanistic models of ecological systems rely on optimization methods that require accurate initial guesses to guarantee convergence. In ecological applications, datasets contain observation noise and are collected at sparse time points. This sparsity creates irregular likelihoods that cause standard optimization methods to struggle, while the ordinary differential equation solvers can become stiff or unstable in certain regions of the parameter space. These instabilities cause long running times or runtime errors. Here we present a computational framework for parameter identification that addresses these numerical instabilities by employing Natural Gradient Ascent, and we apply it to the classical Lotka-Volterra predator-prey model. We exploit the non-dimensionalization of the ordinary differential equations to treat scaling factors as nuisance parameters, reducing the dimensionality of the optimization problem. To prevent the solver step from becoming small, we implement an adaptive solver that switches between two independent second-order equations derived from the two components of the model. This approach allows Natural Gradient Ascent to converge in fewer iterations and with more stability than standard gradient ascent or BFGS methods. This framework provides a reliable method for parameter estimation in ecology when data is limited. The method can be generalized to other dynamical systems as long as the different components of the system do not become numerically problematic at the same time.

Tree-like structures arise in numerous imaging applications, including vascular networks, neuronal arbors, airway trees, and cortical sulcal–gyral folding. We present a nonlinear registration framework based on screened Poisson flow and Wasserstein distance. The screened Poisson equation transforms geometric features into smooth multiscale probability distributions. Registration is formulated by minimizing the Wasserstein distance between these distributions, producing anatomically meaningful correspondences without explicit landmark or branch matching. The framework is demonstrated on the nonlinear registration of cortical sulcal–gyral folding patterns from structural MRI.

Abstract reaction networks appear not only as models of chemical reactions but also as models of complex systems, with applications in areas such as ecology and epidemiology, and as one of several alternative paradigms for non-standard computation. It is therefore of interest to determine whether an abstract reaction network can be realized by a concrete set of molecules and plausible chemical reaction mechanisms. It is known that a reaction network has a realization in terms of chemical graphs (i.e., Lewis structures) if and only if it is conservative. Here we consider the problem of assigning a set M of known molecules to a set X of abstract entities in a reaction network (X,R) such that each reaction satisfies mass balance and adheres to one of an allowed set of chemical reaction mechanisms. We show that this problem is NP-complete. Nevertheless, it can be solved in practice using a backtrack-and-prune algorithm inspired by the VF2 family of algorithms originally designed for the subgraph isomorphism problem.

An information theory-based framework is proposed in attempt to explain insistence on sameness in autism as an instance of a general behavior pattern in which an individual tries to reduce surprise and uncertainty. It offers a new definition of autism as an impairment in which cognitive functions are restricted to discrimination, memorization and prediction of tangible properties of the environment. An analogy between insistence on sameness and constrained minimization of the entropy metric is observed and examined for a set of assumptions that describe cognitive limitations of a person with autism. The metric is given by the formula $D_H(R, M) = H(R|M) + H(M|R)$, where $R$ represents sequences of random stimuli, $M$ is a memory that stores and retrieves them, and where $H(.|.)$ denotes their conditional entropies interpreted as surprise and uncertainty, respectively. It is first inferred that to minimize the metric an individual can learn about $R$ (and store that knowledge in $M$) or can restrict $R$ to the already known $M$. Then, it is concluded that insistence on sameness is a manifestation of the latter. Moreover, it is shown that the proposed framework: (1) Helps to quantify the concepts of surprise, uncertainty, sensory overload and deprivation, anxiety, comfort zone, disappointment, disorientation, pedantry, rigidness, observance or aberrant precision. (2) Leads to a list of guidelines for learning therapies and daily care routines, and allows them to be defined as optimization algorithms and implemented as programs for robotic live-in caregivers. (3) Can be validated with the help of a Turing test-like approach that requires no experiments involving individuals with autism. The framework-if positively validated-will provide formal foundations and design guidelines for therapies aimed at improving self-reliance of individuals with autism in basic activities of daily living.

We investigate the emergence of traveling front solutions in a spatial SIRS epidemic model with diffusion acting on the infected population. The model exhibits a natural slow-fast structure due to the presence of a small parameter governing the loss of immunity, which induces a separation of scales in the dynamics. Using a traveling wave reduction, the PDE system is transformed into a singularly perturbed system of ODEs, which we analyze within the framework of Geometric Singular Perturbation Theory. In the singular limits, we study the fast excursions governed by the layer problem, and the slow evolution close to the critical manifold. In particular, we identify an entry-exit mechanism tracking the transitions between slow and fast regimes, and derive a quantitative characterization of the entry-exit dynamics. Numerical simulations of the full system confirm the validity of the proposed geometric picture. The traveling front is shown to consist of a concatenation of local, fast, and slow segments, in agreement with the theoretical analysis.

Magnetic resonance imaging and histopathology observe the same glioma at radically different scales. We present CrossScale-GLIO, a visual multimodal framework that represents MRI as a tumor-habitat graph and histology as a cell-niche graph, then aligns them with a structure-aware optimal transport objective anchored by diagnostic language. Across paired and external glioma cohorts, CrossScale-GLIO achieved a paired-test subtype macro-F1 of 0.789, IDH AUROC of 0.934, 1p/19q AUROC of 0.884, and MGMT AUROC of 0.802. The subtype gain over feature-only transport was 2.8 percentage points (95% CI: 1.2 to 4.4, adjusted p = 0.0019). Bidirectional patient retrieval reached Recall@1 values of 0.286 and 0.278, and Recall@5 values of 0.621 and 0.608. Pathologists rated 81.2% of high-mass habitat-niche pairs as biologically plausible. Deleting the highest-mass pair reduced correct-class probability by 0.184, compared with 0.049 under random deletion. Degree-preserving graph rewiring reduced subtype macro-F1 by 0.034 and retrieval Recall@1 by 0.090, directly confirming that preserved relational topology drives cross-scale correspondence.

Net charge is a developability-relevant property of therapeutic binders, linked to viscosity, clearance, nonspecific interaction and aggregation, and antibody screens already use charge-related criteria. Yet inverse-folding pipelines expose no way to set it to a target value. ProteinMPNN and BindCraft offer amino-acid biases, weight choices and custom losses, but neither supplies a per-protein feedback loop that measures realised charge after sampling and corrects it to a setpoint. ZetaDial contributes a post-sampling, per-protein secant controller around fixed-backbone ProteinMPNN. On matched stochastic benchmarks the secant loop reduced mean absolute error relative to a fixed-slope loop on RCSB complexes (5.17 vs 6.46 charge units) and Cas13 monomers (5.57 vs 8.23). Relative to the optimised matched global bias, it cut RCSB error from 11.71 to 5.17 (cluster bootstrap p < 0.001) and was statistically indistinguishable on Cas13 (5.47 vs 5.57). Across 800 eight-protein subsets, sensitivity heterogeneity was associated with calibration gain (Pearson r = 0.79); this is descriptive resampling, not a prospective decision rule. Foldability deteriorated as bias magnitude increased. In the full 52-complex seed-0 analysis, reference-based DockQ declined clearly at +/-3 but not at +/-1.5; a selected five-seed replication on eight complexes showed paired declines at every nonzero setting, but does not estimate the effect for all 52. In exploratory BindCraft sweeps, PD-L1 designs moved toward near-neutral charge at similar maximum interface pTM but with overlapping success-rate intervals; IL-7R-alpha responses were non-monotonic and RBD produced no strong designs. A fixed-backbone C-alpha-neighbour analysis found smaller same-sign charge-patch proxies near neutral charge, but this proxy is not a measured electrostatic surface or experimental developability endpoint.

AI models, including large language models, are increasingly integrated into scientific discovery workflows, yet they remain prone to hallucination. In experimental sciences, such errors translate directly into failed wet-lab validations and wasted resources; in self-improving agentic systems, confident errors risk being reinforced rather than corrected. Retrosynthesis provides a representative example of this failure mode: existing models can generate chemically plausible routes, but cannot reliably determine which routes are experimentally feasible. We define Chemical Hallucination as a route that appears valid yet fails under competing reactive sites, unresolved selectivity, or missing mechanistic support, a failure largely invisible to the Recall@$K$ metric. We introduce SureRoute, a chemical verifier-anchored retrosynthesis platform that suppresses Chemical Hallucination. SureRoute combines a multi-model ensemble, data asset retrieval, and ChemHarness, an executable chemical intuition engine for route verification and reliability-first ranking. On a benchmark of 350 real-world industrial targets, SureRoute reaches 74.3% recall@1, 2.2–3.5$\times$ that of seven single-step models and three frontier LLMs, while cutting top-1 Chemical Hallucination to 4.6%, a 4–6$\times$ reduction relative to frontier LLMs. As a model-agnostic reranker, ChemHarness drives detectable hallucination toward near-zero across arbitrary backbone candidates. SureRoute shows that reliable scientific AI requires not only strong generation, but executable verification.

This dissertation presents the first formal theory of metacognitive skill learning. Metacognition, the capacity to monitor and control one's own cognitive processes, has been widely studied, yet the field still lacks a theoretical framework explaining how metacognitive abilities are learned. This gap limits progress in both theory and application across fields such as cognitive science, education, therapeutic practice, and artificial intelligence. The account developed here builds on classic models of skill acquisition from perceptual-motor and cognitive domains. It proposes that metacognitive skill develops primarily through proceduralization, whereby explicit, effortful metacognitive processes are transformed through practice into implicit, automatic routines. The explanatory power of this theory is shown by its ability to unify diverse phenomena, including attentional training, emotion regulation, the metacognitive threshold, and detached mindfulness. The result is an integrated, mechanistic account of metacognitive skill that organizes existing findings, generates testable predictions, informs the design of AI, and supports the strengthening of metacognitive skill in everyday life.

Multiple sclerosis (MS) is diagnosed through clinical assessment, magnetic resonance imaging, laboratory evidence when appropriate, and exclusion of better explanations. Blood RNA expression data may contain disease associated immune signal, but a blood RNA classifier cannot be treated as a replacement for clinical diagnosis. This paper presents MS-MLB (Multiple Sclerosis Machine Learning Benchmark), a reproducible open benchmark for machine learning based MS research classification from whole blood RNA expression data. MS-MLB uses the public GSE17048 cohort, converts it into an MS versus healthy control task, and evaluates multiple algorithms under a shared, leakage controlled pipeline that a researcher can rerun without reconfiguring the evaluation. The evaluation includes nested cross-validation, an untouched stratified holdout set, bootstrap confidence intervals, ROC and precision recall analysis, calibration measurement, and an exploratory MS Research Score. In the final benchmark summary, Gradient Boosting ranked first by MS Research Score on the holdout set, with an MS Research Score of 93.83, AUC-ROC of 0.989, sensitivity of 0.950, specificity of 0.778, $F_{1}$ score of 0.927, and Brier score of 0.050. Prior studies have applied machine learning to MS blood transcriptomic data, including PBMC stage classification and whole blood diagnostic signature modeling. The contribution here is different and narrower. To our knowledge, MS-MLB is the first open benchmark focused on MS versus healthy control classification from GSE17048 whole blood RNA expression data with a documented external model submission pathway built into the framework. The score is intended for research comparison only and has not been clinically validated. The benchmark is accessible here: https://github.com/duckyquang/MS-MLB.

Biological systems must regulate competing needs under limited perceptual bandwidth, where sharpening one estimate costs the capacity to sharpen the others. Any fixed-budget system therefore has to decide where to allocate its perceptual precision. We study this in a foraging agent that must keep several bodily needs satisfied to survive, modelled with active inference. At each step it reads its own body-state beliefs, identifies the most-needed channel, and reallocates a fixed budget of interoceptive precision toward it, so that the same precision-shaped likelihood feeds both belief update and planning. In AffectWorld, a four-channel foraging gridworld, this selective allocation more than doubles learning-phase survival at matched budget against a uniform-precision agent ($0.414$ vs $0.199$ across 11 layouts, $n{=}32$ seeds each, paired cluster-bootstrap $p \leq 10^{-4}$). Two further results sharpen the mechanism. The benefit runs through planning as well as perception, since denying the shaped likelihood to the planner alone removes about half of it. It is also need-aligned, since aiming precision at the least-needed channel does worse than spreading it evenly. The attended channel additionally learns its own dynamics about twice as fast, and stays ahead even at matched observation count, a behavioural trace of the same precision routing, visible in learning speed, not survival.

Whenever we look at an object, we seem to perceive it immediately. However, this is not the case for two reasons. First, it takes hundreds of milliseconds for the brain to process visual information reaching the retina. Second, we have to look at an object for a certain amount of time to perceive it (and we typically look at it for hundreds of milliseconds) – during that time, visual information is continuously received on our retinas. These facts together imply that visual information is both processed and received through time. These two temporal facets of perception, which we term processing time and stimulus time, are often conflated in the literature. Moreover, processing time and stimulus time are usually not considered together in experiments. Here, we argue that, to obtain a more complete portrait of visual perception and constrain further models of vision, it is essential to consider and measure both temporal facets simultaneously. We present a new method designed to do so that is based on reverse correlation: Time^2. We show that this method allows us to precisely characterize many neural phenomena, including rhythmic perception, predictive processing and coarse-to-fine sampling.