Reaching for grasping, and manipulating objects are essential motor functions in everyday life. Decoding human motor intentions is a central challenge for rehabilitation and assistive technologies. This study focuses on predicting intentions by inferring movement direction and target location from multichannel electromyography (EMG) signals, and investigating how spatially and temporally accurate such information can be detected relative to movement onset. We present a computational pipeline that combines data-driven temporal segmentation with classical and deep learning classifiers in order to analyse EMG data recorded during the planning, early execution, and target contact phases of a delayed reaching task. Early intention prediction enables devices to anticipate user actions, improving responsiveness and supporting active motor recovery in adaptive rehabilitation systems. Random Forest achieves $80\%$ accuracy and Convolutional Neural Network $75\%$ accuracy across $25$ spatial targets, each separated by $14^\circ$ azimuth/altitude. Furthermore, a systematic evaluation of EMG channels, feature sets, and temporal windows demonstrates that motor intention can be efficiently decoded even with drastically reduced data. This work sheds light on the temporal and spatial evolution of motor intention, paving the way for anticipatory control in adaptive rehabilitation systems and driving advancements in computational approaches to motor neuroscience.

Hippocampal neurons track positions of self, others, and gaze direction. However, it is unclear how their respective neural codes differ enough to avoid confusion while allowing for abstraction. We recorded from populations of hippocampal neurons while participants performed a joystick-controlled virtual prey pursuit task involving multiple moving agents. We found that neurons have mixed selective responses that map positions of self, prey, and predator, as well as gaze. Their codes occupied mostly orthogonal subspaces, but these subspaces geometric structure allowed them to be aligned by simple linear transformations. Moreover, their geometry supported generalization across spatial maps, such that a linear rule learned on one agent transfers to another. This scheme enables reliable individuation and abstraction across both agent identity and viewpoint. Together, these findings suggest that hippocampal spatial knowledge is structured as a family of geometrically related manifolds that can be flexibly aligned to different agents and gaze directions.

Standard accounts of memory consolidation emphasise the stabilisation of stored representations, but struggle to explain representational drift, semanticisation, or the necessity of offline replay. Here we propose that high-capacity neocortical networks optimise stored representations for generalisation by reducing complexity via predictive forgetting, i.e. the selective retention of experienced information that predicts future outcomes or experience. We show that predictive forgetting formally improves information-theoretic generalisation bounds on stored representations. Under high-fidelity encoding constraints, such compression is generally unattainable in a single pass; high-capacity networks therefore benefit from temporally separated, iterative refinement of stored traces without re-accessing sensory input. We demonstrate this capacity dependence with simulations in autoencoder-based neocortical models, biologically plausible predictive coding circuits, and Transformer-based language models, and derive quantitative predictions for consolidation-dependent changes in neural representational geometry. These results identify a computational role for off-line consolidation beyond stabilisation, showing that outcome-conditioned compression optimises the retention-generalisation trade-off.

Diffusion MRI (dMRI) is sensitive to microstructural barriers, yet most existing methods either assume impermeable boundaries or estimate voxel-level parameters without recovering explicit interfaces. We present Spinverse, a permeability-aware reconstruction method that inverts dMRI measurements through a fully differentiable Bloch-Torrey simulator. Spinverse represents tissue on a fixed tetrahedral grid and treats each interior face permeability as a learnable parameter; low-permeability faces act as diffusion barriers, so microstructural boundaries whose topology is not fixed a priori (up to the resolution of the ambient mesh) emerge without changing mesh connectivity or vertex positions. Given a target signal, we optimize face permeabilities by backpropagating a signal-matching loss through the PDE forward model, and recover an interface by thresholding the learned permeability field. To mitigate the ill-posedness of permeability inversion, we use mesh-based geometric priors; to avoid local minima, we use a staged multi-sequence optimization curriculum. Across a collection of synthetic voxel meshes, Spinverse reconstructs diverse geometries and demonstrates that sequence scheduling and regularization are critical to avoid outline-only solutions while improving both boundary accuracy and structural validity.

Neurons encode information about the environment through their activity. As animals explore the environment, neurons rapidly acquire selectivity for distinct features of the external world; characterizing how these selectivity patterns emerge, reorganize, and overlap is key to linking neural activity to behavior and cognition. Calcium imaging in freely behaving animals can record large neuronal populations, but quantifying neuron-behavior selectivity directly from continuous fluorescence is challenging because both signals are temporally autocorrelated and calcium kinetics introduce time lags. Here we present INTENSE (INformation-Theoretic Evaluation of Neuronal SElectivity), an open-source framework that uses mutual information to detect neuron-behavior associations from raw calcium fluorescence data. INTENSE controls false discoveries using circular-shift permutation testing that preserves temporal structure and optimizes temporal delays to account for indicator kinetics and prospective/retrospective encoding. To separate genuine mixed selectivity from associations driven by behavioral covariance, INTENSE applies conditional mutual information-based disentanglement. We validated INTENSE on synthetic datasets, demonstrating robust detection across diverse signal-to-noise ratios and reliability conditions, whereas methods lacking temporal controls show poor performance. Applied to CA1 miniscope recordings in mice freely exploring an open field, INTENSE reveals robust selectivity to multiple variables (place, head direction, object interaction, locomotion) and refines mixed-selectivity estimates by distinguishing redundant from genuinely multi-variable encoding. Together, INTENSE enables high-throughput, information-theoretic selectivity mapping with principled control of temporal structure and behavioral covariance, bridging large-scale recordings to circuit-level hypotheses.

Machine learning-based antibody design is emerging as one of the most promising approaches to combat infectious diseases, due to significant advancements in the field of artificial intelligence and an exponential surge in experimental antibody data (in particular related to COVID-19). The ability of an antibody to bind to an antigens (called binding affinity) is one of the the most critical properties in designing neutralizing antibodies. In this study we introduce Ab-Affinity, a new large language model that can accurately predict the binding affinity of antibodies against a target peptide, e.g., the SARS-CoV-2 spike protein. Code and model are available at https://github.com/ucrbioinfo/AbAffinity.

Consciousness is the window of the brain and reflects many fundamental cognitive properties involving both computational and cognitive mechanisms. A collection of these properties was described as the "easy problems" by Chalmers, including the ability to discriminate, categorize, and react to stimuli; information integration; reportability; information access; attention; deliberate control; and the difference between wakefulness and sleep. These "easy problems" have not been systematically addressed. This study presents a first attempt to address them systematically based on an executable cognitive system and its implemented computational mechanisms, built upon an understanding of conceptual knowledge proposed by Kant. The study suggests that the abilities to discriminate, categorize, react, report, and integrate information can all be derived from the system's learning mechanism; attention and deliberate control are goal-oriented and can be attributed to emotional states and its information-manipulation mechanism; and the difference between wakefulness and dream sleep lies mainly in the source of stimuli. The connections between the implemented mechanisms in the executive system and conclusions drawn from empirical findings are also discussed, and many of these discussions and conclusions are supported by demonstrations of the executive system.

Oscillatory dynamics are common features of complex networks, often playing essential roles in regulating function. Across scales from gene regulatory networks to ecosystems, delayed feedback mechanisms are key drivers of system-scale oscillations. The analysis and prediction of such dynamics are highly challenging, however, due to the combination of high-dimensionality, non-linearity and delay. Here, we systematically investigate how structural complexity and delayed feedback jointly induce oscillatory dynamics in complex systems, and introduce an analytic framework comprising theoretical dimension reduction and data-driven prediction. We reveal that oscillations emerge from the interplay of structural complexity and delay, with reduced models uncovering their critical thresholds and showing that greater connectivity lowers the delay required for their onset. Our theory is empirically tested in an experiment on a programmable electronic circuit, where oscillations are observed once structural complexity and feedback delay exceeded the critical thresholds predicted by our theory. Finally, we deploy a reservoir computing pipeline to accurately predict the onset of oscillations directly from timeseries data. Our findings deepen understanding of oscillatory regulation and offer new avenues for predicting dynamics in complex networks.

Reasoning is the ability to integrate internal states and external inputs in a meaningful and semantically consistent flow. Contemporary machine learning (ML) systems increasingly rely on such sequential reasoning, from language understanding to multi-modal generation, often operating over dictionaries of prototypical patterns reminiscent of associative memory models. Understanding retrieval and sequentiality in associative memory models provides a powerful bridge to gain insight into ML reasoning. While the static retrieval properties of associative memory models are well understood, the theoretical foundations of sequential retrieval and multi-memory integration remain limited, with existing studies largely relying on numerical evidence. This work develops a dynamical theory of sequential reasoning in Hopfield networks. We consider the recently proposed input-driven plasticity (IDP) Hopfield network and analyze a two-timescale architecture coupling fast associative retrieval with slow reasoning dynamics. We derive explicit conditions for self-sustained memory transitions, including gain thresholds, escape times, and collapse regimes. Together, these results provide a principled mathematical account of sequentiality in associative memory models, bridging classical Hopfield dynamics and modern reasoning architectures.

Protein function relies on dynamic conformational ensembles, yet current generative models like AlphaFold3 often fail to produce ensembles that match experimental data. Recent experiment-guided generators attempt to address this by steering the reverse diffusion process. However, these methods are limited by fixed sampling horizons and sensitivity to initialization, often yielding thermodynamically implausible results. We introduce a general inference-time optimization framework to solve these challenges. First, we optimize over latent representations to maximize ensemble log-likelihood, rather than perturbing structures post hoc. This approach eliminates dependence on diffusion length, removes initialization bias, and easily incorporates external constraints. Second, we present novel sampling schemes for drawing Boltzmann-weighted ensembles. By combining structural priors from AlphaFold3 with force-field-based priors, we sample from their product distribution while balancing experimental likelihoods. Our results show that this framework consistently outperforms state-of-the-art guidance, improving diversity, physical energy, and agreement with data in X-ray crystallography and NMR, often fitting the experimental data better than deposited PDB structures. Finally, inference-time optimization experiments maximizing ipTM scores reveal that perturbing AlphaFold3 embeddings can artificially inflate model confidence. This exposes a vulnerability in current design metrics, whose mitigation could offer a pathway to reduce false discovery rates in binder engineering.

In this paper, we develop a mean-field game model for SEIR epidemics on heterogeneous contact networks, where individuals choose state-dependent contact effort to balance infection losses against the social and economic costs of isolation. The Nash equilibrium is characterized by a coupled Hamilton--Jacobi--Bellman/Kolmogorov system across degree classes. An important feature of the SEIR setting is the exposed compartment: the incubation period separates infection from infectiousness and changes incentives after infection occurs. In the baseline formulation, exposed agents optimally maintain full contact, while susceptible agents reduce contact according to an explicit best-response rule driven by infection pressure and the value gap. We also discuss extensions that yield nontrivial exposed precaution by introducing responsibility or compliance incentives. We establish existence of equilibrium via a fixed-point argument and prove the uniqueness under a suitable monotonicity condition. The analysis identifies a delay in the onset of precaution under longer incubation, which can lead to weaker behavioral responses and larger outbreaks. Numerical experiments illustrate how network degree and the cost exponent shape equilibrium policies and epidemic outcomes.

Stochastic kinetic models describe systems across biology, chemistry, and physics where discrete events and small populations render deterministic approximations inadequate. Parameter inference and inverse design in these systems require optimizing over trajectories generated by the Stochastic Simulation Algorithm, but the discrete reaction events involved are inherently non-differentiable. We present an approach based on straight-through Gumbel-Softmax estimation that maintains exact stochastic simulations in the forward pass while approximating gradients through a continuous relaxation applied only in the backward pass. We demonstrate robust performance on parameter inference in stochastic gene expression, first recovering kinetic rates of telegraph promoter models from both moment statistics and full steady-state distributions across diverse and challenging synthetic parameter regimes, then inferring the kinetic parameters of a four-state promoter model from experimental single-molecule RNA timecourse measurements. We further apply the method to inverse design in stochastic thermodynamics, optimizing non-equilibrium currents in an interacting particle system under kinetic resource constraints and recovering known analytical bounds. The ability to efficiently differentiate through exact stochastic simulations provides a foundation for systematic scalable inference and rational design across the many domains governed by continuous-time Markov dynamics.

For 20 years the beautiful structure in the grid cell code has presented an attractive puzzle: what computation do these representations subserve, and why does it manifest so curiously in neurons. The first question quickly attracted an answer: grid cells subserve path-integration, the ability to keep track of one's position as you move about the world. Subsequent work has only solidified this link: bottom-up mechanistic models that perform path-integration match the measured neural responses, while experimental perturbations that selectively disrupt grid cell activity impair performance on path-integration dependent tasks. A more controversial area of work has been top-down normative modelling: why has the brain chosen to compute like this? Floods of ink have been spilt attempting to build a precise link between the population's objective and the measured implementation. The holy grail is a normative link with broad predictive power which generalises to other neural systems. We review this literature and argue that, despite some controversies, the literature largely agrees that grid cells can be explained as a (1) biologically plausible (2) high fidelity, non-linearly decodable code for position that (3) subserves path-integration. As a rare area of neuroscience with mature theoretical and experimental work, this story holds lessons for normative theories of neural computations, and on the risks and rewards of integrating task-optimised neural networks into such theorising.

Why do neurons encode information the way they do? Normative answers to this question model neural activity as the solution to an optimisation problem; for example, the celebrated efficient coding hypothesis frames neural activity as the optimal encoding of information under efficiency constraints. Successful normative theories have varied dramatically in complexity, from simple linear models (Atick & Redlich '90), to complex deep neural networks (Lindsay '21). What complex models gain in flexibility, they lose in tractability and often understandability. Here, we split the difference by constructing a set of tractable but flexible normative representational theories. Instead of optimising the neural activities directly, following Sengupta et al. '18, we optimise the representational similarity, a matrix formed from the dot products of each pair of neural responses. Using this, we show that a large family of interesting optimisation problems are convex. This family includes problems corresponding to linear and some non-linear neural networks, and problems from the literature not previously recognised as convex, such as modified versions of semi-nonnegative matrix factorisation or nonnegative sparse coding. We put these findings to work in three ways. First, we provide the first necessary and sufficient identifiability result for a form of semi-nonnegative matrix factorisation. Second, we show that if neural tunings are `different enough' then they are uniquely linked to the optimal representational similarity, partially justifying the use of single neuron tuning analysis in neuroscience. Finally, we use the tractable nonlinearity of some of our problems to explain why dense retinal codes, but not sparse cortical codes, optimally split the coding of a single variable into ON & OFF channels. In sum, we identify a space of convex problems, and use them to derive neural coding results.

Precise irrigation management requires robust classification of plant water stress. We expanded a morpho-kinematic (MK) framework that derives canopy-movement features from RGB time-lapse imaging evaluating how methodological refinements affect robustness and fine discrimination across four irrigation treatments representing distinct stress histories. The study tested both a biological (Agg) versus an isogonal (Unif) sectoring of the canopy image, within an additive scheme where to the baseline (i.e. flattened MK features, A0) were sequentially added non-linear descriptors (A1), irrigation-context variables (i.e. dry time, A2), and their interactions with baseline (A3). The multi-class problem was decomposed in biologically meaningful binary tasks, and the final classification confronted an adaptive - to the performance obtained in the out-of-fold predictions inside the leave-one-sample-out validation framework - linear opinion pooling (ALOP) ensemble, evaluated across its full parameter space, against hierarchical cascades (HCC). In our combined dataset from two sequential Lactuca sativa experiments (144 sample-days) ALOP median outperformed HCC in every configuration, while non-linear and contextual enrichments (A1-A2) produced consistent improvements in terms of prediction stability, variability (for ALOP), and balanced accuracy (BA). The highest balanced accuracy (median BA = 0.96) was reached under Unif scheme in A3, yet the Agg configuration in A2 achieved the best compromise between accuracy (median BA approx 0.91) and robustness. Concluding, this study identifies methodological pathways that strengthen resilience and transferability of movement-based water-stress classification, establishing a solid foundation for generalizable, low-cost phenotyping.

The rapid growth of Artificial Intelligence (AI) in healthcare has sparked interest in Trustworthy AI and AI Implementation Science, both of which are essential for accelerating clinical adoption. However, strict regulations, gaps between research and clinical settings, and challenges in evaluating AI systems continue to hinder real-world implementation. This study presents an AI implementation case study within Shriners Childrens (SC), a large multisite pediatric system, showcasing the modernization of SCs Research Data Warehouse (RDW) to OMOP CDM v5.4 within a secure Microsoft Fabric environment. We introduce a Python-based data quality assessment tool compatible with SCs infrastructure, extending OHDsi's R/Java-based Data Quality Dashboard (DQD) and integrating Trustworthy AI principles using the METRIC framework. This extension enhances data quality evaluation by addressing informative missingness, redundancy, timeliness, and distributional consistency. We also compare systematic and case-specific AI implementation strategies for Craniofacial Microsomia (CFM) using the FHIR standard. Our contributions include a real-world evaluation of AI implementations, integration of Trustworthy AI principles into data quality assessment, and insights into hybrid implementation strategies that blend systematic infrastructure with use-case-driven approaches to advance AI in healthcare.

Studying the cellular architecture of the human cerebral cortex is critical for understanding brain organization and function. It requires investigating complex texture patterns in histological images, yet automatic methods that scale across whole brains are still lacking. Here we introduce CytoNet, a foundation model trained on 1 million unlabeled microscopic image patches from over 4,000 histological sections spanning ten postmortem human brains. Using co-localization in the cortical sheet for self-supervision, CytoNet encodes complex cellular patterns into expressive and anatomically meaningful feature representations. CytoNet supports multiple downstream applications, including area classification, laminar segmentation, quantification of microarchitectural variation, and data-driven mapping of previously uncharted areas. In addition, CytoNet captures microarchitectural signatures of macroscale functional organization, enabling decoding of functional network parcellations from cytoarchitectonic features. Together, these results establish CytoNet as a unified framework for scalable analysis of cortical microarchitecture and for linking cellular architecture to structure-function organization in the human cerebral cortex.

RNA function is deeply intertwined with its conformational dynamics. In this review, we survey recent advances in the use of atomistic molecular dynamics simulations to characterize RNA dynamics in diverse contexts, including isolated molecules and complexes with ions, small molecules, or proteins. We highlight how enhanced sampling techniques and integrative approaches can improve both the precision and accuracy of the resulting structural ensembles. Finally, we examine the emerging role of artificial intelligence in accelerating progress in RNA modeling and simulation.

Molecular simulations have assumed a paramount role in the fields of chemistry, biology, and material sciences, being able to capture the intricate dynamic properties of systems. Within this realm, coarse-grained (CG) techniques have emerged as invaluable tools to sample large-scale systems and reach extended timescales by simplifying system representation. However, CG approaches come with a trade-off: they sacrifice atomistic details that might hold significant relevance in deciphering the investigated process. Therefore, a recommended approach is to identify key CG conformations and process them using backmapping methods, which retrieve atomistic coordinates. Currently, rule-based methods yield subpar geometries and rely on energy relaxation, resulting in less-than-optimal outcomes. Conversely, machine learning techniques offer higher accuracy but are either limited in transferability between systems or tied to specific CG mappings. In this work, we introduce HEroBM, a dynamic and scalable method that employs deep equivariant graph neural networks and a hierarchical approach to achieve high-resolution backmapping. HEroBM handles any type of CG mapping, offering a versatile and efficient protocol for reconstructing atomistic structures with high accuracy. Focused on local principles, HEroBM spans the entire chemical space and is transferable to systems of varying sizes. We illustrate the versatility of our framework through diverse biological systems, including a complex real-case scenario. Here, our end-to-end backmapping approach accurately generates the atomistic coordinates of a G protein-coupled receptor bound to an organic small molecule within a cholesterol/phospholipid bilayer.

Critical transitions are the abrupt shifts between qualitatively different states of a system, and they are crucial to understanding tipping points in complex dynamical systems across ecology, climate science, and biology. Detecting these shifts typically involves extensive forward simulations or bifurcation analyses, which are often computationally intensive and limited by parameter sampling. In this study, we propose a novel machine learning approach based on deep neural networks (DNNs) called equilibrium-informed neural networks (EINNs) to identify critical thresholds associated with catastrophic regime shifts. Rather than fixing parameters and searching for solutions, the EINN method reverses this process by using candidate equilibrium states as inputs and training a DNN to infer the corresponding system parameters that satisfy the equilibrium condition. By analyzing the learned parameter landscape and observing abrupt changes in the feasibility or continuity of equilibrium mappings, critical thresholds can be effectively detected. We demonstrate this capability on nonlinear systems exhibiting saddle-node bifurcations and multi-stability, showing that EINNs can recover the parameter regions associated with impending transitions. This method provides a flexible alternative to traditional techniques, offering new insights into the early detection and structure of critical shifts in high-dimensional and nonlinear systems.