https://news.mcmedia.cam/feed/Quantitative_Biology MCMedia News RSS Feed - Quantitative_Biology specific feed https://news.mcmedia.cam/rss-info.html MCMedia RSS Generator v1.0 Fri, 17 Apr 2026 17:30:33 +0000 https://arxiv.org/abs/2604.13281 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13281v1 Announce Type: cross Abstract: Humans and artificial agents must often learn and switch between multiple tasks in dynamic environments. Success in such settings requires cognitive flexibility: the ability to retain prior knowledge (cognitive stability) while also transferring it to novel tasks (cognitive generalization). Cognitive flexibility research has largely focused on the role of model architecture to achieve these complementary goals. However, it is less well understood how the structure of the environment itself influences cognitive flexibility, and how it interacts with model architecture. To address this gap, we design a multi-task learning environment in which tasks are defined by a combination of two cue dimensions, allowing us to characterize the environment with graph-theory methods. We also introduce gating-based (multiplicative) and concatenation-based attention models that can decompose tasks into components and can sequentially allocate attention to them. We compare the attention-based models' performance in the multi-task learning environment to multilayer perceptrons. Generalization and stability are systematically evaluated across environments that vary in richness and task connectivity. We observe that richer environments improve both generalization and stability. In addition, a critical novel observation is that (graph theory based) connectivity between the tasks in the environment strongly modulates both stability and generalization, with especially pronounced benefits for attention-based models. These findings underscore the importance of considering not only cognitive architectures but also environmental structure and their interaction in shaping multi-task learning, generalization, and stability. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.13574 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13574v1 Announce Type: cross Abstract: Brain digital twins aim to provide faithful, individualized computational representations of brains as dynamical systems, enabling mechanistic understanding and supporting prediction of clinical interventions. Yet current approaches remain fragmented across data pipelines, model classes, temporal scales, and computing platforms, which prevents the preservation of execution semantics across the end-toend workflow. This survey introduces physically constrained executability as a unifying perspective for comparing approaches at the level of execution: whether an execution state is persistent, which events are permitted to update it (simulation, measurement, actuation), and how strongly execution is temporally and causally coupled to neurobiological dynamics. Building on modeling and simulation theory, I propose a taxonomy of execution regimes ranging from isolated offline models to coordinated co-simulation, to continuously executing digital twins sustained by online data assimilation, and ultimately to neuro-neuromorphic physical systems in which biological and computational dynamics are co-executed under shared physical constraints. The executability concept clarifies why accuracy alone is insufficient, and motivates an agenda centered on semantic interoperability, hybrid-time correctness, evaluation protocols, scalable reproducible workflows, and safe closed-loop validation. This survey adopts a systems and runtime-oriented perspective, enabling comparison of heterogeneous approaches based on their execution semantics rather than on model form or application domain alone. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.13719 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13719v1 Announce Type: cross Abstract: Self-sustained neural activity in the absence of ongoing external input is a fundamental feature of nervous system dynamics, yet the conditions under which it can emerge in biophysically grounded network models remain incompletely understood. We studied whether a recurrent network of Hodgkin-Huxley neurons with spike-timing-dependent plasticity and intrinsic stochasticity can maintain autonomous activity after brief transient stimulation. The simulated network comprised 200 neurons (160 excitatory, 40 inhibitory) with 80% connection probability, incorporating excitatory and inhibitory STDP, probabilistic vesicle release, probabilistic synapse formation, receptor variability, and voltage-dependent inhibition. After a brief 200 ms initialization stimulus to 30 excitatory neurons, the network received no further external input. In one 1800 s simulation and two additional 500 s simulations, the network maintained sparse, irregular activity without ongoing drive. In the 1800 s run, 67% of neurons exhibited mean firing rates below 1 Hz, the population mean firing rate was 1.13 +/- 1.34 Hz, participation increased across longer observation windows, and population-mean Fano factors remained near 1-2, consistent with irregular spike timing. Raster activity also showed spontaneous qualitative reorganizations in collective firing patterns over time. These findings suggest that recurrent Hodgkin-Huxley networks with plastic and stochastic synapses can sustain long-duration autonomous activity in a sparse firing regime after brief initialization. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2211.11346 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2211.11346v2 Announce Type: replace Abstract: We propose a hierarchically modular, dynamical neural network model whose architecture minimizes a specifically designed energy function and defines its temporal characteristics. The model has an internal and an external space that are connected with a layered internetwork that consists of a pair of forward and backward subnets composed of static neurons (with an instantaneous time-course). Dynamical neurons with large time constants in the internal space determine the overall time-course. The model offers a framework in which state variables in the network relax in a warped space, due to the cooperation between dynamic and static neurons. We assume that the system operates in either a learning or an association mode, depending on the presence or absence of feedback paths and input ports. In the learning mode, synaptic weights in the internetwork are modified by strong inputs corresponding to repetitive neuronal bursting, which represents sinusoidal or quasi-sinusoidal waves in the short-term average density of nerve impulses or in the membrane potential. A two-dimensional mapping relationship can be formed by employing signals with different frequencies based on the same mechanism as Lissajous curves. In the association mode, the speed of convergence to a goal point greatly varies with the mapping relationship of the previously trained internetwork, and owing to this property, the convergence trajectory in the two-dimensional model with the non-linear mapping internetwork cannot go straight but instead must curve. We further introduce a constrained association mode with a given target trajectory and elucidate that in the internal space, an output trajectory is generated, which is mapped from the external space according to the inverse of the mapping relationship of the forward subnet. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2301.07386 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2301.07386v3 Announce Type: replace Abstract: Most functional magnetic resonance imaging studies rely on estimates of hierarchically organized functional brain networks whose segregation and integration reflect the cognitive and behavioral changes in humans. However, most existing methods for estimating the community structure of networks from both individual and group-level analysis methods do not account for the variability between subjects. In this paper, we develop a new multilayer community detection method based on Bayesian latent block model (LBM). The method can robustly detect the community structure of weighted functional networks with an unknown number of communities at both individual and group levels and retain the variability of the individual networks. For validation, we propose a new community structure-based multivariate Gaussian generative model to simulate synthetic signal. Our simulation study shows that the community memberships estimated by hierarchical Bayesian inference are consistent with the predefined node labels in the generative model. The method is also tested via split-half reproducibility using working memory task fMRI data of 100 unrelated healthy subjects from the Human Connectome Project. Analyses using both synthetic and real data show that our proposed method is more accurate and reliable compared with the commonly used (multilayer) modularity models. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2512.20481 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2512.20481v4 Announce Type: replace Abstract: To maintain coherence in language, the brain must satisfy key competing temporal demands: the gradual accumulation of meaning across extended context (drift) and the rapid reconfiguration of representations at event boundaries (shift). How these processes are implemented in the human brain during naturalistic listening remains unclear. Here, we tested whether both can be captured by annotation-free drift and shift signals and whether their neural expression shows distinct regional preferences across the brain. These signals were derived from a large language model (LLM) processing the narrative input. To enable high-precision voxelwise encoding models with stable parameter estimates, we densely sampled one healthy adult across more than 7 hours of listening to crime stories while collecting 7 Tesla fMRI data. We then modeled the feature-informed hemodynamic response using a regularized encoding framework validated on independent stories. Drift predictions were prevalent in default-mode network hubs, whereas shift predictions were evident bilaterally in the primary auditory cortex and language association cortex. Together, these findings show that coherence during language comprehension is implemented through distinct but co-expressed neural regimes of slow contextual integration and rapid event-driven reconfiguration, offering a mechanistic entry point for understanding disturbances of language coherence in psychiatric disorders. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.12416 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2603.12416v2 Announce Type: replace Abstract: As proposed by Hebb's theory, neural assemblies are groups of excitatory neurons that fire synchronously and exhibit high synaptic density, representing external stimuli and supporting cognitive functions such as language and decision-making. Recently, a model called Assembly Calculus (AC) was proposed, enabling the formation of artificial neural assemblies through the $k$-winners-take-all selection process and Hebbian learning. Although the model is capable of forming assemblies according to Hebb's theory, the adopted selection process does not incorporate essential aspects of biological neural computation, as neural activity, which is often governed by statistical distributions consistent with power-law scaling. Given this limitation, the present work aimed to bring the model's dynamics closer to that observed in real cortical networks. To achieve this, a new selection mechanism inspired by the dynamics of gamma oscillation cycles, called E%-winners-take-all, was implemented, combined with an inhibition process based on the ratio between excitatory and inhibitory neurons observed in various regions of the cerebral cortex. The results obtained from our model (called E%-WTA model) were compared with those of the original model, and the analyses demonstrated that the introduced modifications allowed the network's own dynamics to determine the size of the formed assemblies. Furthermore, the recovery rate of these groups, through the evocation of the stimuli that generated them, became superior to that obtained in the original model. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2501.02378 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2501.02378v2 Announce Type: replace-cross Abstract: Abrupt learning is a common phenomenon in recurrent neural networks (RNNs) trained on working memory tasks. In such cases, the networks develop transient slow regions in state space that extend the effective timescales of computation. However, the mechanisms driving sudden performance improvements and their causal role remain unclear. To address this gap, we introduce the ghost mechanism, a process by which dynamical systems exhibit transient slowdown near the remnant of a saddle-node bifurcation. By reducing the high-dimensional dynamics near ghost points, we derive a one-dimensional canonical form that analytically captures learning as a process controlled by a single scale parameter. Using this model, we study a form of abrupt learning emerging from ghost points and identify a critical learning rate that scales as an inverse power law with the timescale of the learned computation. Beyond this rate, learning collapses through two interacting modes: (i) vanishing gradients and (ii) oscillatory gradients near minima. These features can lock the system into high-confidence but incorrect predictions when parameter updates trigger a no-learning zone, a region of parameter space where gradients vanish. We validate these predictions in low-rank RNNs, where ghost points precede abrupt transitions, and further demonstrate their generality in full-rank RNNs trained on canonical working memory tasks. Our theory offers two approaches to address these learning difficulties: increasing trainable ranks stabilizes learning trajectories, while reducing output confidence mitigates entrapment in no-learning zones. Overall, the ghost mechanism reveals how the computational demands of a task constrain the optimization landscape, demonstrating that well-known learning difficulties in RNNs partly arise from the dynamical systems they must learn to implement. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.13344 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13344v1 Announce Type: cross Abstract: Theory and empirical science should be in constant dialogue, but often find it hard to understand one another. Here we describe a graduate-level university course we developed to improve matters. The course was designed to help empirically-focused biology graduate students read and understand theory papers, despite little prior mathematical training. It uses several evidence-based principles of modern teaching: backwards design, active learning, and just-in-time teaching. We believe that this or similar curricular content, emphasizing the nature of evidence and the role of theory in science, will improve critical thinking and scientific progress. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.07309 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.07309v2 Announce Type: replace Abstract: We study the random times between successive cases in a transmission chain of infectious diseases with asymptomatic carriers. We derive the probability distribution of this generation time (in days) from a discrete-time epidemic model with variable infectiousness both along elapsed times and across phases. The introduced non-Markovian model is a compact recursive system featuring random waiting times at each of the three infected stages: latent, asymptomatic, and symptomatic. By rearranging the terms of the basic reproduction number, which represents the expected number of secondary cases produced by an asymptomatic primary case who may eventually develop symptoms, we get to the generation-time probabilities. The expected generation time is a convex combination of the expected generation times before and after the onset of symptoms. Additionally, our analysis reveals that the n-th moment of the generation time is related to the moments up to n-th order of the weighted forward recurrence time at each phase and the moments up to n-th order of the latent period and the incubation period. These weights are the infectiousness along the elapsed times for each transmission phase. Finally, we illustrate several data-driven epidemic scenarios, assuming that infectiousness varies only across phases and discrete Weibull distributions for the waiting times. Each disease analyzed, except measles, exhibits moderate variability in its respective generation time distribution. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.13980 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13980v1 Announce Type: cross Abstract: Antibody lead optimization is inherently a multi-objective challenge in drug discovery. Achieving a balance between different drug-like properties is crucial for the development of viable candidates, and this search becomes exponentially challenging as desired properties grow. The ever-growing zoo of sophisticated in silico tools for predicting antibody properties calls for an efficient joint optimization procedure to overcome resource-intensive sequential filtering pipelines. We present BOAT, a versatile Bayesian optimization framework for multi-property antibody engineering. Our `plug-and-play' framework couples uncertainty-aware surrogate modeling with a genetic algorithm to jointly optimize various predicted antibody traits while enabling efficient exploration of sequence space. Through systematic benchmarking against genetic algorithms and newer generative learning approaches, we demonstrate competitive performance with state-of-the-art methods for multi-objective protein optimization. We identify clear regimes where surrogate-driven optimization outperforms expensive generative approaches and establish practical limits imposed by sequence dimensionality and oracle costs. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.13281 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13281v1 Announce Type: cross Abstract: Humans and artificial agents must often learn and switch between multiple tasks in dynamic environments. Success in such settings requires cognitive flexibility: the ability to retain prior knowledge (cognitive stability) while also transferring it to novel tasks (cognitive generalization). Cognitive flexibility research has largely focused on the role of model architecture to achieve these complementary goals. However, it is less well understood how the structure of the environment itself influences cognitive flexibility, and how it interacts with model architecture. To address this gap, we design a multi-task learning environment in which tasks are defined by a combination of two cue dimensions, allowing us to characterize the environment with graph-theory methods. We also introduce gating-based (multiplicative) and concatenation-based attention models that can decompose tasks into components and can sequentially allocate attention to them. We compare the attention-based models' performance in the multi-task learning environment to multilayer perceptrons. Generalization and stability are systematically evaluated across environments that vary in richness and task connectivity. We observe that richer environments improve both generalization and stability. In addition, a critical novel observation is that (graph theory based) connectivity between the tasks in the environment strongly modulates both stability and generalization, with especially pronounced benefits for attention-based models. These findings underscore the importance of considering not only cognitive architectures but also environmental structure and their interaction in shaping multi-task learning, generalization, and stability. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.13574 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13574v1 Announce Type: cross Abstract: Brain digital twins aim to provide faithful, individualized computational representations of brains as dynamical systems, enabling mechanistic understanding and supporting prediction of clinical interventions. Yet current approaches remain fragmented across data pipelines, model classes, temporal scales, and computing platforms, which prevents the preservation of execution semantics across the end-toend workflow. This survey introduces physically constrained executability as a unifying perspective for comparing approaches at the level of execution: whether an execution state is persistent, which events are permitted to update it (simulation, measurement, actuation), and how strongly execution is temporally and causally coupled to neurobiological dynamics. Building on modeling and simulation theory, I propose a taxonomy of execution regimes ranging from isolated offline models to coordinated co-simulation, to continuously executing digital twins sustained by online data assimilation, and ultimately to neuro-neuromorphic physical systems in which biological and computational dynamics are co-executed under shared physical constraints. The executability concept clarifies why accuracy alone is insufficient, and motivates an agenda centered on semantic interoperability, hybrid-time correctness, evaluation protocols, scalable reproducible workflows, and safe closed-loop validation. This survey adopts a systems and runtime-oriented perspective, enabling comparison of heterogeneous approaches based on their execution semantics rather than on model form or application domain alone. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.13719 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13719v1 Announce Type: cross Abstract: Self-sustained neural activity in the absence of ongoing external input is a fundamental feature of nervous system dynamics, yet the conditions under which it can emerge in biophysically grounded network models remain incompletely understood. We studied whether a recurrent network of Hodgkin-Huxley neurons with spike-timing-dependent plasticity and intrinsic stochasticity can maintain autonomous activity after brief transient stimulation. The simulated network comprised 200 neurons (160 excitatory, 40 inhibitory) with 80% connection probability, incorporating excitatory and inhibitory STDP, probabilistic vesicle release, probabilistic synapse formation, receptor variability, and voltage-dependent inhibition. After a brief 200 ms initialization stimulus to 30 excitatory neurons, the network received no further external input. In one 1800 s simulation and two additional 500 s simulations, the network maintained sparse, irregular activity without ongoing drive. In the 1800 s run, 67% of neurons exhibited mean firing rates below 1 Hz, the population mean firing rate was 1.13 +/- 1.34 Hz, participation increased across longer observation windows, and population-mean Fano factors remained near 1-2, consistent with irregular spike timing. Raster activity also showed spontaneous qualitative reorganizations in collective firing patterns over time. These findings suggest that recurrent Hodgkin-Huxley networks with plastic and stochastic synapses can sustain long-duration autonomous activity in a sparse firing regime after brief initialization. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2211.11346 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2211.11346v2 Announce Type: replace Abstract: We propose a hierarchically modular, dynamical neural network model whose architecture minimizes a specifically designed energy function and defines its temporal characteristics. The model has an internal and an external space that are connected with a layered internetwork that consists of a pair of forward and backward subnets composed of static neurons (with an instantaneous time-course). Dynamical neurons with large time constants in the internal space determine the overall time-course. The model offers a framework in which state variables in the network relax in a warped space, due to the cooperation between dynamic and static neurons. We assume that the system operates in either a learning or an association mode, depending on the presence or absence of feedback paths and input ports. In the learning mode, synaptic weights in the internetwork are modified by strong inputs corresponding to repetitive neuronal bursting, which represents sinusoidal or quasi-sinusoidal waves in the short-term average density of nerve impulses or in the membrane potential. A two-dimensional mapping relationship can be formed by employing signals with different frequencies based on the same mechanism as Lissajous curves. In the association mode, the speed of convergence to a goal point greatly varies with the mapping relationship of the previously trained internetwork, and owing to this property, the convergence trajectory in the two-dimensional model with the non-linear mapping internetwork cannot go straight but instead must curve. We further introduce a constrained association mode with a given target trajectory and elucidate that in the internal space, an output trajectory is generated, which is mapped from the external space according to the inverse of the mapping relationship of the forward subnet. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2301.07386 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2301.07386v3 Announce Type: replace Abstract: Most functional magnetic resonance imaging studies rely on estimates of hierarchically organized functional brain networks whose segregation and integration reflect the cognitive and behavioral changes in humans. However, most existing methods for estimating the community structure of networks from both individual and group-level analysis methods do not account for the variability between subjects. In this paper, we develop a new multilayer community detection method based on Bayesian latent block model (LBM). The method can robustly detect the community structure of weighted functional networks with an unknown number of communities at both individual and group levels and retain the variability of the individual networks. For validation, we propose a new community structure-based multivariate Gaussian generative model to simulate synthetic signal. Our simulation study shows that the community memberships estimated by hierarchical Bayesian inference are consistent with the predefined node labels in the generative model. The method is also tested via split-half reproducibility using working memory task fMRI data of 100 unrelated healthy subjects from the Human Connectome Project. Analyses using both synthetic and real data show that our proposed method is more accurate and reliable compared with the commonly used (multilayer) modularity models. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2512.20481 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2512.20481v4 Announce Type: replace Abstract: To maintain coherence in language, the brain must satisfy key competing temporal demands: the gradual accumulation of meaning across extended context (drift) and the rapid reconfiguration of representations at event boundaries (shift). How these processes are implemented in the human brain during naturalistic listening remains unclear. Here, we tested whether both can be captured by annotation-free drift and shift signals and whether their neural expression shows distinct regional preferences across the brain. These signals were derived from a large language model (LLM) processing the narrative input. To enable high-precision voxelwise encoding models with stable parameter estimates, we densely sampled one healthy adult across more than 7 hours of listening to crime stories while collecting 7 Tesla fMRI data. We then modeled the feature-informed hemodynamic response using a regularized encoding framework validated on independent stories. Drift predictions were prevalent in default-mode network hubs, whereas shift predictions were evident bilaterally in the primary auditory cortex and language association cortex. Together, these findings show that coherence during language comprehension is implemented through distinct but co-expressed neural regimes of slow contextual integration and rapid event-driven reconfiguration, offering a mechanistic entry point for understanding disturbances of language coherence in psychiatric disorders. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.12416 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2603.12416v2 Announce Type: replace Abstract: As proposed by Hebb's theory, neural assemblies are groups of excitatory neurons that fire synchronously and exhibit high synaptic density, representing external stimuli and supporting cognitive functions such as language and decision-making. Recently, a model called Assembly Calculus (AC) was proposed, enabling the formation of artificial neural assemblies through the $k$-winners-take-all selection process and Hebbian learning. Although the model is capable of forming assemblies according to Hebb's theory, the adopted selection process does not incorporate essential aspects of biological neural computation, as neural activity, which is often governed by statistical distributions consistent with power-law scaling. Given this limitation, the present work aimed to bring the model's dynamics closer to that observed in real cortical networks. To achieve this, a new selection mechanism inspired by the dynamics of gamma oscillation cycles, called E%-winners-take-all, was implemented, combined with an inhibition process based on the ratio between excitatory and inhibitory neurons observed in various regions of the cerebral cortex. The results obtained from our model (called E%-WTA model) were compared with those of the original model, and the analyses demonstrated that the introduced modifications allowed the network's own dynamics to determine the size of the formed assemblies. Furthermore, the recovery rate of these groups, through the evocation of the stimuli that generated them, became superior to that obtained in the original model. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2501.02378 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2501.02378v2 Announce Type: replace-cross Abstract: Abrupt learning is a common phenomenon in recurrent neural networks (RNNs) trained on working memory tasks. In such cases, the networks develop transient slow regions in state space that extend the effective timescales of computation. However, the mechanisms driving sudden performance improvements and their causal role remain unclear. To address this gap, we introduce the ghost mechanism, a process by which dynamical systems exhibit transient slowdown near the remnant of a saddle-node bifurcation. By reducing the high-dimensional dynamics near ghost points, we derive a one-dimensional canonical form that analytically captures learning as a process controlled by a single scale parameter. Using this model, we study a form of abrupt learning emerging from ghost points and identify a critical learning rate that scales as an inverse power law with the timescale of the learned computation. Beyond this rate, learning collapses through two interacting modes: (i) vanishing gradients and (ii) oscillatory gradients near minima. These features can lock the system into high-confidence but incorrect predictions when parameter updates trigger a no-learning zone, a region of parameter space where gradients vanish. We validate these predictions in low-rank RNNs, where ghost points precede abrupt transitions, and further demonstrate their generality in full-rank RNNs trained on canonical working memory tasks. Our theory offers two approaches to address these learning difficulties: increasing trainable ranks stabilizes learning trajectories, while reducing output confidence mitigates entrapment in no-learning zones. Overall, the ghost mechanism reveals how the computational demands of a task constrain the optimization landscape, demonstrating that well-known learning difficulties in RNNs partly arise from the dynamical systems they must learn to implement. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.13344 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13344v1 Announce Type: cross Abstract: Theory and empirical science should be in constant dialogue, but often find it hard to understand one another. Here we describe a graduate-level university course we developed to improve matters. The course was designed to help empirically-focused biology graduate students read and understand theory papers, despite little prior mathematical training. It uses several evidence-based principles of modern teaching: backwards design, active learning, and just-in-time teaching. We believe that this or similar curricular content, emphasizing the nature of evidence and the role of theory in science, will improve critical thinking and scientific progress. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.07309 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.07309v2 Announce Type: replace Abstract: We study the random times between successive cases in a transmission chain of infectious diseases with asymptomatic carriers. We derive the probability distribution of this generation time (in days) from a discrete-time epidemic model with variable infectiousness both along elapsed times and across phases. The introduced non-Markovian model is a compact recursive system featuring random waiting times at each of the three infected stages: latent, asymptomatic, and symptomatic. By rearranging the terms of the basic reproduction number, which represents the expected number of secondary cases produced by an asymptomatic primary case who may eventually develop symptoms, we get to the generation-time probabilities. The expected generation time is a convex combination of the expected generation times before and after the onset of symptoms. Additionally, our analysis reveals that the n-th moment of the generation time is related to the moments up to n-th order of the weighted forward recurrence time at each phase and the moments up to n-th order of the latent period and the incubation period. These weights are the infectiousness along the elapsed times for each transmission phase. Finally, we illustrate several data-driven epidemic scenarios, assuming that infectiousness varies only across phases and discrete Weibull distributions for the waiting times. Each disease analyzed, except measles, exhibits moderate variability in its respective generation time distribution. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.13980 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2604.13980v1 Announce Type: cross Abstract: Antibody lead optimization is inherently a multi-objective challenge in drug discovery. Achieving a balance between different drug-like properties is crucial for the development of viable candidates, and this search becomes exponentially challenging as desired properties grow. The ever-growing zoo of sophisticated in silico tools for predicting antibody properties calls for an efficient joint optimization procedure to overcome resource-intensive sequential filtering pipelines. We present BOAT, a versatile Bayesian optimization framework for multi-property antibody engineering. Our `plug-and-play' framework couples uncertainty-aware surrogate modeling with a genetic algorithm to jointly optimize various predicted antibody traits while enabling efficient exploration of sequence space. Through systematic benchmarking against genetic algorithms and newer generative learning approaches, we demonstrate competitive performance with state-of-the-art methods for multi-objective protein optimization. We identify clear regimes where surrogate-driven optimization outperforms expensive generative approaches and establish practical limits imposed by sequence dimensionality and oracle costs. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2601.07215 Thu, 16 Apr 2026 00:00:00 -0400 arXiv:2601.07215v3 Announce Type: replace Abstract: The action potential constitutes the digital component of the signaling dynamics of neurons. But the biophysical nature of the full-time course of the action potential associated with changes in membrane potential is mathematically distinct from its representation as a discrete set of events that encode when action potentials are triggered in a collection of spike trains. In this paper, we develop from first principles a unified functional-analytic framework for neuronal spike trains, grounded in Schwartz distribution theory. We show how this representation provides an exact operational calculus for convolution, distributional differentiation, and distributional support, which enables closed-form analysis of spike train dynamics without discretization, rate approximation, or smoothing. We then analyze the framework in the context of a two-neuron reciprocal circuit with propagation latencies and refractoriness, deriving exact results for synaptic drive, spike timing sensitivity, and causal admissibility of inputs, quantities that are either ill-defined or require approximation in conventional treatments. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.29977 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2603.29977v2 Announce Type: replace-cross Abstract: Multimodal deep learning for cancer prognosis is commonly assumed to benefit from synergistic cross-modal interactions, yet this assumption has not been directly tested in survival prediction settings. This work adapts InterSHAP, a Shapley interaction index-based metric, from classification to Cox proportional hazards models and applies it to quantify cross-modal interactions in glioma survival prediction. Using TCGA-GBM and TCGA-LGG data (n=575), we evaluate four fusion architectures combining whole-slide image (WSI) and RNA-seq features. Our central finding is an inverse relationship between predictive performance and measured interaction: architectures achieving superior discrimination (C-index 0.64$\to$0.82) exhibit equivalent or lower cross-modal interaction (4.8\%$\to$3.0\%). Variance decomposition reveals stable additive contributions across all architectures (WSI${\approx}$40\%, RNA${\approx}$55\%, Interaction${\approx}$4\%), indicating that performance gains arise from complementary signal aggregation rather than learned synergy. These findings provide a practical model auditing tool for comparing fusion strategies, reframe the role of architectural complexity in multimodal fusion, and have implications for privacy-preserving federated deployment. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2508.12260 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2508.12260v5 Announce Type: replace-cross Abstract: Infectious disease forecasting in novel outbreaks or low-resource settings is hampered by the need for large disease and covariate data sets, bespoke training, and expert tuning, all of which can hinder rapid generation of forecasts for new settings. To help address these challenges, we developed Mantis, a foundation model trained entirely on mechanistic simulations, which enables out-of-the-box forecasting across diseases, regions, and outcomes, even in settings with limited historical data. We evaluated Mantis against 78 forecasting models across sixteen diseases with diverse modes of transmission, assessing both point forecast accuracy (mean absolute error) and probabilistic performance (weighted interval score and coverage). Despite using no real-world data during training, Mantis achieved lower mean absolute error than all models in the CDC's COVID-19 Forecast Hub when backtested on early pandemic forecasts which it had not previously seen. Across all other diseases tested, Mantis consistently ranked in the top two models across evaluation metrics. Mantis further generalized to diseases with transmission mechanisms not represented in its training data, demonstrating that it can capture fundamental contagion dynamics rather than memorizing disease-specific patterns. These capabilities illustrate that purely simulation-based foundation models such as Mantis can provide a practical foundation for disease forecasting: general-purpose, accurate, and deployable where traditional models struggle. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2505.15653 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2505.15653v3 Announce Type: replace-cross Abstract: Dynamical systems in biology are complex, and one often does not have comprehensive knowledge about the interactions involved. Chemical reaction network (CRN) inference aims to identify, from observing species concentrations over time, the unknown reactions between the species. Existing approaches such as sparse regularisation largely focus on identifying a single, most likely CRN, without addressing uncertainty about the network structure. However, it is important to quantify structural uncertainty to have confidence in our inference and predictions. In this work, we explore how effective sparse regularisation methods are for quantifying structural uncertainty. Locally optimal solutions to sparse regularisation are mapped to CRN structures; however, it is unclear whether this approach encompasses all plausible CRNs. We find that inducing sparsity with nonconvex penalty functions results in better coverage of the plausible CRNs compared to the popular lasso regularisation. To validate our approach, we apply our methods to real-world data examples, and are able to simultaneously recover reactions proposed across multiple literature sources for a reaction system. Our emphasis on network-level probabilities enables a novel, hierarchical representation of structural ambiguities in the space of CRNs. This representation translates into alternative reaction pathways suggested by the available data, thus guiding the efforts of future experimental design. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2511.13790 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2511.13790v2 Announce Type: replace Abstract: This paper describes GeoPl@ntNet, an interactive web application designed to make Essential Biodiversity Variables accessible and understandable to everyone through dynamic maps and fact sheets. Its core purpose is to allow users to explore high-resolution AI-generated maps of species distributions, habitat types, and biodiversity indicators across Europe. These maps, developed through a cascading pipeline involving convolutional neural networks and large language models, provide an intuitive yet information-rich interface to better understand biodiversity, with resolutions as precise as 50x50 meters. The website also enables exploration of specific regions, allowing users to select areas of interest on the map (e.g., urban green spaces, protected areas, or riverbanks) to view local species and their coverage. Additionally, GeoPl@ntNet generates comprehensive reports for selected regions, including insights into the number of protected species, invasive species, and endemic species. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2508.19420 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2508.19420v2 Announce Type: replace Abstract: Data generated in studies of cellular regulatory systems are often qualitative. For example, measurements of signaling readouts in the presence and absence of mutations may reveal a rank ordering of responses across conditions but not the precise extents of mutation-induced differences. Qualitative data are often ignored by mathematical modelers or are considered in an ad hoc manner, as in the study of Kocieniewski and Lipniacki (2013) [Phys Biol 10: 035006], which was focused on the roles of MEK isoforms in ERK activation. In this earlier study, model parameter values were tuned manually to obtain consistency with a combination of qualitative and quantitative data. This approach is not reproducible, nor does it provide insights into parametric or prediction uncertainties. Here, starting from the same data and the same ordinary differential equation (ODE) model structure, we generate formalized statements of qualitative observations, making these observations more reusable, and we improve the model parameterization procedure by applying a systematic and automated approach enabled by the software package PyBioNetFit. We also demonstrate uncertainty quantification (UQ), which was absent in the original study. Our results show that PyBioNetFit enables qualitative data to be leveraged, together with quantitative data, in parameterization of systems biology models and facilitates UQ. These capabilities are important for reliable estimation of model parameters and model analyses in studies of cellular regulatory systems and reproducibility. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2505.10517 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2505.10517v5 Announce Type: replace Abstract: Structural identifiability is the theoretical ability to uniquely recover model parameters from ideal, noise-free data and is a prerequisite for reliable parameter estimation in epidemic modeling. Despite its importance for calibration and inference, structural identifiability analysis remains underused and inconsistently applied in infectious disease modeling. This paper presents a user-oriented methodological tutorial demonstrating how global structural identifiability analysis can be systematically integrated into epidemic modeling workflows. We provide a reproducible framework for conducting structural identifiability analysis of ordinary differential equation models using the Julia package StructuralIdentifiability.jl. The workflow is illustrated across commonly used epidemic models, including SEIR variants with asymptomatic and presymptomatic transmission, vector-borne disease models, and systems incorporating hospitalization and disease-induced mortality. We also introduce a visual communication strategy that embeds identifiability results directly into compartmental diagrams, facilitating interpretation and interdisciplinary communication. Our results show that identifiability depends critically on model structure, the choice of observed variables, and assumptions about initial conditions, and that identifiable parameter combinations may exist even when individual parameters are not globally identifiable. Emphasizing transparent implementation, interpretation, and communication, this work provides practical guidance and comparative insights across model classes. The tutorial is designed as both a reference and a teaching resource for researchers and educators seeking to incorporate structural identifiability analysis into epidemic model development. All code and annotated diagrams are publicly available to ensure reproducibility and reuse. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2410.00532 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2410.00532v4 Announce Type: replace Abstract: Advanced microscopy techniques are essential in biomedical research for visualising and tracking biomolecules within living cells and their compartments. Conventional fluorescence microscopy methods, however, often struggle with accurately measuring the absolute concentrations of fluorescent probes in living cells. To overcome these limitations, we introduce an open-source analysis tool, smICA (Single-Molecule Image to Concentration Analyser). The smICA method offers quantitative mapping of absolute fluorophore concentrations, lifetime-resolved filtering methods of the signal, intensity-based cell segmentation, and requires only a few photons per pixel. Our approach also reduces the time required for the determination of the mean concentration per cell, compared to the standard FCS measurement performed in multiple posts. To highlight the robustness of the method, we validated it against standard fluorescence correlation spectroscopy (FCS) measurements by performing in vitro (aqueous solutions of polymers) and in vivo (polymers and EGFP in living cells) experiments. The presented methodology, along with the software, is a promising tool for quantitative single-cell studies, including, but not limited to, protein expression, degradation of biomolecules (such as proteins and mRNA), and monitoring of enzymatic reactions. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.12075 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.12075v1 Announce Type: cross Abstract: The tumor microenvironment (TME) plays a central role in cancer progression, treatment response, and patient outcomes, yet large-scale, consistent, and quantitative TME characterization from routine hematoxylin and eosin (H&E)-stained histopathology remains scarce. We introduce OpenTME, an open-access dataset of pre-computed TME profiles derived from 3,634 H&E-stained whole-slide images across five cancer types (bladder, breast, colorectal, liver, and lung cancer) from The Cancer Genome Atlas (TCGA). All outputs were generated using Atlas H&E-TME, an AI-powered application built on the Atlas family of pathology foundation models, which performs tissue quality control, tissue segmentation, cell detection and classification, and spatial neighborhood analysis, yielding over 4,500 quantitative readouts per slide at cell-level resolution. OpenTME is available for non-commercial academic research on Hugging Face. We will continue to expand OpenTME over time and anticipate it will serve as a resource for biomarker discovery, spatial biology research, and the development of computational methods for TME analysis. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.11944 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.11944v1 Announce Type: cross Abstract: Diabetes devices, including Continuous Glucose Monitoring (CGM), Smart Insulin Pens, and Automated Insulin Delivery systems, generate rich time-series data widely used in research and machine learning. However, inconsistent data formats across sources hinder sharing, integration, and analysis. We present DIAX (DIAbetes eXchange), a standardized JSON-based format for unifying diabetes time-series data, including CGM, insulin, and meal signals. DIAX promotes interoperability, reproducibility, and extensibility, particularly for machine learning applications. An open-source repository provides tools for dataset conversion, cross-format compatibility, visualization, and community contributions. DIAX is a translational resource, not a data host, ensuring flexibility without imposing data-sharing constraints. Currently, DIAX is compatible with other standardization efforts and supports major datasets (DCLP3, DCLP5, IOBP2, PEDAP, T1Dexi, Loop), totaling over 10 million patient-hours of data. https://github.com/Center-for-Diabetes-Technology/DIAX Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.12294 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.12294v1 Announce Type: new Abstract: Multi-site autism neuroimaging studies routinely control for the confound between full-scale IQ and head motion by regressing framewise displacement against IQ scores and removing shared variance. This procedure assumes that ordinary least squares (OLS) provides an unbiased estimate of the confound magnitude. We tested this assumption on the ABIDE-I phenotypic dataset (n=935 subjects across 19 international scanning sites) using Probability Cloud Regression, an errors-in-variables (EIV) estimator that models per-observation measurement uncertainty in both variables. IQ measurement error was derived from published Wechsler test-retest reliability coefficients; response-side uncertainty was represented by a site-level proxy equal to the within-site standard deviation of mean framewise displacement. Three findings emerged. First, OLS overestimates the IQ-motion slope by a factor of 4.67 relative to the EIV-corrected estimate when the bias factor is computed from the full-precision fitted coefficients (OLS -0.00125, EIV -0.00027 mm per IQ point after rounding for display). Second, under leave-site-out cross-validation a single pooled predictor of raw FD produces negative out-of-sample R^2 at all 19 sites (overall R^2 = -0.074), indicating that the pooled predictor does not transport cleanly across sites once site information is removed. Third, the direction of the EIV-corrected slope is robust across all 64 configurations of an 8x8 sensitivity grid spanning 12-fold ranges of each noise parameter. These results suggest that pooled OLS may overstate the IQ-motion association in ABIDE-I, but direct downstream consequences for motion-correction pipelines remain to be quantified using raw motion traces and connectivity-level re-analysis. Formal EIV methods appear to remain uncommon in multi-site neuroimaging confound estimation. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.11852 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.11852v1 Announce Type: new Abstract: The identification of reliable molecular biomarkers for Parkinson's disease remains challenging due to its multifactorial nature. Although protein sequences constitute a fundamental and widely available source of biological information, their standalone discriminative capacity for complex disease classification remains unclear. In this work, we present a controlled and leakage-free evaluation of multiple representations derived exclusively from protein primary sequences, including amino acid composition, k-mers, physicochemical descriptors, hybrid representations, and embeddings from protein language models, all assessed under a nested stratified cross-validation framework to ensure unbiased performance estimation. The best-performing configuration (ProtBERT + MLP) achieves an F1-score of 0.704 +/- 0.028 and ROC-AUC of 0.748 +/- 0.047, indicating only moderate discriminative performance. Classical representations such as k-mers reach comparable F1 values (up to approximately 0.667), but exhibit highly imbalanced behavior, with recall close to 0.98 and precision around 0.50, reflecting a strong bias toward positive predictions. Across representations, performance differences remain within a narrow range (F1 between 0.60 and 0.70), while unsupervised analyses reveal no intrinsic structure aligned with class labels, and statistical testing (Friedman test, p = 0.1749) does not indicate significant differences across models. These results demonstrate substantial overlap between classes and indicate that primary sequence information alone provides limited discriminative power for Parkinson's disease classification. This work establishes a reproducible baseline and provides empirical evidence that more informative biological features, such as structural, functional, or interaction-based descriptors, are required for robust disease modeling. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2602.14863 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2602.14863v2 Announce Type: replace Abstract: When mutations are rampant, quasispecies theory or Eigen's model predicts that the fittest type in a population may not dominate. Beyond a critical mutation rate, the population may even be delocalized completely from the peak of the fitness landscape and the fittest is ironically lost. Extensive efforts have been made to understand this exceptional scenario. But in general, there is no simple prescription that predicts the eventual degree of localization for arbitrary fitness landscapes and mutation rates. Here, we derive a simple and general relation linking the quasispecies' Hill numbers, which are diversity metrics in ecology, and the ratio of an effective fitness variance to the mean mutation rate squared. This ratio, which we call the localization factor, emerges from mean approximations of decomposed surprisal or stochastic entropy change rates. On the side of application, the relation we obtained here defines a combination of Hill numbers that may complement other complexity or diversity measures for real viral quasispecies. Its advantage being that there is an underlying biological interpretation under Eigen's model. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.12884 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.12884v1 Announce Type: cross Abstract: At the fundamental conceptual level, two alternatives have traditionally been considered for how mutations arise and how evolution happens: 1) random mutation and natural selection, and 2) Lamarckism. Recently, the theory of Interaction-based Evolution (IBE) has been proposed, according to which mutations are neither random nor Lamarckian, but are influenced by information accumulating internally in the genome over generations. Based on the estimation-of-distribution algorithms framework, we present a simulation model that demonstrates nonrandom, non-Lamarckian mutation concretely while capturing indirectly several aspects of IBE: selection, recombination, and nonrandom, non-Lamarckian mutation interact in a complementary fashion; evolution is driven by the interaction of parsimony and fit; and random bits do not directly encode improvement but enable generalization by the manner in which they connect with the rest of the evolutionary process. Connections are drawn to Darwin's observations that changed conditions increase the rate of production of heritable variation; to the causes of bell-shaped distributions of traits and how these distributions respond to selection; and to computational learning theory, where analogizing evolution to learning in accord with IBE casts individuals as examples and places the learned hypothesis at the population level. The model highlights the importance of incorporating internal integration of information through heritable change in both evolutionary theory and evolutionary computation. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.11915 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.11915v1 Announce Type: cross Abstract: Modern machine learning methods have been proposed to detect life in extraterrestrial samples, drawing on their ability to distinguish biotic from abiotic samples based on training models using natural and synthetic organic molecular mixtures. Here we show using Artificial Life that such methods are easily fooled into detecting life with near 100% confidence even if the analyzed sample is not capable of life. This is due to modern machine learning methods' propensity to be easily fooled by out-of-distribution samples. Because extra-terrestrial samples are very likely out of the distribution provided by terrestrial biotic and abiotic samples, using AI methods for life detection is bound to yield significant false positives. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.12004 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.12004v1 Announce Type: new Abstract: Fixation probabilities are essential for characterizing stochastic evolutionary dynamics, but analytical results remain limited mainly to systems with two competing types. We develop a perturbative framework to compute fixation probabilities in multi-allele Moran processes under weak selection. Exploiting the general structure of the backward Fokker-Planck operator in this regime, we show that fixation probabilities admit a systematic expansion around their neutral solution. We first introduce the framework in a general case with $M$ competing alleles and arbitrary fitness functions, and then apply it to three biologically motivated examples: a simple model of three competing alleles with a constant fitness function, a coordination game in which allele fitness increases with its frequency in the population, and a model of clonal interference between mutualistic alleles. These results extend the analytical understanding of fixation probabilities beyond pairwise interactions, establishing a framework for investigating multi-strategy stochastic evolutionary dynamics. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2602.05971 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2602.05971v2 Announce Type: replace-cross Abstract: Semantic representations can be framed as a structured, dynamic knowledge space through which humans navigate to retrieve and manipulate meaning. To investigate how humans traverse this geometry, we introduce a framework that represents concept production as navigation through embedding space. Using different transformer text embedding models, we construct participant-specific semantic trajectories based on cumulative embeddings and extract geometric and dynamical metrics, including distance to next, distance to centroid, entropy, velocity, and acceleration. These measures capture both scalar and directional aspects of semantic navigation, providing a computationally grounded view of semantic representation search as movement in a geometric space. We evaluate the framework on four datasets across different languages, spanning different property generation tasks: Neurodegenerative, Swear verbal fluency, Property listing task in Italian, and in German. Across these contexts, our approach distinguishes between clinical groups and concept types, offering a mathematical framework that requires minimal human intervention compared to typical labor-intensive linguistic pre-processing methods. Comparison with a non-cumulative approach reveals that cumulative embeddings work best for longer trajectories, whereas shorter ones may provide too little context, favoring the non-cumulative alternative. Critically, different embedding models yielded similar results, highlighting similarities between different learned representations despite different training pipelines. By framing semantic navigation as a structured trajectory through embedding space, bridging cognitive modeling with learned representation, thereby establishing a pipeline for quantifying semantic representation dynamics with applications in clinical research, cross-linguistic analysis, and the assessment of artificial cognition. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2503.14333 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2503.14333v4 Announce Type: replace-cross Abstract: Brains construct not only "first-order" representations of the environment but also "higher-order" representations about those representations -- including higher-order uncertainty estimates that guide learning and adaptive behavior. Higher-order expectations about representational uncertainty -- i.e., learned through experience -- may play a key role in guiding behavior and learning, but their characterization remains empirically and theoretically challenging. Here, we introduce the Noise Estimation through Reinforcement-based Diffusion (NERD) model, a novel computational framework that trains denoising diffusion models via reinforcement learning to infer distributions of noise in functional MRI data from a decoded neurofeedback task, where healthy human participants learn to achieve target neural states. We hypothesize that participants accomplish this task by learning about and then minimizing their own representational uncertainty. We test this hypothesis with NERD, which mirrors brain-like unsupervised learning. Our results show that NERD outperforms backpropagation-trained control models in capturing human performance with explanatory power enhanced by clustering learned noise distributions. Importantly, our results also reveal individual differences in expected-uncertainty representations that predict task success, demonstrating NERD's utility as a powerful tool for probing higher-order neural representations. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2412.07238 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2412.07238v3 Announce Type: replace-cross Abstract: The identity of a speaker influences language comprehension through modulating perception and expectation. This review explores speaker effects and proposes an integrative model of language and speaker processing that integrates distinct mechanistic perspectives. We argue that speaker effects arise from the interplay between bottom-up perception-based processes, driven by acoustic-episodic memory, and top-down expectation-based processes, driven by a speaker model. We show that language and speaker processing are functionally integrated through multi-level probabilistic processing: prior beliefs about a speaker modulate language processing at the phonetic, lexical, and semantic levels, while the unfolding speech and message continuously update the speaker model, refining broad demographic priors into precise individualized representations. Within this framework, we distinguish between speaker-idiosyncrasy effects arising from familiarity with an individual and speaker-demographics effects arising from social group expectations. We discuss how speaker effects serve as indices for assessing language development and social cognition, and we encourage future research to extend these findings to the emerging domain of artificial intelligence (AI) speakers, as AI agents represent a new class of social interlocutors that are transforming the way we engage in communication. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.12683 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.12683v1 Announce Type: cross Abstract: Current fMRI foundation models primarily rely on a limited range of brain states and mismatched pretraining tasks, restricting their ability to learn generalized representations across diverse brain states. We present \textit{Brain-DiT}, a universal multi-state fMRI foundation model pretrained on 349,898 sessions from 24 datasets spanning resting, task, naturalistic, disease, and sleep states. Unlike prior fMRI foundation models that rely on masked reconstruction in the raw-signal space or a latent space, \textit{Brain-DiT} adopts metadata-conditioned diffusion pretraining with a Diffusion Transformer (DiT), enabling the model to learn multi-scale representations that capture both fine-grained functional structure and global semantics. Across extensive evaluations and ablations on 7 downstream tasks, we find consistent evidence that diffusion-based generative pretraining is a stronger proxy than reconstruction or alignment, with metadata-conditioned pretraining further improving downstream performance by disentangling intrinsic neural dynamics from population-level variability. We also observe that downstream tasks exhibit distinct preferences for representational scale: ADNI classification benefits more from global semantic representations, whereas age/sex prediction comparatively relies more on fine-grained local structure. Code and parameters of Brain-DiT are available at \href{https://github.com/REDMAO4869/Brain-DiT}{Link}. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.24626 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2603.24626v2 Announce Type: replace Abstract: Background: Single-cell RNA sequencing (scRNA-seq) enables gene expression profiling at cellular resolution but is inherently affected by sparsity caused by dropout events, where expressed genes are recorded as zeros due to technical limitations. These artifacts distort gene expression distributions and compromise downstream analyses. Numerous imputation methods have been proposed to recover latent transcriptional signals. These methods range from traditional statistical models to deep learning (DL)-based methods. However, their comparative performance remains unclear, as existing benchmarks evaluate only a limited subset of methods, datasets, and downstream analyses. Results: We present a comprehensive benchmark of 15 scRNA-seq imputation methods spanning 7 methodological categories, including traditional and DL-based methods. Methods are evaluated across 30 datasets from 10 experimental protocols on 6 downstream analyses. Results show that traditional methods, such as model-based, smoothing-based, and low-rank matrix-based methods, generally outperform DL-based methods, including diffusion-based, GAN-based, GNN-based, and autoencoder-based methods. In addition, strong performance in numerical gene expression recovery does not necessarily translate into improved biological interpretability in downstream analyses, including cell clustering, differential expression analysis, marker gene analysis, trajectory analysis, and cell type annotation. Furthermore, method performance varies substantially across datasets, protocols, and downstream analyses, with no single method consistently outperforming others. Conclusions: Our findings provide practical guidance for selecting imputation methods tailored to specific analytical objectives and underscore the importance of task-specific evaluation when assessing imputation performance in scRNA-seq data analysis. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.12060 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.12060v1 Announce Type: cross Abstract: The analysis of DNA sequences has become critical in numerous fields, from evolutionary biology to understanding gene regulation and disease mechanisms. While deep neural networks can achieve remarkable predictive performance, they typically operate as black boxes. Contrasting these black boxes, axis-aligned decision trees offer a promising direction for interpretable DNA sequence analysis, yet they suffer from a fundamental limitation: considering individual raw features in isolation at each split limits their expressivity, which results in prohibitive tree depths that hinder both interpretability and generalization performance. We address this challenge by introducing DEFT, a novel framework that adaptively generates high-level sequence features during tree construction. DEFT leverages large language models to propose biologically-informed features tailored to the local sequence distributions at each node and to iteratively refine them with a reflection mechanism. Empirically, we demonstrate that DEFT discovers human-interpretable and highly predictive sequence features across a diverse range of genomic tasks. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.12671 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.12671v1 Announce Type: new Abstract: Objective: This study aimed to assess how wearable physiological signals, alone and combined with salivary cortisol, distinguish physical and psychological stress and their recovery states. Methods: Six healthy adults completed three laboratory sessions on separate days: rest, physical stress (high-intensity cycling), or psychological stress (modified Trier Social Stress Test). Heart rate, heart rate variability, electrodermal activity, and wrist accelerometry were recorded continuously, and salivary cortisol was sampled at five time points. Features were extracted in non-overlapping 10-minute windows and labelled as rest, physical stress, physical recovery, psychological stress, or psychological recovery. A gradient boosting classifier was trained using wearable features alone and with five additional cortisol features per window. Performance was evaluated using leave-one-participant-out cross-validation. Results: Wearable-only classification achieved 77.8% overall accuracy, with high accuracy for physical stress and recovery but frequent misclassification of psychological stress and recovery (recall 50.0% and 54.2%). Including cortisol improved overall accuracy (94.4%), particularly for psychological states, increasing recall to 83.3% and 87.5%. Cortisol also reduced misclassification between psychological stress and rest. Conclusion: Wearable signals alone were insufficient to reliably distinguish psychological stress from rest and recovery. Integrating salivary cortisol improved classification of psychological stress and recovery and reduced confusion with rest, highlighting the value of endocrine context alongside wearable physiology. Significance: These findings support multimodal stress monitoring and motivate larger, ecologically valid studies and scalable alternatives to repeated cortisol sampling. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.12546 Wed, 15 Apr 2026 00:00:00 -0400 arXiv:2604.12546v1 Announce Type: new Abstract: Cooperation is central to the organization of complex biological and social systems. Most theoretical models assume homogeneous environments; in reality, populations inhabit spatially varying landscapes in which the payoffs of cooperation differ across space. Here, we introduce a general framework for the evolution of cooperation in complex, heterogeneous environments where the benefit of cooperation depends on local environmental quality. Cooperators in environmentally rich sites confer greater benefits than those on poor sites. We show that whether heterogeneity promotes or suppresses cooperation is determined primarily by the spatial organization of environmental states. Across arbitrary environmental landscapes, a single quantity, the spatial correlation index (SCI), predicts the fixation probability of cooperators. Under weak selection, segregated environments enhance cooperation, whereas highly intermixed, checkerboard-like landscapes suppress it. Beyond fixation probabilities, environmental organization also controls evolutionary timescales: segregated landscapes generate long-lived metastable coexistence, whereas intermixed landscapes lead to faster but less successful fixation of cooperators. Together, these results provide a unifying description of how spatial environmental heterogeneity shapes the evolution of cooperation and suggest measurable predictors of cooperative success in biological and social settings. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2602.20218 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2602.20218v2 Announce Type: replace-cross Abstract: Objectives: To determine whether targeted T2 fluid-attenuated inversion recovery (T2-FLAIR) dropout training improves robustness of glioblastoma MRI tumor segmentation and whole-tumor volumetry when T2-FLAIR is unavailable, without degrading performance when T2-FLAIR is available. Materials and Methods: In this retrospective multi-dataset study, 3D nnU-Net models were trained on a subset of the BraTS 2021 cohort (n=848) and externally validated on the University of Pennsylvania glioblastoma cohort (n=403). Models were trained with no dropout or targeted T2-FLAIR dropout (probability rate (r)=0.35 or 0.50) by replacing only the T2-FLAIR channel with zeros during training. Testing used prespecified T2-FLAIR-present and T2-FLAIR-absent scenarios, with the absent scenario simulated by zeroing the T2-FLAIR channel at inference. The primary endpoint was per-patient overall region-wise Dice similarity coefficient (DSC), secondary endpoints were region-specific DSC, 95th percentile Hausdorff distance and Bland-Altman whole-tumor volume bias. Results: With T2-FLAIR present, overall median DSC was 94.8% (interquartile range [IQR] 90.0%-97.1%) with dropout (r=0.35) and 95.0% (IQR 90.3%-97.1%) without dropout, supporting equivalence (p<0.001). With T2-FLAIR absent, overall median DSC improved from 81.0% (IQR 75.1%-86.4%) without dropout to 93.4% (IQR 89.1%-96.2%) with dropout (r=0.35). Whole-tumor DSC improved from 60.4% to 92.6%, whole tumor 95th percentile Hausdorff distance improved from 17.24 mm to 2.45 mm, and whole-tumor volume bias improved from -45.6 mL to 0.83 mL. Conclusions: In a simulated T2-FLAIR-unavailable scenario, targeted T2-FLAIR dropout preserved segmentation performance when T2-FLAIR was available and substantially reduced whole-tumor segmentation error and volumetric bias when T2-FLAIR was absent. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2507.03951 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2507.03951v3 Announce Type: replace-cross Abstract: The computational pipelines of single-particle cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) include an early particle-picking stage, in which a micrograph or tomogram is scanned to extract candidate particles, typically via template matching or deep-learning-based techniques. The extracted particles are then passed to downstream tasks such as classification and 3D reconstruction. Although it is well understood empirically that particle picking can be sensitive to the choice of templates or learned priors, a quantitative theory of the bias introduced by this stage has been lacking. Here, we develop a mathematical framework for analyzing bias in template matching-based detection with concrete applications to cryo-EM and cryo-ET. We study this bias through two downstream tasks: (i) maximum-likelihood estimation of class means in a Gaussian mixture model (GMM) and (ii) 3D volume reconstruction from the extracted particle stack. We show that when template matching is applied to pure noise, then under broad noise models, the resulting maximum-likelihood estimates converge asymptotically to deterministic, noise-dependent transforms of the user-specified templates, yielding a structure from noise effect. We further characterize how the resulting bias depends on the noise statistics, sample size, dimension, and detection threshold. Finally, controlled experiments using standard cryo-EM software corroborate the theory, demonstrating reproducible structure from noise artifacts in low-SNR data. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2409.06565 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2409.06565v3 Announce Type: replace-cross Abstract: We study a class of Stochastic Differential Equations (SDEs) with jumps modeling multistage Michaelis--Menten enzyme kinetics, in which a substrate is sequentially transformed into a product via a cascade of intermediate complexes. These networks are typically high-dimensional and exhibit multiscale behavior with a strong coupling between different components, posing substantial analytical and computational challenges. In particular, the problem of statistical inference of reaction rates is significantly difficult and becomes even more intricate when direct observations of system states are unavailable and only a random sample of product formation times is observed. We address this problem in two stages. First, in a suitable scaling regime consistent with the Quasi-Steady State Approximation (QSSA), we rigorously establish a stochastic averaging principle yielding a reduced model for the product-substrate dynamics. Guided by the reduced-order dynamics, we next construct a novel Interacting Particle System (IPS) that approximates the product-substrate process at the particle level. This IPS plays a pivotal role in the inference methodology, and we prove several non-asymptotic bounds and limiting results for this system. These results facilitate the construction of an estimator based on a product-form approximate likelihood requiring only a random sample of product formation times. This approach does not need access to the system states, and we rigorously prove consistency of the estimator. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.11483 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2604.11483v1 Announce Type: cross Abstract: Goal-directed molecular generation requires satisfying heterogeneous constraints such as protein--ligand compatibility and multi-objective drug-like properties, yet existing methods often optimize these constraints in isolation, failing to reconcile conflicting objectives (e.g., affinity vs. safety), and struggle to navigate the non-differentiable chemical space without compromising structural validity. To address these challenges, we propose CAGenMol, a condition-aware discrete diffusion framework over molecular sequences that formulates molecular design as conditional denoising guided by heterogeneous structural and property signals. By coupling discrete diffusion with reinforcement learning, the model aligns the generation trajectory with non-differentiable objectives while preserving chemical validity and diversity. The non-autoregressive nature of diffusion language model further enables iterative refinement of molecular fragments at inference time. Experiments on structure-conditioned, property-conditioned, and dual-conditioned benchmarks demonstrate consistent improvements over state-of-the-art methods in binding affinity, drug-likeness, and success rate, highlighting the effectiveness of our framework. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.10609 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2604.10609v1 Announce Type: cross Abstract: Instance segmentation enables the analysis of spatial and temporal properties of cells in microscopy images by identifying the pixels belonging to each cell. However, progress is constrained by the scarcity of high-quality labeled microscopy datasets. Many recent approaches address this challenge by initializing models with segmentation-pretrained weights from large-scale natural-image models such as Segment Anything Model (SAM). However, representations learned from natural images often encode objectness and texture priors that are poorly aligned with microscopy data, leading to degraded performance under domain shift. We propose DINOCell, a self-supervised framework for cell instance segmentation that leverages representations from DINOv2 and adapts them to microscopy through continued self-supervised training on unlabeled cell images prior to supervised fine-tuning. On the LIVECell benchmark, DINOCell achieves a SEG score of 0.784, improving by 10.42% over leading SAM-based models, and demonstrates strong zero-shot performance on three out-of-distribution microscopy datasets. These results highlight the benefits of domain-adapted self-supervised pretraining for robust cell segmentation. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2509.02651 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2509.02651v3 Announce Type: replace Abstract: The emergency department (ED) is a high stress environment with increased risk of clinician bias exposure. In the United States, Black patients are more likely than other racial/ethnic groups to obtain their first schizophrenia (SCZ) diagnosis in the ED, a highly stigmatizing disorder. Therefore, understanding the link between clinician bias exposure and psychiatric outcomes is critical for promoting nondiscriminatory decision-making in the ED. This study examines the association between clinician bias exposure and psychiatric diagnosis using a sample of patients with anxiety, bipolar, depression, trauma, and SCZ diagnoses (N=29,005) from a diverse, large medical center. Clinician bias exposure was quantified as the ratio of negative to total number of sentences in psychiatric notes, labeled using a large language model (Mistral). We utilized logistic regression to predict SCZ diagnosis when controlling for patient demographics, risk factors, and negative sentence ratio (NSR). A high NSR significantly increased one's odds of obtaining a SCZ diagnosis and attenuated the effects of patient race. Black male patients with high NSR had the highest odds of being diagnosed with SCZ. Our findings suggest sentiment-based metrics can operationalize clinician bias exposure with real world data and reveal disparities beyond race or ethnicity. Quantitative_Biology/q-bio.OT_(Other_Quantitative_Biology) https://arxiv.org/abs/2602.07131 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2602.07131v2 Announce Type: replace-cross Abstract: Early clinical assessment of Alzheimer's disease relies on behavior scores that measure a subject's language, memory, and cognitive skills. On the medical imaging side, functional magnetic resonance imaging has provided invaluable insights into the neural pathways underlying Alzheimer's disease. While prior studies have used resting-state functional MRI by extracting functional connectivity matrices, these approaches neglect the temporal dynamics inherent in functional data. In this work, we present a deep state space modeling framework that directly leverages the blood-oxygenation-level-dependent time series to learn a sparse collection of brain regions to predict behavior scores. Our model extracts temporal features that encapsulate nuanced patterns of intrinsic brain activity, thereby enhancing predictive performance compared to traditional connectivity methods. We identify specific brain regions that are most predictive of cognitive impairment through experiments on data provided by the Michigan Alzheimer's Disease Research Center, providing new insights into the neural substrates of early Alzheimer's pathology. These findings have important implications for the possible development of risk monitoring and intervention strategies in Alzheimer's disease. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.04069 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2604.04069v2 Announce Type: replace Abstract: Information flow is central to contemporary accounts of cognition, yet its physical basis in living neural matter remains poorly specified. Here, we develop a multiscale resource-theoretical framework motivated by the \textit{thermocoherent effect}, where heat flow is reciprocally coupled to a delocalized information flow carried by shared coherence and not reducible to local subsystem variables. Extending this line of work in light of recent results on correlation-enabled Mpemba-type thermal relaxation, we argue that the operational relevance of correlations depends less on their taxonomy than on their dynamical accessibility under the underlying interaction geometry. Relational structure encoded in the state of a single composite system -- including quantum entanglement, quantum discord, and classical correlations -- may therefore act as a usable physical resource that remains hidden from local subsystem descriptions. We propose that electrical, chemical, ionic, and thermal transport processes in neural matter may, under suitable microscopic conditions, generate or transduce partially hidden relational resources whose mutual coupling can progressively build larger-scale thermocoherent organization across spatial or spatiotemporal partitions in neural tissue. Ion-channel interfaces, hydrogen-bonded proton networks, aromatic $\pi$-electron architectures, and phosphate-rich motifs emerge as plausible substrate classes in which such resources may arise, become transiently accessible under environmental coupling, and leave coarse-grained signatures in neural dynamics. The resulting picture is neither a claim of macroscopic quantum cognition nor a reduction of cognition to abstract coding, but a falsifiable framework in which microscopic relational resources can bias transport, relaxation, signaling, and cross-scale neural coordination. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.01475 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2604.01475v2 Announce Type: replace Abstract: Parkinsons disease (PD) alters cortical neural dynamics, yet reliable non-invasive electrophysiological biomarkers remain elusive. This study examined whether interpretable EEG features capturing complementary aspects of neural dynamics can discriminate Parkinsonian neural states. A comprehensive set of interpretable features was extracted and grouped into Standard descriptors (spectral power, phase synchronization, time-domain statistics) and Dynamical descriptors (aperiodic activity, cross-frequency coupling, scale-free dynamics, neuronal avalanche statistics, and instantaneous frequency measures). A multi-head attention transformer classifier was trained using strict LOSO validation. Group-level comparisons were performed to identify electrophysiological differences associated with disease and medication state. Standard feature sets achieved strongest performance in discriminating medication states (PDoff vs PDon), whereas Dynamical performed competitively in contrasts between PD patients and healthy controls. Random feature ablation analyses indicated that Dynamical descriptors provide complementary information distributed across features while correlation analysis revealed low redundancy within both feature sets. Group-level comparisons revealed medication-sensitive reductions in delta power and voltage variance, modulation of neuronal avalanche statistics, persistent increases in theta phase synchronization in PD patients, and disease-related alterations in cross-frequency interactions. Traditional spectral and synchronization features primarily reflect medication-related neural modulation, whereas dynamical descriptors reveal broader alterations in cortical network organization associated with disease but also with medication. These findings support multivariate EEG representations as a promising framework for developing non-invasive biomarkers of PD. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.19019 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2601.19019v2 Announce Type: replace Abstract: Neural population activity in sensory cortex is organized on low-dimensional manifolds, but why such manifolds arise and what determines their geometry remain unclear. We model cortical populations as recurrent circuits driven by low-dimensional regular sensory dynamics (circles, tori). Combining generalized synchronization and delay-embedding theory, we show that contracting recurrent networks generically develop smooth internal manifolds embedding the sensory dynamics. The dimensional requirement is modest: N>2d suffices, where d is the intrinsic sensory dimension (compatible with Whitney and Takens bounds). We prove a prediction-separation result linking representational geometry to predictive performance without assuming contraction: accurate prediction forces state separation up to a resolution set by prediction error, yielding categorical boundaries, metameric equivalence, and discrimination thresholds. Numerical experiments with trained tanh RNNs recover ring- and torus-shaped hidden manifolds; state separation improves sharply at the 2d+1 threshold. Training pushes networks beyond strict contraction, yet embedding persists, indicating sufficient but not necessary conditions. These results provide a mechanistic account of why sensory manifolds emerge in recurrent circuits and how prediction constrains their resolution. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.15689 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2601.15689v2 Announce Type: replace Abstract: Volitional memory control supports adaptive cognition by enabling intentional suppression of goal-irrelevant, interfering memories and recall of goal-relevant memories. Neural mechanisms of suppression and recall have been studied largely in isolation, and their operation under concurrent working memory load in the context of subclinical anxiety remains unclear. We examined control of emotionally valenced memories in 47 healthy participants with varying levels of subclinical anxiety under dual-task conditions involving directed suppression and recall while concurrently performing a secondary task imposing visual working memory load. Cognitive efficiency in controlling dual-task memory-linked interference, measured by the Balanced Integration Score (BIS), showed no differences between suppression and recall, across emotions, or by anxiety. Intrinsic functional brain networks measured by seed-to-voxel resting-state functional connectivity (rsFC) revealed dissociable rsFC profiles linked to cognitive control across emotional valences, moderated by anxiety. Efficient suppression of positive memories correlated with reduced connectivity between anterior cingulate cortex and posterior perceptual-midline regions, and diminished hippocampal-frontal pole coupling. Efficient suppression of negative memories correlated with increased posterior parietal to lateral occipital connectivity. Anxiety moderated associations between cognitive control and prefrontal connectivity during suppression of positive memories and recall of positive and neutral memories. Direct comparisons revealed stronger hippocampal-thalamic rsFC during suppression versus recall of positive memories. Together, these findings delineate neural correlates of volitional emotional memory control under cognitive load and suggest that subclinical anxiety shapes these networks selectively Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.08056 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2601.08056v2 Announce Type: replace Abstract: Animal behavior reflects interactions between the nervous system, body, and environment. Therefore, biomechanics and environmental context must be considered to understand algorithms for behavioral control. Neuromechanical digital twins, namely computational models that embed artificial neural controllers within realistic body models in simulated environments, are a powerful tool for this purpose. Here, we review advances in neuromechanical digital twins while also highlighting emerging opportunities ahead. We first show how these models enable inference of biophysical variables that are difficult to measure experimentally. Through systematic perturbation, one can generate new experimentally testable hypotheses through these models. We then examine how neuromechanical twins facilitate the exchange between neuroscience, robotics, and machine learning, and showcase their applications in healthcare. We envision that coupling experimental studies with active probing of their neuromechanical twins will significantly accelerate progress in neuroscience. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2505.03458 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2505.03458v4 Announce Type: replace Abstract: Brain networks from functional MRI have advanced our understanding of cortical activity and its disruption in neurodegenerative disorders. Recent work has increasingly focused on dynamic (time-varying) brain networks that capture both spatial and temporal patterns of regional co-activity, yet this approach remains underexplored across the Alzheimer's disease (AD). We analysed age- and sex-matched static and dynamic functional brain networks derived from resting-state fMRI data in 315 individuals with AD, mild cognitive impairment (MCI), and cognitively normal healthy controls (HC) from the ADNI-3 cohort. Functional networks were constructed using the Juelich brain atlas, with static connectivity estimated from full time series and dynamic connectivity derived using a sliding-window approach. Group differences were assessed at both link and node levels using non-parametric statistics and bootstrap resampling. While HC and MCI exhibited similar static and dynamic patterns at the node level, clearer differences emerged in AD. Stable (stationary) differences in functional connectivity were identified between white matter regions and parietal and somatosensory cortices, whereas temporally varying differences were consistently observed in connections involving the amygdala and hippocampal formation. Node centrality analysis further suggested that white matter connectivity differences are predominantly local in nature. These findings highlight both shared and distinct functional connectivity patterns across static and dynamic networks, underscoring the importance of incorporating temporal dynamics into brain network analyses of the Alzheimer's spectrum. Additionally, a Random Forest model trained on regional BOLD time series informed by static and dynamic metrics achieved robust classification of MCI, AD, and HC groups, demonstrating the diagnostic potential of time-varying connectivity. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.11482 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2604.11482v1 Announce Type: new Abstract: The integrated information theory of consciousness (IIT) is uniquely ambitious in proposing a mathematical formula, derived from apparently fundamental properties of conscious experience, to describe the quantity and quality of consciousness for any physical system that possesses it. IIT has generated considerable debate, which has engendered some misunderstandings and misrepresentations. Here we address and hope to remedy this. We begin by concisely summarising the essentials of IIT. Given IIT is supposed to apply universally, we do this with reference to an arbitrary patch of matter, as opposed to the usual system of discrete computational units. Then, after briefly summarising IIT's theoretical and empirical achievements, we focus on five points which we consider especially important for driving forward new theory and increasing understanding. First, a high value of the measure $\Phi$ is not synonymous with `more consciousness'. We describe how $\Phi$ might be replaced with a suite of quantities to obtain a multi-dimensional characterisation of states of consciousness. Second, we describe with nuance the distinct flavour of panpsychism implied by IIT -- whereby space (and time) are tiled with substrates of (proto-) consciousness -- and find this is not problematic for the theory. Third, $\Phi$ is not well-defined for real physical systems, and has not been computed on any real physical system. Fourth, so far only proxies for IIT measures have been computed, and not approximations. Fifth, for IIT to fit with current successful theories in fundamental physics, a reformulation in terms of continuous fields would be needed. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.11208 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2604.11208v1 Announce Type: new Abstract: Humans are inherently social and seek connection with others for survival. Recent studies suggest that acute social isolation leads to craving for social interactions, but the brain mechanisms of social craving and their relationship to brain networks underlying drug and food craving remain incompletely understood. Here we harnessed an existing dataset and tested whether the Neurobiological Craving Signature (NCS)-a recently developed fMRI-based brain-signature of drug and food craving-also predicts social craving. During fMRI, participants rated their craving for images of food, social interactions, and flowers in three different sessions: after 10h of fasting from food, 10h of social isolation, or neither (baseline; order of sessions counterbalanced). The NCS significantly predicted self-reported craving for food and social cues but not flower cues. Further, NCS responses to food were higher after fasting compared to baseline, and higher for social cues after social isolation compared to baseline, demonstrating its responsiveness to both food and social deprivation. These findings resonate with recent work showing shared brainstem circuits for hunger and social isolation, and indicate shared whole-brain circuits for social, food, and drug craving. They open new avenues for testing the NCS across different primary rewards, for assessing the consequences of their deprivation, and for examining how social deprivation-such as loneliness and isolation-interacts with overeating and drug use. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.11178 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2604.11178v1 Announce Type: new Abstract: Forecasting neural activity in response to naturalistic stimuli remains a key challenge for understanding brain dynamics and enabling downstream neurotechnological applications. Here, we introduce a generative forecasting framework for modeling neural dynamics based on autoregressive flow matching (AFM). Building on recent advances in transport-based generative modeling, our approach probabilistically predicts neural responses at scale from multimodal sensory input. Specifically, we learn the conditional distribution of future neural activity given past neural dynamics and concurrent sensory input, explicitly modeling neural activity as a temporally evolving process in which future states depend on recent neural history. We evaluate our framework on the Algonauts project 2025 challenge functional magnetic resonance imaging dataset using subject-specific models. AFM significantly outperforms both a non-autoregressive flow-matching baseline and the official challenge general linear model baseline in predicting short-term parcel-wise blood oxygenation level-dependent (BOLD) activity, demonstrating improved generalization and widespread cortical prediction performance. Ablation analyses show that access to past BOLD dynamics is a dominant driver of performance, while autoregressive factorization yields consistent, modest gains under short-horizon, context-rich conditions. Together, these findings position autoregressive flow-based generative modeling as an effective approach for short-term probabilistic forecasting of neural dynamics with promising applications in closed-loop neurotechnology. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.10606 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2604.10606v1 Announce Type: new Abstract: We propose a dynamical neural network model with a hierarchical and modular structure. The network architecture can be derived by minimizing an energy function that is originally designed based on two kinds of neurons with quite different time constants. It has multiple subspaces that are spanned by neural parameters employed in the energy function, and adjacent subspaces are related to each other with a layered internetwork. Each internetwork further consists of a pair of a forward subnet and a backward one, and signals flowing through these subnets determine total dynamics of the network. The model can operate in either a learning or an association mode. In the learning mode, when periodic signals equivalent to repetitive neuronal bursting are suitably applied to input ports in all subspaces, mapping relationships corresponding to those input signals are eventually formed in internetworks between subspaces. Various two-dimensional mapping relationships between subspaces can be shaped by employing an appropriate set of periodic input signals with different frequencies based on the same mechanism as a Lissajous curve. The model in the association mode provides an overall framework such that state variables inside the network individually relax in warped spaces, each of which has been designed as favorable for a (or some) state variable(s). The association mode is further classified into two modes; unconstrained and constrained. In the latter mode, for instance, when a sufficiently slow periodic trajectory is set as an input, a warped output trajectory appears in each subspace as if imaginary layered networks with the inverse mapping relationships to existing forward subnets' were located hierarchically from outside to inside. These results suggest that a certainty/uncertainty relation exists between an input trajectory and an output trajectory. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.20792 Tue, 14 Apr 2026 00:00:00 -0400 arXiv:2510.20792v4 Announce Type: replace-cross Abstract: The rapid progress of graph generation has raised new security concerns, particularly regarding backdoor vulnerabilities. While prior work has explored backdoor attacks in image diffusion and unconditional graph generation, conditional, especially text-guided graph generation remains largely unexamined. This paper proposes BadGraph, a backdoor attack method against latent diffusion models for text-guided graph generation. BadGraph leverages textual triggers to poison training data, covertly implanting backdoors that induce attacker-specified subgraphs during inference when triggers appear, while preserving normal performance on clean inputs. Extensive experiments on four benchmark datasets (PubChem, ChEBI-20, PCDes, MoMu) demonstrate the effectiveness and stealth of the attack: less than 10% poisoning rate can achieves 50% attack success rate, while 24% suffices for over 80% success rate, with negligible performance degradation on benign samples. Ablation studies further reveal that the backdoor is implanted during VAE and diffusion training rather than pretraining. These findings reveal the security vulnerabilities in latent diffusion models of text-guided graph generation, highlight the serious risks in models' applications such as drug discovery and underscore the need for robust defenses against the backdoor attack in such diffusion models. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2604.09540 Mon, 13 Apr 2026 00:00:00 -0400 arXiv:2604.09540v1 Announce Type: cross Abstract: Molecular docking is a crucial step in the development of new drugs as it guides the positioning of a small molecule (ligand) within the pocket of a target protein. In the literature, a feasibility study explored the potential of D-Wave quantum annealers for purely geometric molecular docking, neglecting physicochemical interactions between the protein and the ligand and focusing solely on their simplified geometries. To achieve this, the ligands were represented as graphs incorporating their geometric properties and then mapped onto a grid that discretized the three-dimensional space of the protein pocket. The quality of the ligand pose on the protein pocket was evaluated through the isomorphism between the ligand graph and the spatial grid. This paper builds on the previous study by introducing physicochemical interactions between the protein-ligand pair into the QUBO problem to improve the accuracy of the docking results. This paper presents a novel QUBO formulation that includes Coulomb and van der Waals forces, together with components representing H-bond and hydrophobic interactions. We integrate these physical interactions as corrective terms to the previous purely geometric QUBO formulation, and provide experimental results using the D-Wave quantum annealers to demonstrate their impact on the accuracy of the docking results. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2510.07265 Mon, 13 Apr 2026 00:00:00 -0400 arXiv:2510.07265v2 Announce Type: replace Abstract: Aging is a universal consequence of life, yet researchers have identified no universal theme. This manuscript considers aging from the perspective of entropy, wherein things fall apart. We first examine biological information change as a mutational distance, analogous to physical distance. In this model, informational change over time is fitted to an advection-diffusion equation, a normal distribution with a time component. The solution of the advection-diffusion equation provides a means of measuring the entropy of diverse biological systems. The binomial distribution is also sufficient to demonstrate that entropy increases as mutations or epimutations accumulate. As modeled, entropy scales with lifespans across the tree of life. This perspective provides potential mechanistic insights and testable hypotheses as to how evolution has attained enhanced longevity: entropy management. We find entropy is an inclusive rather than exclusive aging theory. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.07602 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2604.07602v1 Announce Type: cross Abstract: The world is full of systems of distributed agents, collaborating and competing in complex ways: firms and workers specialise within economies, neurons adapt their tuning across brain circuits, and species compete and coexist within ecosystems. In that context, individual research fields built theories explaining how comparative advantage drives trade specialisation, how balanced neural representations emerge from sensory coding, and how biodiversity sustains ecological productivity. Here we propose that many of these well-understood findings across fields can be captured in one simple joint cross-disciplinary model, which we call the Distributed Production System. It captures how agent heterogeneity, resource constraints, communication topology, and task structure jointly determine the productivity, efficiency, and robustness of distributed systems across biology, economics, neuroscience, and computing. This model reveals that a small set of underlying laws generates the complex dynamics observed across fields. These can be summarised in our Principle of Maximum Heterogeneity: any distributed production system optimising for performance will converge on an increasingly heterogeneous configuration; environmental demands place an upper bound on the degree of heterogeneity required; and the communication topology determines the spatial scale over which heterogeneity spreads, with this principle applying recursively across all layers of nested production systems. Beyond explaining existing systems, these principles act as a blueprint for constructing ideal ones. We demonstrate this by suggesting specific redesigns for compute systems executing large-scale AI. In total, The Principle of Maximum Heterogeneity reveals a unique convergence of complex phenomena across fields onto simple underlying design principles with important predictive value for future distributed production systems. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.07745 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2604.07745v1 Announce Type: cross Abstract: LLMs gain competence by predicting words in human text, which often reflects how people perform tasks. Consequently, coupling an LLM to an engineered runtime turns prediction into control: outputs trigger interventions that enact goal-oriented behavior. We argue that a central design lever is where control resides in these systems. Brains embed prediction within layered feedback controllers calibrated by the consequences of action. By contrast, LLM agents implement Cartesian agency: a learned core coupled to an engineered runtime via a symbolic interface that externalizes control state and policies. The split enables bootstrapping, modularity, and governance, but can induce sensitivity and bottlenecks. We outline bounded services, Cartesian agents, and integrated agents as contrasting approaches to control that trade off autonomy, robustness, and oversight. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.08537 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2604.08537v1 Announce Type: cross Abstract: Visual decoding from brain signals is a key challenge at the intersection of computer vision and neuroscience, requiring methods that bridge neural representations and computational models of vision. A field-wide goal is to achieve generalizable, cross-subject models. A major obstacle towards this goal is the substantial variability in neural representations across individuals, which has so far required training bespoke models or fine-tuning separately for each subject. To address this challenge, we introduce a meta-optimized approach for semantic visual decoding from fMRI that generalizes to novel subjects without any fine-tuning. By simply conditioning on a small set of image-brain activation examples from the new individual, our model rapidly infers their unique neural encoding patterns to facilitate robust and efficient visual decoding. Our approach is explicitly optimized for in-context learning of the new subject's encoding model and performs decoding by hierarchical inference, inverting the encoder. First, for multiple brain regions, we estimate the per-voxel visual response encoder parameters by constructing a context over multiple stimuli and responses. Second, we construct a context consisting of encoder parameters and response values over multiple voxels to perform aggregated functional inversion. We demonstrate strong cross-subject and cross-scanner generalization across diverse visual backbones without retraining or fine-tuning. Moreover, our approach requires neither anatomical alignment nor stimulus overlap. This work is a critical step towards a generalizable foundation model for non-invasive brain decoding. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2511.20179 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2511.20179v4 Announce Type: replace Abstract: Scalable assessments of mental illness remain a critical roadblock toward accessible and equitable care. Here, we show that everyday human-computer interactions encode mental health with biomarker accuracy. We introduce MAILA, a MAchine-learning framework for Inferring Latent mental states from digital Activity. We trained MAILA on 18,200 cursor and touchscreen recordings labelled with 1.3 million mental-health self-reports collected from 9,500 participants. MAILA tracks dynamic mental states along 13 clinically relevant dimensions, resolves circadian fluctuations and experimental manipulations of arousal and valence, achieves near-ceiling accuracy at the group level, and captures information about mental health that is only partially reflected in verbal self-report. By extracting signatures of psychological function that have so far remained untapped, MAILA establishes human-computer interactions as a new modality for scalable digital phenotyping of mental health. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2511.20162 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2511.20162v2 Announce Type: replace-cross Abstract: Large multi-modal models (LMMs) show increasing performance in realistic visual tasks for images and, more recently, for videos. For example, given a video sequence, such models are able to describe in detail objects, the surroundings and dynamic actions. In this study, we explored the extent to which these models ground their semantic understanding in the actual visual input. Specifically, given sequences of hands interacting with objects, we asked models when and where the interaction begins or ends. For this purpose, we introduce a first of its kind, large-scale dataset with more than 20K annotated interactions on videos from the Something-Something-V2 dataset. 250 AMTurk human annotators labeled core interaction events, particularly when and where objects and agents become attached (`contact') or detached (`release'). We asked SoTA LMMs, including GPT, Gemini and Qwen to locate these events in short videos, each with a single event. The results show that while models reliably name target objects and identify actions, they exhibit a form of `shortcut learning' where semantic success masks a failure in physical grounding. Specifically, they consistently fail to identify the frame where the interaction begins or ends and poorly localize the physical event within the scene. This disconnect suggests that while LMMs excel at System 1 intuitive pattern recognition (naming the action and objects), they lack the System 2 cognitive foundations required to reason about physical primitives like `contact' and `release', hence truly ground dynamic scenes in physical reality. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.07560 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2604.07560v1 Announce Type: new Abstract: Activity cliff prediction - identifying positions where small structural changes cause large potency shifts - has been a persistent challenge in computational medicinal chemistry. This work focuses on a parsimonious definition: which small modifications, at which positions, confer the highest probability of an outcome change. Position-level sensitivity is calculated using 25 million matched molecular pairs from 50 ChEMBL targets across six protein families, revealing that two questions have fundamentally different answers. "Which positions vary most?" is answered by scaffold size alone (NDCG@3 = 0.966), requiring no machine learning. "Which are true activity cliffs?" - where small modifications cause disproportionately large effects, as captured by SALI normalization - requires an 11-feature model with 3D pharmacophore context (NDCG@3 = 0.910 vs. 0.839 random), generalizing across all six protein families, novel scaffolds (0.913), and temporal splits (0.878). The model identifies the cliff-prone position first 53% of the time (vs. 27% random - 2x lift), reducing positions a chemist must explore from 3.1 to 2.1 - a 31% reduction in first-round experiments. Predicting which modification to make is not tractable from structure alone (Spearman 0.268, collapsing to -0.31 on novel scaffolds). The system is released as open-source code and an interactive webapp. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.07576 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2604.07576v1 Announce Type: new Abstract: Brightfield time-lapse imaging is widely used in cardiac tissue engineering, yet the absence of standardized, interpretable analytical frameworks limits reproducibility and cross-platform comparison. We present an open, scalable computational pipeline for quantifying spatiotemporal contractile dynamics in microscopy videos of human induced pluripotent stem cell-derived cardiac microbundles. Building on our open-source tools "MicroBundleCompute" and "MicroBundlePillarTrack," we define a suite of 16 interpretable structural, functional, and spatiotemporal metrics that capture tissue deformation, synchrony, and heterogeneity. The framework integrates full-field displacement tracking, strain reconstruction, spatial registration, dimensionality reduction, and topology-based vector-field analysis within a unified workflow. Applied to a dataset of 670 cardiac microbundles spanning 20 experimental conditions, the pipeline reveals continuous variation in contractile phenotypes rather than discrete condition-specific clustering, with intra-condition variability often exceeding inter-condition differences. Redundancy analysis identifies a reduced core set of 10 metrics that retain most informational content while minimizing multicollinearity. Analysis of denoised displacement fields shows that contraction is dominated by a global isotropic mode, with localized saddle-type deformation patterns present in approximately half of the samples. All software and workflows are released openly to enable reproducible, scalable analysis of dynamic tissue mechanics. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.07557 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2604.07557v1 Announce Type: cross Abstract: Small longitudinal clinical cohorts, common in maternal health, rare diseases, and early-phase trials, limit computational modeling: too few patients to train reliable models, yet too costly and slow to expand through additional enrollment. We present multiplicity-weighted Stochastic Attention (SA), a generative framework based on modern Hopfield network theory that addresses this gap. SA embeds real patient profiles as memory patterns in a continuous energy landscape and generates novel synthetic patients via Langevin dynamics that interpolate between stored patterns while preserving the geometry of the original cohort. Per-pattern multiplicity weights enable targeted amplification of rare clinical subgroups at inference time without retraining. We applied SA to a longitudinal coagulation dataset from 23 pregnant patients spanning 72 biochemical features across 3 visits (pre-pregnancy baseline, first trimester, and third trimester), including rare subgroups such as polycystic ovary syndrome and preeclampsia. Synthetic patients generated by SA were statistically, structurally, and mechanistically indistinguishable from their real counterparts across multiple independent validation tests, including an ordinary differential equation model of the coagulation cascade. A downstream utility test further showed that a mechanistic model calibrated entirely on synthetic patients predicted held-out real patient outcomes as well as one calibrated on real data. These results demonstrate that SA can produce clinically useful synthetic cohorts from very small longitudinal datasets, enabling data-augmented modeling in small-cohort settings. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.08507 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2604.08507v1 Announce Type: cross Abstract: Recent advances in single-cell technologies have advanced our understanding of gene regulation and cellular heterogeneity at single-cell resolution. Single-cell data contain both gene expression levels and the proportion of expressing cells, which makes them structurally different from bulk data. Currently, methodological work on causal mediation analysis for single-cell data remains limited and often requires specific distributional assumptions. To address this challenge, we present QuasiMed, a mediation framework specialized for single-cell data. Our proposed method comprises three steps, including (i) screening mediator candidates through penalized regression and marginal models (similar to sure independence screening), (ii) estimation of indirect effects through the average expression and the proportion of expressing cells, (iii) and hypothesis testing with multiplicity control. The key benefit of QuasiMed is that it specifies only the mean functions of the mediation models through a quasi-regression framework, thereby relaxing strict distributional assumptions. The method performance was evaluated through the real-data-inspired simulations, and demonstrated high power, false discovery rate control, and computational efficiency. Lastly, we applied QuasiMed to ROSMAP single-cell data to illustrate its potential to identify mediating causal pathways. R package is freely available on GitHub repository at https://github.com/sjahnn/QuasiMed. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2510.11752 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2510.11752v2 Announce Type: replace Abstract: Proteins are essential biological macromolecules that execute life functions. Local structural motifs, such as active sites, are the most critical components for linking structure to function and are key to understanding protein evolution and enabling protein engineering. Existing computational methods struggle to identify and compare these local structures, which leaves a significant gap in understanding protein structures and harnessing their functions. This study presents PLASMA, a deep-learning-based framework for efficient and interpretable residue-level local structural alignment. We reformulate the problem as a regularized optimal transport task and leverage differentiable Sinkhorn iterations. For a pair of input protein structures, PLASMA outputs a clear alignment matrix with an interpretable overall similarity score. Through extensive quantitative evaluations and three biological case studies, we demonstrate that PLASMA achieves accurate, lightweight, and interpretable residue-level alignment. Additionally, we introduce PLASMA-PF, a training-free variant that provides a practical alternative when training data are unavailable. Our method addresses a critical gap in protein structure analysis tools and offers new opportunities for functional annotation, evolutionary studies, and structure-based drug design. Reproducibility is ensured via our official implementation at https://github.com/ZW471/PLASMA-Protein-Local-Alignment.git. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2511.06140 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2511.06140v2 Announce Type: replace Abstract: Forces transmitted by bones are routinely studied in human biomechanics, but it is challenging to measure them non-invasively, especially outside of laboratory settings. We introduce a technique for non-invasive, in vivo measurement of tibial compressive force using flexural waves propagating in the tibia. Modelling the tibia as an axially compressed Euler-Bernoulli beam, we show that tibial flexural waves have load-dependent frequency spectra. Specifically, under physiological conditions, peak locations in the wave acceleration spectra vary linearly with the compressive force on the tibia and may be used as proxies for the compressive force. We test the validity of this technique using a proof-of-concept wearable system that generates flexural waves via a skin-mounted mechanical transducer and measures the spectra of these waves using a skin-mounted accelerometer. In agreement with beam theory, data from 9 participants demonstrate linear relationships between tibial compressive force and spectral peak location, with Pearson correlation coefficients $r=0.82 - 0.99$ (mean $r=0.93$) for medial-lateral swaying and $r=0.81 - 0.98$ (mean $r=0.93$) for walking trials. This flexural wave-based technique could give rise to a new class of wearable sensors for non-invasive physiological bone load monitoring and measurement, impacting research in human locomotion and sports medicine. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2509.12873 Fri, 10 Apr 2026 00:00:00 -0400 arXiv:2509.12873v2 Announce Type: replace Abstract: The simulation of whole-brain dynamics should reproduce realistic spontaneous and evoked neural activity across different scales, including emergent rhythms, spatio-temporal activation patterns, and macroscale complexity. Once a mathematical model is selected, its configuration must be determined by properly setting its parameters. A critical preliminary step in this process is defining an appropriate set of observables to guide the selection of model configurations (parameter tuning), laying the groundwork for quantitative calibration of accurate whole-brain models. Here, we address this challenge by presenting a framework that integrates two complementary tools: The Virtual Brain (TVB) platform for simulating whole-brain dynamics, and the Collaborative Brain Wave Analysis Pipeline (Cobrawap) for analyzing simulation outputs using a set of standardized metrics. We apply this framework to a 998-node human connectome, using two configurations of the Larter-Breakspear neural mass model: one with the TVB default parameters, the other tuned using Cobrawap. The results reveal that the tuned configuration exhibits several biologically relevant features, absent in the default model for both spontaneous and evoked dynamics. In response to external perturbations, the tuned model generates non-stereotyped, complex spatio-temporal activity, as measured by the perturbational complexity index. In spontaneous activity, it exhibits robust alpha-band oscillations, infra-slow rhythms, scale-free characteristics, greater spatio-temporal heterogeneity, and asymmetric functional connectivity. This work demonstrates how combining TVB and Cobrawap can guide parameter tuning and lays the groundwork for data-driven calibration and validation of accurate whole-brain models. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.06569 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2604.06569v1 Announce Type: new Abstract: Extrachromosomal DNA (ecDNA) represents one of the most pressing challenges in cancer biology: circular DNA structures that amplify oncogenes, evade targeted therapies, and drive tumor evolution in ~30% of aggressive cancers. Despite its clinical importance, computational ecDNA research has been built on broken foundations. We discover that existing benchmarks suffer from circular reasoning -- models trained on features that already require knowing ecDNA status -- artificially inflating performance from AUROC 0.724 to 0.967. We introduce ECLIPSE, the first methodologically sound framework for ecDNA analysis, comprising three modules that transform how we predict, model, and target these structures. ecDNA-Former achieves AUROC 0.812 using only standard genomic features, demonstrating for the first time that ecDNA status is predictable without specialized sequencing, and that careful feature curation matters more than complex architectures. CircularODE captures ecDNA's unique stochastic dynamics through physics-constrained neural SDEs, achieving r > 0.997 on experimental data via zero-shot transfer. VulnCausal applies causal inference to identify therapeutic vulnerabilities, achieving 80x enrichment over chance and 3.7x higher validation than standard approaches by filtering spurious correlations. Together, these modules establish rigorous baselines for an emerging application area and reveal a broader lesson: in high-stakes biomedical ML, methodological rigor -- eliminating leakage, encoding domain physics, addressing confounding -- outweighs architectural innovation. ECLIPSE provides both the tools and the template for principled computational oncology. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.07196 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2604.07196v1 Announce Type: new Abstract: DNA language models like Evo2 now fit million-token contexts large enough to cover entire TADs, yet whether they learn 3D chromatin structure, a key regulatory layer acting atop primary sequence, remains untested and questionable, given that Evo2's training data includes prokaryotes lacking this structure. We probed Evo2-7B on TAD boundaries and convergent CTCF loops in 1 Mb windows using two complementary tests: likelihood-based perturbation and sequence generation. Evo2 did not distinguish functional perturbations from matched random controls and failed to reliably generate convergent CTCF loops, recovering TAD boundaries only partially. Together, these results indicate that Evo2 has learned local CTCF grammar but misses higher-order 3D organization, pointing to bidirectional model architectures integrating cell types and 3D contacts, rather than longer contexts, as the path to developing 3D-aware DNA language models. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.06835 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2604.06835v1 Announce Type: cross Abstract: CVTree is an alignment-free methodology for inferring species phylogeny and taxonomy. This method allows for the efficient and accurate resolution of evolutionary relationships among large numbers of species based on whole-genome sequence data. Since 2004, we have been continuously providing CVTree web services. Recently, the server has undergone a significant upgrade, culminating in the release of the WebCVTree4 platform. This upgrade encompasses a comprehensive update of the inbuilt genomic database. Concurrently, the core algorithm has been optimized to support online phylogenetic reconstruction for tens of thousands of species, thereby facilitating the construction of genome-based trees of life. Moreover, we have developed a novel algorithm for comparing phylogenetic trees with established taxonomic systems. This algorithm allows for rapid tree rooting, taxonomic annotation, and topology comparison. Through an interactive web-based visualization tool, users can dynamically adjust tree layouts and export high-quality phylogenetic tree figures. This functionality provides robust support for comparative analysis between CVTree-generated phylogeny and taxonomy. As genome sequencing costs continue to decline, research into microbial evolution and the revision of taxonomic frameworks will increasingly rely on whole-genome data. WebCVTree4 will serve as an efficient web-based platform to support studies in microbial phylogenetics and taxonomy, accessible at https://cvtree.online/. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.06395 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2604.06395v1 Announce Type: cross Abstract: Spiking reservoir computing provides an energy-efficient approach to temporal processing, but reliably tuning reservoirs to operate at the edge-of-chaos is challenging due to experimental uncertainty. This work bridges abstract notions of criticality and practical stability by introducing and exploiting the robustness interval, an operational measure of the hyperparameter range over which a reservoir maintains performance above task-dependent thresholds. Through systematic evaluations of Leaky Integrate-and-Fire (LIF) architectures on both static (MNIST) and temporal (synthetic Ball Trajectories) tasks, we identify consistent monotonic trends in the robustness interval across a broad spectrum of network configurations: the robustness-interval width decreases with presynaptic connection density $\beta$ (i.e., directly with sparsity) and directly with the firing threshold $\theta$. We further identify specific $(\beta, \theta)$ pairs that preserve the analytical mean-field critical point $w_{\text{crit}}$, revealing iso-performance manifolds in the hyperparameter space. Control experiments on Erd\H{o}s-R\'enyi graphs show the phenomena persist beyond small-world topologies. Finally, our results show that $w_{\text{crit}}$ consistently falls within empirical high-performance regions, validating $w_{\text{crit}}$ as a robust starting coordinate for parameter search and fine-tuning. To ensure reproducibility, the full Python code is publicly available. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2409.20318 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2409.20318v2 Announce Type: replace Abstract: Consciousness science faces the challenge of bridging first-person experience with third-person empirical measurements. Neurophenomenology aims to build such `generative passages' connecting the content of experience with behavioural and neuroscientific data. However, the mathematical machinery for such bridges remains underdeveloped. Here we develop a Rosetta Stone hypothesis from predictive processing, where beliefs serve as a central hub connecting phenomenology, behaviour, and neural dynamics. This hinges on a central technical assumption that phenomenology is a function of beliefs. We pursue a conditional approach: if this assumption holds, then certain predictions mathematically follow. We derive predictions for subjective similarity judgements, cognitive metabolic cost, subjective cognitive effort, and time perception. We review the connection between beliefs and neural dynamics to complete the generative passage for neurophenomenology, omitting the connection between beliefs and behaviour as this is already well-documented elsewhere. Testing our predictions will inform the validity of the central assumption connecting beliefs and phenomenology, and advance the neurophenomenology research programme. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2503.02642 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2503.02642v3 Announce Type: replace Abstract: In both machine learning and in computational neuroscience, plasticity in functional neural networks is frequently expressed as gradient descent on a cost. Often, this imposes symmetry constraints that are difficult to reconcile with local computation, as is required for biological networks or neuromorphic hardware. For example, wake-sleep learning in networks characterized by Boltzmann distributions assumes symmetric connectivity. Similarly, the error backpropagation algorithm is notoriously plagued by the weight transport problem between the representation and the error stream. Existing solutions such as feedback alignment circumvent the problem by deferring to the robustness of these algorithms to weight asymmetry. However, they scale poorly with network size and depth. We introduce spike-based alignment learning (SAL), a complementary learning rule for spiking neural networks, which uses spike timing statistics to extract and correct the asymmetry between effective reciprocal connections. Apart from being spike-based and fully local, our proposed mechanism takes advantage of noise. Based on an interplay between Hebbian and anti-Hebbian plasticity, synapses can thereby recover the true local gradient. This also alleviates discrepancies that arise from neuron and synapse variability -- an omnipresent property of physical neuronal networks. We demonstrate the efficacy of our mechanism using different spiking network models. First, SAL can significantly improve convergence to the target distribution in probabilistic spiking networks versus Hebbian plasticity alone. Second, in neuronal hierarchies based on cortical microcircuits, SAL effectively aligns feedback weights to the forward pathway, thus allowing the backpropagation of correct feedback errors. Third, our approach enables competitive performance in deep networks using only local plasticity for weight transport. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.02824 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2510.02824v2 Announce Type: replace Abstract: Background: The locus of the gene PTK2B encoding the tyrosine kinase Pyk2 has been associated with the risk of late-onset Alzheimer's disease, the predominant form of dementia. Pyk2 is primarily expressed in neurons where it is involved in excitatory neurotransmission and synaptic functions. Although previous studies have implicated Pyk2 in amyloid-beta and Tau pathologies of Alzheimer's disease, its exact role remains unresolved, with evidence showing both detrimental and protective effects in mouse models. Here, we investigate the role of Pyk2 in hippocampal hyperactivity, Tau synaptic localization and synaptic loss associated with Alzheimer's disease-related alterations occurring in the early stages of the disease. Methods: Pyk2's involvement in amyloid-beta oligomer-induced hippocampal neuronal hyperactivity was investigated using whole-cell patch clamp in hippocampal slices from WT and Pyk2 KO mice. Various Pyk2 mutants were overexpressed in cultured cortical neurons to study Pyk2's role in synaptic loss. Pyk2 and Tau interaction was assessed with bimolecular fluorescence complementation assays in cultured neurons and co-immunoprecipitation in mouse cortex. To evaluate the impact of Pyk2 on Tau expression in synapses, cellular fractionation was performed on hippocampi from WT and Pyk2 KO mice. Results: Genetic deletion of Pyk2 prevented amyloid-beta oligomer-induced hippocampal neuronal hyperactivity and synaptic loss. Overexpression of Pyk2 in neurons decreased dendritic spine density independently of its autophosphorylation or kinase activity, but through its proline-rich motif 1. Furthermore, Pyk2 interacted with Tau in synapses, while Pyk2 deletion decreased Tau synaptic localization in the hippocampus. Conclusions: Pyk2 contributes to hippocampal neuronal hyperactivity and synaptic loss, two early events in Alzheimer's disease pathogenesis. It is also involved in Tau synaptic localization, a process known to be detrimental in Alzheimer's disease. These findings highlight Pyk2 as a critical player in Alzheimer's disease pathophysiology and suggest its potential as a promising therapeutic target for early intervention. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2512.02503 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2512.02503v2 Announce Type: replace Abstract: Studying learning-related plasticity is central to understanding the acquisition of complex skills, for example learning to master a musical instrument. Over the past three decades, conventional group-based functional magnetic resonance imaging (fMRI) studies have advanced our understanding of how humans' neural representations change during skill acquisition. However, group-based fMRI studies average across heterogeneous learners and often rely on coarse pre- versus post-training comparisons, limiting the spatial and temporal precision with which neural changes can be estimated. Here, we outline an individual-specific precision approach that tracks neural changes within individuals by collecting high-quality neuroimaging data frequently over the course of training, mapping brain function in each person's own anatomical space, and gathering detailed behavioral measures of learning, allowing neural trajectories to be directly linked to individual learning progress. Complementing fMRI with mobile neuroimaging methods, such as functional near-infrared spectroscopy (fNIRS), will enable researchers to track plasticity during naturalistic practice and across extended time scales. This multi-modal approach will enhance sensitivity to individual learning trajectories and will offer more nuanced insights into how neural representations change with training. We also discuss how findings can be generalized beyond individuals, including through statistical methods based on replication in additional individuals. Together, this approach allows researchers to design highly informative longitudinal training studies that advance a personalized account of skill learning in the human brain. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.04958 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2604.04958v2 Announce Type: replace-cross Abstract: Recent work suggests that large-scale, multi-animal modeling can significantly improve neural recording analysis. However, for functional calcium traces, existing approaches remain task-specific, limiting transfer across common neuroscience objectives. To address this challenge, we propose \textbf{CalM}, a self-supervised neural foundation model trained solely on neuronal calcium traces and adaptable to multiple downstream tasks, including forecasting and decoding. Our key contribution is a pretraining framework, composed of a high-performance tokenizer mapping single-neuron traces into a shared discrete vocabulary, and a dual-axis autoregressive transformer modeling dependencies along both the neural and the temporal axis. We evaluate CalM on a large-scale, multi-animal, multi-session dataset. On the neural population dynamics forecasting task, CalM outperforms strong specialized baselines after pretraining. With a task-specific head, CalM further adapts to the behavior decoding task and achieves superior results compared with supervised decoding models. Moreover, linear analyses of CalM representations reveal interpretable functional structures beyond predictive accuracy. Taken together, we propose a novel and effective self-supervised pretraining paradigm for foundation models based on calcium traces, paving the way for scalable pretraining and broad applications in functional neural analysis. Code will be released soon. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.06264 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2604.06264v1 Announce Type: new Abstract: Recent advances in large language models (LLMs) have enabled molecular reasoning for property prediction. However, toxicity arises from complex biological mechanisms beyond chemical structure, necessitating mechanistic reasoning for reliable prediction. Despite its importance, current benchmarks fail to systematically evaluate this capability. LLMs can generate fluent but biologically unfaithful explanations, making it difficult to assess whether predicted toxicities are grounded invalid mechanisms. To bridge this gap, we introduce ToxReason, a benchmark grounded in the Adverse Outcome Pathway (AOP) that evaluates organ-level toxicity reasoning across multiple organs. ToxReason integrates experimental drug-target interaction evidence with toxicity labels, requiring models to infer both toxic outcomes and their underlying mechanisms from Molecular Initiating Event (MIE) to Adverse Outcome (AO). Using ToxReason, we evaluate toxicity prediction performance and reasoning quality across diverse LLMs. We find that strong predictive performance does not necessarily imply reliable reasoning. Furthermore, we show that reasoning-aware training improves mechanistic reasoning and, consequently, toxicity prediction performance. Together, these results underscore the necessity of integrating reasoning into both evaluation and training for trustworthy toxicity modeling. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.06269 Thu, 09 Apr 2026 00:00:00 -0400 arXiv:2604.06269v1 Announce Type: new Abstract: Automated cellular reasoning faces a core dichotomy: supervised methods fall into the Reference Trap and fail to generalize to out-of-distribution cell states, while large language models (LLMs), without grounded biological priors, suffer from a Signal-to-Noise Paradox that produces spurious associations. We propose MAT-Cell, a neuro-symbolic reasoning framework that reframes single-cell analysis from black-box classification into constructive, verifiable proof generation. MAT-Cell injects symbolic constraints through adaptive Retrieval-Augmented Generation (RAG) to ground neural reasoning in biological axioms and reduce transcriptomic noise. It further employs a dialectic verification process with homogeneous rebuttal agents to audit and prune reasoning paths, forming syllogistic derivation trees that enforce logical consistency.Across large-scale and cross-species benchmarks, MAT-Cell significantly outperforms state-of-the-art (SOTA) models and maintains robust per-formance in challenging scenarios where baselinemethods severely degrade. Code is available at https://gith ub.com/jiangliu91/MAT-Cell-A-Mul ti-Agent-Tree-Structured-Reasoni ng-Framework-for-Batch-Level-Sin gle-Cell-Annotation. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2602.07816 Wed, 08 Apr 2026 00:00:00 -0400 arXiv:2602.07816v3 Announce Type: replace Abstract: Human eye-hand coordination relies on internal forward models that predict future states and compensate for sensory delays. During line tracing, the gaze typically leads the hand through predictive saccades, yet the extent to which this predictive window reflects expertise or intrinsic individual traits remains unclear. In this study, I examined eye-hand coordination in professional calligraphers and non-experts performing a controlled line tracing task. The temporal coupling between saccade distance (SD) and pen speed (PS) revealed substantial interpersonal variability: SD-PS peak times ranged from approximately -50 to 400 ms, forming stable, participant-specific predictive windows that were consistent across trials. These predictive windows closely matched each individual's pen catch-up time, indicating that the oculomotor system stabilizes fixation in anticipation of the hand's future velocity rather than relying on reactive pursuit. Neither the spatial indices (mean gaze-pen distance, mean saccade distance) nor the temporal index (SD-PS peak time) differed between calligraphers and non-calligraphers, and none of these predictive parameters correlated with tracing accuracy. These findings suggest that diverse predictive strategies can achieve equivalent performance, consistent with the minimum intervention principle of optimal feedback control. Together, the results indicate that predictive timing in eye-hand coordination reflects a stable, idiosyncratic Predictive Protocol shaped by individual neuromotor constraints rather than by expertise or training history. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2509.10547 Wed, 08 Apr 2026 00:00:00 -0400 arXiv:2509.10547v2 Announce Type: replace Abstract: Despite the diversity and volume of brain data acquired and advanced AI-based algorithms to analyze them, brain features are rarely used in clinics for diagnosis and prognosis. Here we argue that the field continues to rely on cohort comparisons to seek biomarkers, despite the well-established degeneracy of brain features. Using a thought experiment (Brain Swap), we show that more data and more powerful algorithms will not be sufficient to identify biomarkers of brain diseases. We argue that instead of comparing patient versus healthy controls using single data type, we should use multimodal (e.g. brain activity, neurotransmitters, neuromodulators, brain imaging) and longitudinal brain data to guide the grouping before defining multidimensional biomarkers for brain diseases. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.05215 Wed, 08 Apr 2026 00:00:00 -0400 arXiv:2604.05215v1 Announce Type: cross Abstract: Representation learning on large-scale unstructured volumetric and surface meshes poses significant challenges in neuroimaging, especially when models must incorporate diverse vertex-level morphometric descriptors, such as cortical thickness, curvature, sulcal depth, and myelin content, which carry subtle disease-related signals. Current approaches either ignore these clinically informative features or support only a single mesh topology, restricting their use across imaging pipelines. We introduce a hierarchical transformer framework designed for heterogeneous mesh analysis that operates on spatially adaptive tree partitions constructed from simplicial complexes of arbitrary order. This design accommodates both volumetric and surface discretizations within a single architecture, enabling efficient multi-scale attention without topology-specific modifications. A feature projection module maps variable-length per-vertex clinical descriptors into the spatial hierarchy, separating geometric structure from feature dimensionality and allowing seamless integration of different neuroimaging feature sets. Self-supervised pretraining via masked reconstruction of both coordinates and morphometric channels on large unlabeled cohorts yields a transferable encoder backbone applicable to diverse downstream tasks and mesh modalities. We validate our approach on Alzheimer's disease classification and amyloid burden prediction using volumetric brain meshes from ADNI, as well as focal cortical dysplasia detection on cortical surface meshes from the MELD dataset, achieving state-of-the-art results across all benchmarks. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.05775 Wed, 08 Apr 2026 00:00:00 -0400 arXiv:2604.05775v1 Announce Type: cross Abstract: Bacteriophages, often referred to as the dark matter of the biosphere, play a critical role in regulating microbial ecosystems and in antibiotic alternatives. Thus, accurate interpretation of their genomes holds significant scientific and practical value. While general-purpose Large Language Models (LLMs) excel at understanding biological texts, their ability to directly interpret raw nucleotide sequences and perform biological reasoning remains underexplored. To address this, we introduce PhageBench, the first benchmark designed to evaluate phage genome understanding by mirroring the workflow of bioinformatics experts. The dataset contains 5,600 high-quality samples covering five core tasks across three stages: Screening, Quality Control, and Phenotype Annotation. Our evaluation of eight LLMs reveals that general-purpose reasoning models significantly outperform random baselines in phage contig identification and host prediction, demonstrating promising potential for genomic understanding. However, they exhibit significant limitations in complex reasoning tasks involving long-range dependencies and fine-grained functional localization. These findings highlight the necessity of developing next-generation models with enhanced reasoning capabilities for biological sequences. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.05774 Wed, 08 Apr 2026 00:00:00 -0400 arXiv:2604.05774v1 Announce Type: new Abstract: Large Language Models (LLMs) are increasingly adopted as conversational assistants in genomics, where they are mainly used to reason over biological knowledge, annotations, and analysis outputs through natural language interfaces. However, existing benchmarks either focus on specialized DNA models trained for sequence prediction or evaluate biological knowledge using text-only questions, leaving the behavior of general-purpose LLMs when directly exposed to raw genome sequences underexplored. We introduce GenomeQA, a benchmark designed to provide a controlled evaluation setting for general-purpose LLMs on sequence-based genome inference tasks. GenomeQA comprises 5,200 samples drawn from multiple biological databases, with sequence lengths ranging from 6 to 1,000 base pairs (bp), spanning six task families: Enhancer and Promoter Identification, Splice Site Identification, Taxonomic Classification, Histone Mark Prediction, Transcription Factor Binding Site Prediction, and TF Motif Prediction. Across six frontier LLMs, we find that models consistently outperform random baselines and can exploit local sequence signals such as GC content and short motifs, while performance degrades on tasks that require more indirect or multi-step inference over sequence patterns. GenomeQA establishes a diagnostic benchmark for studying and improving the use of general-purpose LLMs on raw genomic sequences. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.05478 Wed, 08 Apr 2026 00:00:00 -0400 arXiv:2604.05478v1 Announce Type: new Abstract: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; yet substantial proportion of patients exhibit intrinsic or acquired resistance, making accurate pre-treatment response prediction a critical unmet need. Transcriptomics-based biomarkers derived from bulk and single-cell RNA sequencing (scRNA-seq) offer a promising avenue for capturing tumour-immune interactions, yet the cross-cohort generalisability of existing prediction models remains unclear.We systematically benchmark nine state-of-the-art transcriptomic ICI response predictors, five bulk RNA-seq-based models (COMPASS, IRNet, NetBio, IKCScore, and TNBC-ICI) and four scRNA-seq-based models (PRECISE, DeepGeneX, Tres and scCURE), using publicly available independent datasets unseen during model development. Overall, predictive performance was modest: bulk RNA-seq models performed at or near chance level across most cohorts, while scRNA-seq models showed only marginal improvements. Pathway-level analyses revealed sparse and inconsistent biomarker signals across models. Although scRNA-seq-based predictors converged on immune-related programs such as allograft rejection, bulk RNA-seq-based models exhibited little reproducible overlap. PRECISE and NetBio identified the most coherent immune-related themes, whereas IRNet predominantly captured metabolic pathways weakly aligned with ICI biology. Together, these findings demonstrate the limited cross-cohort robustness and biological consistency of current transcriptomic ICI prediction models, underscoring the need for improved domain adaptation, standardised preprocessing, and biologically grounded model design. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.03476 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.03476v1 Announce Type: cross Abstract: Optical Chemical Structure Recognition (OCSR) is critical for converting 2D molecular diagrams from printed literature into machine-readable formats. While Vision-Language Models have shown promise in end-to-end OCR tasks, their direct application to OCSR remains challenging, and direct full-parameter supervised fine-tuning often fails. In this work, we adapt DeepSeek-OCR-2 for molecular optical recognition by formulating the task as image-conditioned SMILES generation. To overcome training instabilities, we propose a two-stage progressive supervised fine-tuning strategy: starting with parameter-efficient LoRA and transitioning to selective full-parameter fine-tuning with split learning rates. We train our model on a large-scale corpus combining synthetic renderings from PubChem and realistic patent images from USPTO-MOL to improve coverage and robustness. Our fine-tuned model, MolSeek-OCR, demonstrates competitive capabilities, achieving exact matching accuracies comparable to the best-performing image-to-sequence model. However, it remains inferior to state-of-the-art image-to-graph modelS. Furthermore, we explore reinforcement-style post-training and data-curation-based refinement, finding that they fail to improve the strict sequence-level fidelity required for exact SMILES matching. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2604.04033 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.04033v1 Announce Type: new Abstract: Connectome-constrained neural networks are often evaluated against sparse random controls and then interpreted as evidence that biological graph topology improves learning efficiency. We revisit that claim in a controlled flyvis-based study using a Drosophila connectome, a naive self-loop-matched random graph, and a degree-preserving rewired null. Under weak controls, in which both models were recovered from a connectome-trained checkpoint and the null matched only global graph counts, the connectome appeared substantially better in early loss, mean activity, and runtime. That picture changed under stricter controls. Training both graphs from a shared random initialization removed the early loss advantage, and replacing the naive null by a degree-preserving null removed the apparent activity advantage. A five-sample degree-preserving ensemble and a pre-training activity-scale diagnostic further strengthened this revised interpretation. We also report a descriptive mechanism analysis of the earlier weak-control comparison, but we treat it as behavioral characterization rather than proof of causal superiority. We show that previously reported topology advantages in connectome-constrained neural networks can arise from initialization and null-model confounds, and largely disappear under fair from-scratch initialization and degree-preserving controls. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.04770 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.04770v1 Announce Type: cross Abstract: Balanced spiking networks can transition between silent, asynchronous-irregular, and oscillatory states depending on interacting synaptic and temporal time scales, while their joint parameter structure remains incompletely characterized. In this work, we systematically map how postsynaptic decay ({\tau}s), conduction delay (d), and plasticity rate ({\lambda}p) jointly shape oscillatory regimes in recurrent leaky integrate-and-fire networks. By combining Brian2 simulations across the ({\tau}s, d, {\lambda}p) space with a coarse Hopf-reference boundary, we construct regime maps that directly visualize SIL-AI-OSC transitions and corresponding spectral prominence landscapes. The mapped results show that increasing {\lambda}p expands oscillatory regions toward shorter {\tau}s and moderate-to-long delays, while prominence maps identify parameter regions with the strongest rhythmic coherence. Representative control experiments further connect this global landscape to local rhythm-forming mechanisms, showing that STDP freezing weakens rhythmic coherence whereas delay jitter enhances it with minimal change in mean firing rate. As a result, these findings provide a useful reference for operating-point selection, synchrony modulation studies, and future biologically grounded spiking-network modeling within similar balanced-network settings. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2410.08823 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2410.08823v3 Announce Type: replace Abstract: It is still challenging for computer vision to imitate human color perception, e.g., color constancy, which is a fundamental perceptual ability in humans to perceive, interpret and interact with their surroundings. Among others, the anchoring theory provides impressive insights for human lightness perception, yet the specific anchoring rules underlying color constancy have remained contentious for decades. In this work, we introduced a novel computational theory - gray-anchoring (GA) theory - to explain how the early stage of visual system contributes to color constancy and demonstrate how our GA rule applies to the chromatic domain by identifying gray surfaces within complex scenes. Furthermore, we also demonstrate the potential neural implementation of gray-anchoring by quantitatively analyzing the computational flows of concentric double-opponent (DO) cells in V1. The simulational results show that the concentric DO cells have the ability to identify gray surfaces within color-biased scenes and these gray surfaces can then be used by the higher-level cortices to easily estimate the illuminant. This finding offers not only a clear functional explanation of the concentric DO receptive fields of this cell type in the visual system but also an effective and efficient solution to computational color constancy for computer vision. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2505.22680 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2505.22680v3 Announce Type: replace Abstract: When substrate-constrained covariance flow on the Bures--Wasserstein manifold reaches the Williamson boundary, single-mode compression saturates and further admissible covariance evolution is forced into the cross-mode complement. This paper derives how that substrate boundary transition becomes experimentally visible in an embedded spin probe in the living human brain. We formulate a boundary-conditioned transfer theorem: when the substrate enters the deep boundary regime in a coupled mode, the boundary-selected cross-mode continuation of substrate covariance flow enters the reduced spin dynamics as a nonzero inter-spin correlation block. The spin probe does not inherit the substrate boundary as a state; it detects the boundary indirectly through the transferred cross-mode sector of the reduced dynamics. To leading order, this transfer is selective: it acts through an additive cross-diffusion channel while leaving conventional single-mode NMR observables such as \(T_1\), \(T_2\), linewidths, and the ordinary single-quantum response dominated by the thermal background. Projecting the induced spin cross-mode structure into the two-spin algebra, we argue that the experimentally relevant dominant recipient is the double-quantum SU(1,1) pair sector rather than the compact zero-quantum SU(2) exchange sector. We then derive the coherence-transfer pathway through which this double-quantum pair coherence is converted into a detectable signal by the \(45^\circ\)--gradient--\(45^\circ\) readout block. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.03361 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.03361v1 Announce Type: cross Abstract: The modeling of bio-molecular system across molecular scales remains a central challenge in scientific research. Large language models (LLMs) are increasingly applied to bio-molecular discovery, yet systematic evaluation across multi-scale biological problems and rigorous assessment of their tool-augmented capabilities remain limited. We reveal a systematic gap between LLM performance and mechanistic understanding through the proposed cross-scale bio-molecular benchmark: BioMol-LLM-Bench, a unified framework comprising 26 downstream tasks that covers 4 distinct difficulty levels, and computational tools are integrated for a more comprehensive evaluation. Evaluation on 13 representative models reveals 4 main findings: chain-of-thought data provides limited benefit and may even reduce performance on biological tasks; hybrid mamba-attention architectures are more effective for long bio-molecular sequences; supervised fine-tuning improves specialization at the cost of generalization; and current LLMs perform well on classification tasks but remain weak on challenging regression tasks. Together, these findings provide practical guidance for future LLM-based modeling of molecular systems. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.03630 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.03630v1 Announce Type: cross Abstract: Spatial transcriptomics (ST) enables gene expression mapping within anatomical context but remains costly and low-throughput. Hematoxylin and eosin (H\&E) staining offers rich morphology yet lacks molecular resolution. We present \textbf{\ours} (\textbf{S}patial \textbf{T}ranscriptomics and hist\textbf{O}logy \textbf{R}epresentation \textbf{M}odel), a foundation model trained on 1.2 million spatially resolved transcriptomic profiles with matched histology across 18 organs. Using a hierarchical architecture integrating morphological features, gene expression, and spatial context, STORM bridges imaging and omics through robust molecular--morphological representations. STORM enhances spatial domain discovery, producing biologically coherent tissue maps, and outperforms existing methods in predicting spatial gene expression from H\&E images across 11 tumor types. The model is platform-agnostic, performing consistently across Visium, Xenium, Visium HD, and CosMx. Applied to 23 independent cohorts comprising 7,245 patients, STORM significantly improves immunotherapy response prediction and prognostication over established biomarkers, providing a scalable framework for spatially informed discovery and clinical precision medicine. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.03911 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.03911v1 Announce Type: cross Abstract: Generating molecular dynamics (MD) trajectories using deep generative models has attracted increasing attention, yet remains inherently challenging due to the limited availability of MD data and the complexities involved in modeling high-dimensional MD distributions. To overcome these challenges, we propose a novel framework that leverages structure pretraining for MD trajectory generation. Specifically, we first train a diffusion-based structure generation model on a large-scale conformer dataset, on top of which we introduce an interpolator module trained on MD trajectory data, designed to enforce temporal consistency among generated structures. Our approach effectively harnesses abundant structural data to mitigate the scarcity of MD trajectory data and effectively decomposes the intricate MD modeling task into two manageable subproblems: structural generation and temporal alignment. We comprehensively evaluate our method on the QM9 and DRUGS small-molecule datasets across unconditional generation, forward simulation, and interpolation tasks, and further extend our framework and analysis to tetrapeptide and protein monomer systems. Experimental results confirm that our approach excels in generating chemically realistic MD trajectories, as evidenced by remarkable improvements of accuracy in geometric, dynamical, and energetic measurements. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.03952 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.03952v1 Announce Type: cross Abstract: Dementia affects over 55 million people worldwide, yet whether distinct domains of physical fitness independently protect against neurodegeneration through shared or divergent biological mechanisms remains unknown. Using the UK Biobank (n = 51,517; 12-year follow-up), we integrated epidemiological, proteomic, and neuroimaging analyses to systematically characterize the multidimensional fitness-dementia relationship. Higher handgrip strength, cardiorespiratory fitness, and pulmonary function were each independently associated with reduced dementia risk (HRs 0.50, 0.62, and 0.73, respectively, for highest vs. lowest tertiles), with stronger associations in women and younger individuals. Plasma proteomic profiling revealed domain-specific molecular signatures--neurofilament light chain predominating for muscular and cardiorespiratory fitness, and inflammatory mediators including GDF15 for pulmonary function--with 22-40 proteins per domain independently predicting dementia, converging on neuroinflammatory and neurovascular pathways. Brain MRI analyses identified hippocampal volume as a significant structural mediator (proportion mediated: 3.7-10.1%), indicating structural preservation as one of multiple mechanistic pathways. Population attributable fraction analyses estimated that suboptimal fitness may account for approximately 26% of dementia cases. These findings reveal that multidimensional physical fitness shapes dementia risk through distinct yet converging neuroinflammatory, neurovascular, and structural brain mechanisms, with implications for life-course prevention. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.04239 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.04239v1 Announce Type: cross Abstract: Multimodal deep learning models that fuse whole-slide histopathology images with genomic data have achieved strong discriminative performance for cancer survival prediction, as measured by the concordance index. Yet whether the survival probabilities derived from these models - either directly from native outputs or via standard post-hoc reconstruction - are calibrated remains largely unexamined. We conduct, to our knowledge, the first systematic fold-level 1-calibration audit of multimodal WSI-genomics survival architectures, evaluating native discrete-time survival outputs (Experiment A: 3 models on TCGA-BRCA) and Breslow-reconstructed survival curves from scalar risk scores (Experiment B: 11 architectures across 5 TCGA cancer types). In Experiment A, all three models fail 1-calibration on a majority of folds (12 of 15 fold-level tests reject after Benjamini-Hochberg correction). Across the full 290 fold-level tests, 166 reject the null of correct calibration at the median event time after Benjamini-Hochberg correction (FDR = 0.05). MCAT achieves C-index 0.817 on GBMLGG yet fails 1-calibration on all five folds. Gating-based fusion is associated with better calibration; bilinear and concatenation fusion are not. Post-hoc Platt scaling reduces miscalibration at the evaluated horizon (e.g., MCAT: 5/5 folds failing to 2/5) without affecting discrimination. The concordance index alone is insufficient for evaluating survival models intended for clinical use. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.04469 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.04469v1 Announce Type: cross Abstract: Scalar variability -- the finding that representational noise scales proportionally with magnitude, producing a constant coefficient of variation -- is a hallmark of biological magnitude systems. We tested whether transformer language models exhibit this property by analysing the dispersion of hidden-state representations across carrier sentences for 26 numerical magnitudes in three 7-8B parameter models (Llama-3-8B-Instruct, Mistral-7B-Instruct-v0.3, Llama-3-8B-Base; data from Cacioli, 2026). We found the opposite: representational variability decreased with magnitude along the magnitude axis (scaling exponent alpha approx -0.19; 0/16 primary layers with alpha > 0, all three models). The negative sign was consistent in full-dimensional space (alpha approx -0.04) and after sentence-identity correction (alpha approx -0.007). The anti-scalar pattern was 3-5x stronger along the magnitude axis than orthogonal dimensions, and corpus frequency strongly predicted per-magnitude variability (rho = .84). These results demonstrate that distributional learning alone is insufficient to produce scalar variability: transformers reproduce log-compressive magnitude geometry but not the constant-CV noise signature observed in biological systems. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.04858 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2604.04858v1 Announce Type: cross Abstract: Objective: Algorithmic fairness is essential for equitable and trustworthy machine learning in healthcare. Most fairness tools emphasize single-axis demographic comparisons and may miss compounded disparities affecting intersectional populations. This study introduces Fairlogue, a toolkit designed to operationalize intersectional fairness assessment in observational and counterfactual contexts within clinical settings. Methods: Fairlogue is a Python-based toolkit composed of three components: 1) an observational framework extending demographic parity, equalized odds, and equal opportunity difference to intersectional populations; 2) a counterfactual framework evaluating fairness under treatment-based contexts; and 3) a generalized counterfactual framework assessing fairness under interventions on intersectional group membership. The toolkit was evaluated using electronic health record data from the All of Us Controlled Tier V8 dataset in a glaucoma surgery prediction task using logistic regression with race and gender as protected attributes. Results: Observational analysis identified substantial intersectional disparities despite moderate model performance (AUROC = 0.709; accuracy = 0.651). Intersectional evaluation revealed larger fairness gaps than single-axis analyses, including demographic parity differences of 0.20 and equalized odds true positive and false positive rate gaps of 0.33 and 0.15, respectively. Counterfactual analysis using permutation-based null distributions produced unfairness ("u-value") estimates near zero, suggesting observed disparities were consistent with chance after conditioning on covariates. Conclusion: Fairlogue provides a modular toolkit integrating observational and counterfactual methods for quantifying and evaluating intersectional bias in clinical machine learning workflows. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2502.20076 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2502.20076v3 Announce Type: replace Abstract: A prominent report claimed substantial support for two introductions of SARS-CoV-2 into humans using a calculation that combined phylodynamic inferences and epidemic models. Inspection of the calculation identifies an imbalance in the hypothesis testing framework that confounds this result; the single-introduction model was tested against more stringent conditions than the two-introduction model. Here, I show that when the two-introduction model is tested against the same conditions, the support disappears. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.09033 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2603.09033v2 Announce Type: replace Abstract: We introduce a filtration-based framework for studying when and why adding taxa improves phylodynamic inference, by constructing a natural ordering of observed tips and applying sequential Bayesian analysis to the resulting filtration. We decompose the expected variance reduction on taxa addition into learning, mismatch, and covariance components, classify estimands into learning classes based on the pathwise behaviour of the mismatch, and show that for absorbing estimands an oracle who knows the latent absorption status obtains event-wise learning guarantees unavailable to the analyst. The gap between oracle and analyst is irreducible assumptions that are likely to hold for many real phylodynamic estimands, establishing a fundamental limit on what sequence data alone can reveal about the latent genealogy. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2511.09216 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2511.09216v2 Announce Type: replace-cross Abstract: Proteins underpin most biological function, and the ability to design them with tailored structures and properties is central to advances in biotechnology. Diffusion-based generative models have emerged as powerful tools for protein design, but steering them toward proteins with specified properties remains challenging. The Feynman-Kac (FK) framework provides a principled way to guide diffusion models using user-defined rewards. In this paper, we enable FK-based steering of RFdiffusion through the development of guiding potentials that leverage ProteinMPNN and structural relaxation to guide the diffusion process towards desired properties. We show that steering can be used to consistently improve predicted interface energetics and increase binder designability by $89.5\%$. Together, these results establish that diffusion-based protein design can be effectively steered toward arbitrary, non-differentiable objectives, providing a model-independent framework for controllable protein generation. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.21743 Tue, 07 Apr 2026 00:00:00 -0400 arXiv:2603.21743v3 Announce Type: replace-cross Abstract: Building virtual cells with generative models to simulate cellular behavior in silico is emerging as a promising paradigm for accelerating drug discovery. However, prior image-based generative approaches can produce implausible cell images that violate basic physical and biological constraints. To address this, we propose to post-train virtual cell models with reinforcement learning (RL), leveraging biologically meaningful evaluators as reward functions. We design seven rewards spanning three categories-biological function, structural validity, and morphological correctness-and optimize the state-of-the-art CellFlux model to yield CellFluxRL. CellFluxRL consistently improves over CellFlux across all rewards, with further performance boosts from test-time scaling. Overall, our results present a virtual cell modeling framework that enforces physically-based constraints through RL, advancing beyond "visually realistic" generations towards "biologically meaningful" ones. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.03312 Mon, 06 Apr 2026 00:00:00 -0400 arXiv:2603.03312v2 Announce Type: replace-cross Abstract: Decoding natural language from non-invasive EEG signals is a promising yet challenging task. However, current state-of-the-art models remain constrained by three fundamental limitations: Semantic Bias (mode collapse into generic templates), Signal Neglect (hallucination based on linguistic priors rather than neural inputs), and the BLEU Trap, where evaluation metrics are artificially inflated by high-frequency stopwords, masking a lack of true semantic fidelity. To address these challenges, we propose SemKey, a novel multi-stage framework that enforces signal-grounded generation through four decoupled semantic objectives: sentiment, topic, length, and surprisal. We redesign the interaction between the neural encoder and the Large Language Model (LLM) by injecting semantic prompts as Queries and EEG embeddings as Key-Value pairs, strictly forcing the model to attend to neural inputs. Furthermore, we move beyond standard translation metrics by adopting N-way Retrieval Accuracy and Fr\'echet Distance to rigorously assess diversity and alignment. Extensive experiments demonstrate that our approach effectively eliminates hallucinations on noise inputs and achieves SOTA performance on these robust protocols. Code will be released upon acceptance at https://github.com/xmed-lab/SemKey. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.20847 Mon, 06 Apr 2026 00:00:00 -0400 arXiv:2510.20847v2 Announce Type: replace Abstract: The extent to which different neural or artificial neural networks (models) rely on equivalent representations to support similar tasks remains a central question in neuroscience and machine learning. Prior work has typically compared systems using a single representational similarity metric, yet each captures only one facet of representational structure. To address this, we leverage a suite of representational similarity metrics-each capturing a distinct facet of representational correspondence, such as geometry, unit-level tuning, or linear decodability-and assess brain region or model separability using multiple complementary measures. Metrics that preserve geometric or tuning structure (e.g., RSA, Soft Matching) yield stronger region-based discrimination, whereas more flexible mappings such as Linear Predictivity show weaker separation. These findings suggest that geometry and tuning encode brain-region- or model-family-specific signatures, while linearly decodable information tends to be more globally shared across regions or models. To integrate these complementary representational facets, we adapt Similarity Network Fusion (SNF), a framework originally developed for multi-omics data integration. SNF produces substantially sharper regional and model family-level separation than any single metric and yields robust composite similarity profiles. Moreover, clustering cortical regions using SNF-derived similarity scores reveals a clearer hierarchical organization that aligns closely with established anatomical and functional hierarchies of the visual cortex-surpassing the correspondence achieved by individual metrics. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.08736 Mon, 06 Apr 2026 00:00:00 -0400 arXiv:2510.08736v2 Announce Type: replace Abstract: Despite many years of research, the quest to identify neural correlates of perceptual consciousness (NCC) remains unresolved. One major obstacle lies in methodological limitations: most studies rely on non-invasive neural measures with limited spatial or temporal resolution making it difficult to disentangle proper NCCs from concurrent cognitive processes. Additionally, the relatively low sensitivity of non-invasive neural measures limits the interpretation of null findings in studies targeting proper NCCs. In this review, we discuss how human intracranial recordings can advance the search for NCCs, by offering high spatiotemporal resolution, improved signal sensitivity, and broad cortical and subcortical coverage. We review studies that have examined NCCs at the level of single neurons and populations of neurons, and evaluate their implications on the debates between cognitive and sensory theories of consciousness. Finally, we highlight the limits of current intracranial human recordings and propose future directions based on emerging technologies and novel experimental paradigms. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.06778 Mon, 06 Apr 2026 00:00:00 -0400 arXiv:2603.06778v2 Announce Type: replace Abstract: We continue recent attempts to put together concepts and results of Chemical Reaction Networks theory (CRNT) and Mathematical Epidemiology (ME), for solving problems of stability of positive ODEs. We provide first an elegant CRN-flavored generalization of the most cited result in ME, the Next Generation Matrix (NGM) theorem. We review next the "symbolic-numeric approach of Vassena and Stadler, which tackles bifurcation problems by viewing the characteristic polynomial of the Jacobian at fixed points as a formal polynomial in the "symbolic reactivities", and identifies its coefficients as "Child Selection minors of the stoichiometric matrix". We also review two applications of this approach using the Mathematica package Epid-CRN tools from both CRNT and ME. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2604.02346 Mon, 06 Apr 2026 00:00:00 -0400 arXiv:2604.02346v1 Announce Type: cross Abstract: Large language models (LLMs) are in the ascendancy for research in drug discovery, offering unprecedented opportunities to reshape drug research by accelerating hypothesis generation, optimizing candidate prioritization, and enabling more scalable and cost-effective drug discovery pipelines. However there is currently a lack of objective assessments of LLM performance to ascertain their advantages and limitations over traditional drug discovery platforms. To tackle this emergent problem, we have developed DrugPlayGround, a framework to evaluate and benchmark LLM performance for generating meaningful text-based descriptions of physiochemical drug characteristics, drug synergism, drug-protein interactions, and the physiological response to perturbations introduced by drug molecules. Moreover, DrugPlayGround is designed to work with domain experts to provide detailed explanations for justifying the predictions of LLMs, thereby testing LLMs for chemical and biological reasoning capabilities to push their greater use at the frontier of drug discovery at all of its stages. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2604.03028 Mon, 06 Apr 2026 00:00:00 -0400 arXiv:2604.03028v1 Announce Type: cross Abstract: Convergent evolution provides powerful evidence for natural selection, yet its molecular basis is typically sought in protein-coding amino acid substitutions. Whether adaptive pressures can drive the convergent evolution of synonymous codon usage bias (CUB) to override phylogenetic history remains a fundamental question. Here, we investigate this within the rapidly radiating fern family Thelypteridaceae by establishing a comparative framework that integrates chloroplast phylogenomics with dimensionality reduction of codon usage, morphological data, and divergence time estimation. Our results reveal that chloroplast CUB patterns are strikingly incongruent with the phylogeny of this family. Instead, they partition species into distinct clusters that strongly correlate with a convergently evolved morphological trait, lamina base architecture, a key adaptation whose radiation we date to the early Neogene. This convergent molecular signal is driven by a specific subset of photosynthesis-related genes (ndhJ, psaA, and psbD), which exhibit a high density of type-specific, third-position codon substitutions. These findings demonstrate that CUB can serve as a powerful, quantifiable indicator of adaptive history, revealing a cryptic layer of molecular convergence linked to the regulation of protein synthesis. Our work providing a new framework for uncovering adaptive histories obscured by complex evolutionary processes. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.02886 Mon, 06 Apr 2026 00:00:00 -0400 arXiv:2604.02886v1 Announce Type: cross Abstract: We study high-dimensional mediation analysis in which exposures, mediators, and outcomes are all multivariate, and both exposures and mediators may be high-dimensional. We formalize this as a many (exposures)-to-many (mediators)-to-many (outcomes) (MMM) mediation analysis problem. Methodologically, MMM mediation analysis simultaneously performs variable selection for high-dimensional exposures and mediators, estimates the indirect effect matrix (i.e., the coefficient matrices linking exposure-to-mediator and mediator-to-outcome pathways), and enables prediction of multivariate outcomes. Theoretically, we show that the estimated indirect effect matrices are consistent and element-wise asymptotically normal, and we derive error bounds for the estimators. To evaluate the efficacy of the MMM mediation framework, we first investigate its finite-sample performance, including convergence properties, the behavior of the asymptotic approximations, and robustness to noise, via simulation studies. We then apply MMM mediation analysis to data from the Alzheimer's Disease Neuroimaging Initiative to study how cortical thickness of 202 brain regions may mediate the effects of 688 genome-wide significant single nucleotide polymorphisms (SNPs) (selected from approximately 1.5 million SNPs) on eleven cognitive-behavioral and diagnostic outcomes. The MMM mediation framework identifies biologically interpretable, many-to-many-to-many genetic-neural-cognitive pathways and improves downstream out-of-sample classification and prediction performance. Taken together, our results demonstrate the potential of MMM mediation analysis and highlight the value of statistical methodology for investigating complex, high-dimensional multi-layer pathways in science. The MMM package is available at https://github.com/THELabTop/MMM-Mediation. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.02511 Mon, 06 Apr 2026 00:00:00 -0400 arXiv:2604.02511v1 Announce Type: cross Abstract: Public pooled single-cell perturbation atlases are valuable resources for studying transcription factor (TF) function, but downstream re-analysis can be limited by incomplete deposited metadata and missing internal controls. Here we re-analyze the human TF Atlas dataset (GSE216481), a MORF-based pooled overexpression screen spanning 3,550 TF open reading frames and 254,519 cells, with a reproducible pipeline for quality control, MORF barcode demultiplexing, per-TF differential expression, and functional enrichment. From 77,018 cells in the pooled screen, we assign 60,997 (79.2\%) to 87 TF identities. Because the deposited barcode mapping lacks the GFP and mCherry negative controls present in the original library, we use embryoid body (EB) cells as an external baseline and remove shared batch/transduction artifacts by background subtraction. This strategy recovers TF-specific signatures for 59 of 61 testable TFs, compared with 27 detected by one-vs-rest alone, showing that robust TF-level signal can be rescued despite missing intra-pool controls. HOPX, MAZ, PAX6, FOS, and FEZF2 emerge as the strongest transcriptional remodelers, while per-TF enrichment links FEZF2 to regulation of differentiation, EGR1 to Hippo and cardiac programs, FOS to focal adhesion, and NFIC to collagen biosynthesis. Condition-level analyses reveal convergent Wnt, neurogenic, EMT, and Hippo signatures, and Harmony indicates minimal confounding batch effects across pooled replicates. Our per-TF effect sizes significantly agree with Joung et al.'s published rankings (Spearman $\rho = -0.316$, $p = 0.013$; negative because lower rank indicates stronger effect). Together, these results show that the deposited TF Atlas data can support validated TF-specific transcriptional and pathway analyses when paired with principled external controls, artifact removal, and reproducible computation. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.02394 Mon, 06 Apr 2026 00:00:00 -0400 arXiv:2604.02394v1 Announce Type: new Abstract: Objective: SNP heritability estimates vary substantially across estimation strategies, yet the downstream consequences for polygenic risk score (PRS) construction remain poorly characterised. We systematically benchmarked heritability estimation configurations and assessed their propagation into downstream PRS performance. Methods: We benchmarked 86 heritability-estimation configurations spanning six tool families (GEMMA, GCTA, LDAK, DPR, LDSC, and SumHer) and ten method groups across 10 UK Biobank phenotypes, yielding 844 configuration-level estimates. Each estimate was propagated into GCTA-SBLUP and LDpred2-lassosum2 PRS frameworks and evaluated across five cross-validation folds using null, PRS-only, and full models. Eleven binary analytical contrasts were tested using Mann-Whitney U tests to identify drivers of heritability variability. Results: Heritability ranged from -0.862 to 2.735 (mean = 0.134, SD = 0.284), with 133 of 844 estimates (15.8%) being negative and concentrated in unconstrained estimation regimes. Ten of eleven analytical contrasts significantly affected heritability magnitude, with algorithm choice and GRM standardisation showing the largest effects. Despite this upstream variability, downstream PRS test performance was only weakly coupled to heritability magnitude: pooled Pearson correlations between h^2 and test AUC were r = -0.023 for GCTA-SBLUP and r = +0.014 for LDpred2-lassosum2, with both being non-significant. Conclusion: SNP heritability is best interpreted as a configuration-sensitive modelling parameter rather than a universally stable scalar input. Heritability estimates should always be reported alongside their full estimation specification, and downstream PRS performance is comparatively robust to moderate variation in the heritability input. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2509.12073 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2509.12073v3 Announce Type: replace Abstract: Single-cell RNA sequencing (scRNA-seq) frameworks lack explainable approaches for identifying cell subpopulations harboring strong pairwise monotonic gene-module relationships between a gene of interest (GOI) and its co-expressed genes. CEP-IP is introduced as a novel explainable machine learning framework to address this gap. In the primary dataset, TRPM4 served as the GOI and its co-expressed ribosomal genes (Ribo) were identified via Spearman-Kendall dual-filter (i.e., dual-filtered gene, DFG). Generalized additive modeling quantified TRPM4-Ribo relationship strength via deviance explained (DE), which was then mapped to individual cells via CEP classification to identify top-ranked explanatory power (TREP) cells. TRPM4-Ribo transcriptional space was then stratified into pre-IP and post-IP regions using inflection point (IP) analysis, producing four subpopulations per patient for pathway analysis. TRPM4-Ribo modeling outperformed alternative gene set modules (FDR<0.05). In each prostate cancer (PCa) patient, CEP-IP yielded four cell subpopulations, where pre-IP TREP cells showed enrichment of immune-related processes, and post-IP TREP cells were enriched for ribosomal, translation, and cell adhesion pathways. Validation was performed in the Allen middle temporal gyrus (MTG) and Neftel glioblastoma (GBM) datasets. In the MTG dataset (CARM1P1-DFG module), post-IP TREP cells showed enrichment of neuron projection ontologies. In the GBM dataset, FOXM1 was the sole GOI yielding mesenchymal-state DFGs, with FOXM1-DFG post-IP TREP cells enriched for cell division and microtubule pathways; 3D trajectory analysis demonstrated continuous trajectories of TREP cells that were obscured in 2D embeddings. CEP-IP identifies biologically distinct cell subpopulations in three independent scRNA-seq datasets, and it may be applicable to other pairwise GOI-DFG modules in single-cell transcriptomics. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2507.20598 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2507.20598v2 Announce Type: replace-cross Abstract: Differential expression (DE) analysis is a key task in RNA-seq studies, aiming to identify genes with expression differences across conditions. A central challenge is balancing false discovery rate (FDR) control with statistical power. Parametric methods such as DESeq2 and edgeR achieve high power by modeling gene-level counts using negative binomial distributions and applying empirical Bayes shrinkage. However, these methods may suffer from FDR inflation when model assumptions are mildly violated, especially in large-sample settings. In contrast, non-parametric tests like Wilcoxon offer more robust FDR control but often lack power and do not support covariate adjustment. We propose Nullstrap-DE, a general add-on framework that combines the strengths of both approaches. Designed to augment tools like DESeq2 and edgeR, Nullstrap-DE calibrates FDR while preserving power, without modifying the original method's implementation. It generates synthetic null data from a model fitted under the gene-specific null (no DE), applies the same test statistic to both observed and synthetic data, and derives a threshold that satisfies the target FDR level. We show theoretically that Nullstrap-DE asymptotically controls FDR while maintaining power consistency. Simulations confirm that it achieves reliable FDR control and high power across diverse settings, where DESeq2, edgeR, or Wilcoxon often show inflated FDR or low power. Applications to real datasets show that Nullstrap-DE enhances statistical rigor and identifies biologically meaningful genes. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.02212 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2604.02212v1 Announce Type: new Abstract: Accurate phase estimation at the edge of data segments is crucial for EEG applications such as EEG-TMS in offline and real-time data analysis. Our research evaluates the phase estimation performance of four commonly used methods (Phastimate, SSPE, ETP, and PhastPadding) for accuracy and systemic biases, using data from young and elderly healthy controls and chronic stroke participants. To address the identified limitations of the established methods, we introduce Phase Estimation with Autoregressive Padding (PEAP), a method that prevents strong bandpass filtering-induced artifacts. Contrary to the established methods, PEAP does not show significant biases and improves accuracy by 3.2 to 9.2% for the continuous phase estimation. Our offline analysis demonstrates how established methods are systematically biased towards some estimates and how they induce phase shifts. We also show that differences between methods do not vary between clinical and control populations, supporting their translatability. This work indicates that systematic biases in established phase estimation methods may compromise the validity and comparability of phase-dependent findings. PEAP addresses these limitations and thus offers a more reliable and more accurate alternative method. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2412.04172 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2412.04172v3 Announce Type: replace Abstract: Neurons rely on two interdependent mechanisms, homeostasis and neuromodulation, to maintain robust and adaptable functionality. Calcium homeostasis stabilizes neuronal activity by adjusting ionic conductances, whereas neuromodulation dynamically modifies ionic properties in response to external signals carried by neuromodulators. Combining these mechanisms in conductance-based models often produces unreliable outcomes, particularly when sharp neuromodulation interferes with calcium-homeostatic tuning. This study explores how a biologically inspired neuromodulation controller can harmonize with calcium homeostasis to ensure reliable neuronal function. Using computational models of stomatogastric ganglion and dopaminergic neurons, we demonstrate that controlled neuromodulation preserves neuronal firing patterns while calcium homeostasis simultaneously maintains target intracellular calcium levels. Unlike sharp neuromodulation, the neuromodulation controller integrates activity-dependent feedback through mechanisms mimicking G-protein-coupled receptor cascades. The interaction between these controllers critically depends on the existence of an intersection in conductance space, representing a balance between target calcium levels and neuromodulated firing patterns. Maximizing neuronal degeneracy enhances the likelihood of such intersections, enabling robust modulation and compensation for channel blockades. We further show that this controller pairing extends to network-level activity, reliably modulating the rhythmic activity of central pattern generators. This study highlights the complementary roles of calcium homeostasis and neuromodulation, proposing a unified control framework for maintaining robust and adaptive neural activity under physiological and pathological conditions. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2511.22828 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2511.22828v2 Announce Type: replace-cross Abstract: Understanding how nonlinear dynamical systems (e.g., artificial neural networks and neural circuits) process information requires comparing their underlying dynamics at scale, across diverse architectures and large neural recordings. While many similarity metrics exist, current approaches fall short for large-scale comparisons. Geometric methods are computationally efficient but fail to capture governing dynamics, limiting their accuracy. In contrast, traditional dynamical similarity methods are faithful to system dynamics but are often computationally prohibitive. We bridge this gap by combining the efficiency of geometric approaches with the fidelity of dynamical methods. We introduce fast dynamical similarity analysis (fastDSA), a computationally efficient and accurate metric for measuring (dis)similarity between nonlinear dynamical systems. FastDSA leverages modern computational tools, including random matrix theory to determine optimal system rank, novel optimization pipelines for aligning system flow fields, and Koopman embeddings. Across benchmark nonlinear systems and recurrent network models, fastDSA is robust to arbitrary coordinate choices while remaining sensitive to meaningful dynamical differences, capturing variations in system evolution that geometric methods may miss and traditional methods detect only at high computational cost. To our knowledge, fastDSA is the fastest method that retains accuracy in comparing nonlinear dynamical systems. It enables scalable, statistical analyses across diverse systems, significantly expanding the practical applicability of dynamical similarity analysis. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.02491 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2603.02491v2 Announce Type: replace-cross Abstract: As artificial agents become increasingly capable, what internal structure is *necessary* for an agent to act competently under uncertainty? Classical results show that optimal control can be *implemented* using belief states or world models, but not that such representations are required. We prove quantitative "selection theorems" showing that strong task performance (low *average-case regret*) forces world models, belief-like memory and -- under task mixtures -- persistent variables resembling core primitives associated with emotion, along with informational modularity under block-structured tasks. Our results cover stochastic policies, partial observability, and evaluation under task distributions, without assuming optimality, determinism, or access to an explicit model. Technically, we reduce predictive modeling to binary "betting" decisions and show that regret bounds limit probability mass on suboptimal bets, enforcing the predictive distinctions needed to separate high-margin outcomes. In fully observed settings, this yields approximate recovery of the interventional transition kernel; under partial observability, it implies necessity of predictive state and belief-like memory, addressing an open question in prior world-model recovery work. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.16880 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2603.16880v2 Announce Type: replace-cross Abstract: Electroencephalography (EEG) provides a non-invasive window into neural dynamics at high temporal resolution and plays a pivotal role in clinical neuroscience research. Despite this potential, prevailing computational approaches to EEG analysis remain largely confined to task-specific classification objectives or coarse-grained pattern recognition, offering limited support for clinically meaningful interpretation. To address these limitations, we introduce NeuroNarrator, the first generalist EEG-to-text foundation model designed to translate electrophysiological segments into precise clinical narratives. A cornerstone of this framework is the curation of NeuroCorpus-160K, the first harmonized large-scale resource pairing over 160,000 EEG segments with structured, clinically grounded natural-language descriptions. Our architecture first aligns temporal EEG waveforms with spatial topographic maps via a rigorous contrastive objective, establishing spectro-spatially grounded representations. Building on this grounding, we condition a Large Language Model through a state-space-inspired formulation that integrates historical temporal and spectral context to support coherent clinical narrative generation. This approach establishes a principled bridge between continuous signal dynamics and discrete clinical language, enabling interpretable narrative generation that facilitates expert interpretation and supports clinical reporting workflows. Extensive evaluations across diverse benchmarks and zero-shot transfer tasks highlight NeuroNarrator's capacity to integrate temporal, spectral, and spatial dynamics, positioning it as a foundational framework for time-frequency-aware, open-ended clinical interpretation of electrophysiological data. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2509.07013 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2509.07013v3 Announce Type: replace-cross Abstract: Agent-based models (ABMs) are widely used to study infectious disease dynamics, but their calibration is often computationally intensive, limiting their applicability in time-sensitive public health settings. We propose DeepIMC (Deep Inverse Mapping Calibration), a machine learning-based calibration framework that directly learns the inverse mapping from epidemic time series to epidemiological parameters. DeepIMC trains a bidirectional Long Short-Term Memory (BiLSTM) neural network on synthetic epidemic trajectories generated from agent-based models such as the Susceptible-Infected-Recovered (SIR) model, enabling rapid parameter estimation without repeated simulation at inference time. We evaluate DeepIMC through an extensive simulation study comprising 5,000 heterogeneous epidemic scenarios and benchmark its performance against Approximate Bayesian Computation (ABC) using likelihood-free Markov Chain Monte Carlo. The results show that DeepIMC substantially improves parameter recovery accuracy, produces sharp and well-calibrated predictive intervals, and reduces computational time by more than an order of magnitude relative to ABC. Although structural parameter identifiability constraints limit the precise recovery of all model parameters simultaneously, the calibrated models reliably reproduce epidemic trajectories and support accurate forward prediction with their estimated parameters. DeepIMC is implemented in the open-source R package epiworldRCalibrate, facilitating practical adoption for real-time epidemic modeling and policy analysis. Overall, our findings demonstrate that DeepIMC provides a scalable, operationally effective alternative to traditional simulation-based calibration methods for agent-based epidemic models. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.01385 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2604.01385v1 Announce Type: new Abstract: The evolutionary and ecological dynamics of tumors under immune responses and therapeutic interventions pose major challenges to long-term treatment success. Although treatment may initially achieve short-term disease control, resistant cancer cell subpopulations often arise, leading to relapse with more aggressive and treatment-resistant forms of the disease. Here, we develop and analyze mathematical models describing the interactions among effector cells, chemo-resistant tumor cells, and immuno-resistant tumor cells under distinct immune-evasion strategies. The models incorporate competition and cooperation between resistant and sensitive tumor subpopulations. We identify threshold conditions governing tumor persistence, elimination, and phenotype dominance under varying therapeutic intensities. These findings provide a theoretical framework for designing targeted and combination therapies and offer insights into strategies for mitigating the treatment resistance. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.01734 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2604.01734v1 Announce Type: new Abstract: Effectively modeling irregularly sampled longitudinal data is essential for understanding disease progression and improving risk prediction. We propose a two-view mixture model that integrates static baseline covariates and longitudinal biomarker trajectories within a unified probabilistic clustering framework. Temporal patterns are modeled using Neural Ordinary Differential Equations. Model training uses an EM algorithm with a sparsity-inducing log-penalty for interpretable subgroup discovery. Application of the model to an Irish cohort of ANCA-associated vasculitis patients reveals subgroups with heterogeneous serum creatinine trajectories and variation in end-stage kidney disease outcomes. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.01990 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2604.01990v1 Announce Type: new Abstract: Background and Objective: Accurate surrogate modeling of knee joint contact mechanics is important for reconstructing stress distributions and identifying risk-relevant regions, yet the relative suitability of different modeling paradigms under practically relevant input-limited conditions remains unclear. Methods: Nine male soccer players performed 90{\deg} change-of-direction trials. Finite element simulations driven by subject-specific joint posture and reaction forces were converted into graph-structured samples. Five surrogate architectures representing local diffusion, history-context enhancement, hierarchical multi-scale modeling, explicit global interaction, and local-global hybridization were compared using three-fold cross-subject validation under full, pose-corrupted, load-corrupted, and minimal-input conditions. Performance was evaluated using full-field error, high-stress error, high-risk region overlap, and hotspot localization metrics. Results: The hybrid model achieved the best overall performance under full inputs and remained the most robust under pose- and load-corrupted conditions. Under minimal inputs, no single model dominated all metrics: the history-context model yielded lower overall and high-stress errors, the hybrid model better preserved high-risk region reconstruction, and the hierarchical model showed an advantage in hotspot localization. Conclusion: Evaluation of surrogate models for knee joint contact mechanics should shift from accuracy comparisons under ideal inputs to a comprehensive assessment of the preservation of risk-relevant information under realistic input constraints. Although the local-global hybrid model showed the best overall robustness, the optimal model under minimal-input conditions remained task-dependent. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2510.16082 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2510.16082v5 Announce Type: replace Abstract: Interpreting gene clusters from RNA sequencing (RNA-seq) remains challenging, especially in antimicrobial resistance studies where mechanistic insight is important for hypothesis generation. Existing pathway enrichment methods can summarize co-expressed modules, but they often provide limited cluster-specific explanations and weak connections to supporting literature. We present BIOGEN, an evidence-grounded multi-agent framework for post hoc interpretation of RNA-seq transcriptional modules. BIOGEN combines biomedical retrieval, structured reasoning, and multi-critic verification to generate traceable cluster-level explanations with explicit evidence and confidence labels. On a primary Salmonella enterica dataset, BIOGEN achieved strong biological grounding, including BERTScore 0.689, Semantic Alignment Score 0.715, KEGG Functional Similarity 0.342, and a hallucination rate of 0.000, compared with 0.100 for an LLM-only baseline. Across four additional bacterial RNA-seq datasets, BIOGEN also maintained zero hallucination under the same fixed pipeline. In comparisons with representative open-source agentic AI baselines, BIOGEN was the only framework that consistently preserved zero hallucination across all five datasets. These findings suggest that retrieval alone is not enough for reliable biological interpretation, and that evidence-grounded orchestration is important for transparent and source-traceable transcriptomic reasoning. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2503.03485 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2503.03485v2 Announce Type: replace-cross Abstract: Understanding the biological mechanisms of disease is crucial for medicine, and in particular, for drug discovery. AI-powered analysis of genome-scale biological data holds great potential in this regard. The increasing availability of single-cell RNA sequencing data has enabled the development of large foundation models for disease biology. However, existing foundation models only modestly improve over task-specific models in downstream applications. Here, we explored two avenues for improving single-cell foundation models. First, we scaled the pre-training data to a diverse collection of 116 million cells, which is larger than those used by previous models. Second, we leveraged the availability of large-scale biological annotations as a form of supervision during pre-training. We trained the \model family of models comprising six transformer-based state-of-the-art single-cell foundation models with 70 million, 160 million, and 400 million parameters. We vetted our models on several downstream evaluation tasks, including identifying the underlying disease state of held-out donors not seen during training, distinguishing between diseased and healthy cells for disease conditions and donors not seen during training, and probing the learned representations for known biology. Our models showed substantial improvement over existing works, and scaling experiments showed that performance improved predictably with both data volume and parameter count. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2604.02203 Fri, 03 Apr 2026 00:00:00 -0400 arXiv:2604.02203v1 Announce Type: cross Abstract: Inferring cell-cell communication (CCC) from single-cell transcriptomics remains fundamentally limited by reliance on curated ligand-receptor databases, which primarily capture co-expression rather than the system-level effects of signaling on cellular states. Here, we introduce QuantumXCT, a hybrid quantum-classical generative framework that reframes CCC as the problem of learning interaction-induced state transformations between cellular state distributions. By encoding transcriptomic profiles into a high-dimensional Hilbert space, QuantumXCT trains parameterized quantum circuits to learn a unitary transformation that maps a baseline non-interacting cellular state to an interacting state. This approach enables the discovery of communication-driven changes in cellular state distributions without requiring prior biological assumptions. We validate QuantumXCT using both synthetic data with known ground-truth interactions and single-cell RNA-seq data from ovarian cancer-fibroblast co-culture systems. The model accurately recovers complex regulatory dependencies, including feedback structures, and identifies dominant communication hubs such as the PDGFB-PDGFRB-STAT3 axis. Importantly, the learned quantum circuit is interpretable: its entangling topology can be translated into biologically meaningful interaction networks, while post hoc contribution analysis quantifies the relative influence of individual interactions on the observed state transitions. By shifting CCC inference from static interaction lookup to learning data-driven state transformations, QuantumXCT provides a generative framework for modeling intercellular communication. This work establishes a new paradigm for de novo discovery of communication programs in complex biological systems and highlights the potential of quantum machine learning in single-cell biology. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.01187 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.01187v1 Announce Type: new Abstract: When competing species grow into new territory, the population is dominated by descendants of successful ancestors at the expansion front. Successful ancestry depends on both the reproductive advantage (fitness), as well as ability and opportunity to colonize new domains. We present a model that integrates both elements by coupling the classic description of one-dimensional competition (Fisher equation) to the minimal model of front shape (KPZ equation). Macroscopic manifestations of these equations are distinct growth morphologies controlled by expansion rates, competitive abilities, or spatial anisotropy. In some cases the ability to expand in space may overcome reproductive advantage in colonizing new territory. When new traits appear with accumulating mutations, we find that variations in fitness in range expansion may be described by the Tracy--Widom distribution. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2604.00393 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.00393v1 Announce Type: new Abstract: Foraging is a central decision-making behavior performed by all animals, essential to garnishing enough energy for an organism to survive. Similarly, mating is crucial for evolutionary continuity and offspring production. Mate choice is one of the central tenets of sexual selection, driving major evolutionary processes, and can be regarded as a decision-making process between potential mating partners. Often researchers have used coarse-grained models to describe macroscopic phenomenology pertaining to mate choice without detailed quantitative mechanisms of how animals use individual and environmental signals to guide their mating decisions. In this letter, we show that mate choice can be cast as a foraging problem, and we present an analytically tractable optimal foraging-inspired mechanistic theory of decision-making underlying mate choice. We begin from the premise that deciding upon which partner with which to mate is at its core a stochastic decision-making process. Agents adopt a variety of decision strategies, tuned by decision thresholds for leaving or committing to a mate. We find that sensitive leaving thresholds are favored independently of signal availability in the population. By contrast, optimal thresholds for committing to a mate depend upon signal availability in the population, with signal-rich populations generally favoring less eager strategies compared to signal-poor populations. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2504.09614 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2504.09614v2 Announce Type: replace Abstract: This review synthesizes advances in predictive processing within the sensory cortex. Predictive processing theorizes that the brain continuously predicts sensory inputs, refining neuronal responses by highlighting prediction errors. We identify key computational primitives, such as stimulus adaptation, dendritic computation, excitatory/inhibitory balance and hierarchical processing, as central to this framework. Our review highlights convergences, such as top-down inputs and inhibitory interneurons shaping mismatch signals, and divergences, including species-specific hierarchies and modality-dependent layer roles. To address these conflicts, we propose experiments in mice and primates using in-vivo two-photon imaging and electrophysiological recordings to test whether temporal, motor, and omission mismatch stimuli engage shared or distinct mechanisms. The resulting dataset, collected and shared via the OpenScope program, will enable model validation and community analysis, fostering iterative refinement and refutability to decode the neural circuits of predictive processing. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.00349 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.00349v1 Announce Type: new Abstract: Low-intensity transcranial focused ultrasound (tFUS) is rapidly emerging as a transformative non-invasive brain stimulation (NIBS) modality characterized by high spatial resolution and ability to target deep brain circuits. Unlike electromagnetic techniques such as transcranial magnetic stimulation and transcranial direct current stimulation, which are constrained by centimeter-scale resolution and a depth-focality tradeoff, tFUS leverages mechanical pressure waves to modulate both superficial cortical and deep subcortical structures with millimeter precision. This article discusses recent scientific observations and engineering breakthroughs in the advancement of tFUS for next-generation ultrasonic brain-computer interfaces (uBCIs) and human-machine interfaces. These advancements move beyond open-loop systems and demonstrate closed-loop architectures that incorporate real-time electrophysiological feedback to optimize cognitive variables such as attention, learning, trust, and cooperation in various applications. Other advances in the development of ultrasound sensors for sonomyography to decode muscle activation and functional ultrasound to monitor hemodynamic brain activity are discussed as potential elements in bidirectional uBCIs. Together, these advances position ultrasound as a foundational technology for the development of intelligent, adaptive, and bidirectional neural interfaces that will seamlessly integrate human cognition with next-generation automation and robotic systems. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2604.00763 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.00763v1 Announce Type: cross Abstract: RNA-seq count data are often affected by read-to-gene alignment ambiguity, especially in high-dimensional transcriptomics. This type of ambiguity can be conveniently expressed through granular counts, namely fuzzy-valued observations of latent discrete quantities. We study a class of fuzzy-reporting mechanisms and show that, when reporting exploits graded membership, ignorability fails generically, leading to a coarsening-not-at-random structure. A hierarchical model is then introduced as a tractable instance of this construction and illustrated using RNA-seq data. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.00075 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.00075v1 Announce Type: new Abstract: Functional evidence is essential for clinical interpretation of genomic variants, but identifying relevant studies and translating experimental results into structured evidence remains labor intensive. We developed a benchmark based on ClinGen curated annotations to evaluate two large language models (LLMs), a non reasoning model (gpt-4o-mini) and a reasoning model (o4-mini), on tasks relevant to functional evidence curation: (1) abstract screening to determine whether a study reports functional experiments directly testing specific variants, and (2) full text evidence extraction and classification from matched variant-paper pairs, including interpretation of evidence direction and generation of evidence summaries. Starting from ClinGen variants annotated with functional evidence, we processed curator comments with an LLM to extract PubMed identifiers, evidence labels, and narrative, and retrieved titles, abstracts, and open access PDFs to construct variant-paper pairs. In abstract screening, both models achieved high recall (0.88-0.90) with moderate specificity (0.59-0.65). For full text evidence classification under an explicit variant matching gate, o4-mini achieved 96% accuracy and higher specificity (0.83 vs. 0.37) while maintaining high F1 (0.98 vs. 0.96) compared with gpt-4o-mini. We also used an LLM-as-judge protocol to compare model generated evidence summaries with expert curator comments. Finally, we developed AcmGENTIC, an end to end pipeline that expands variant identifiers, retrieves literature via LitVar2, filters abstracts with LLMs, acquires PDFs, performs multimodal evidence extraction, and generates evidence reports for curator review, with optional agentic parsing of figures and tables. Together, this benchmark and pipeline provide a practical framework for scaling functional evidence curation with human in the loop LLM assistance. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2604.00065 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.00065v1 Announce Type: new Abstract: Multi-omic datasets offer opportunities for improved biomarker discovery in cancer research, but their high dimensionality and limited sample sizes make identifying compact and effective biomarker panels challenging. Feature selection in large-scale omics can be efficiently addressed by combining machine learning with genetic algorithms, which naturally support multi-objective optimization of predictive accuracy and biomarker set size. However, genetic algorithms remain relatively underexplored for multi-omic feature selection, where most approaches concatenate all layers into a single feature space. To address this limitation, we introduce Sweeping*, a multi-view, multi-objective algorithm alternating between single- and multi-view optimization. It employs a nested single-view multi-objective optimizer, and for this study we use the genetic algorithm NSGA3-CHS. It first identifies informative biomarkers within each layer, then jointly evaluates cross-layer interactions; these multi-omic solutions guide the next single-view search. Through repeated sweeps, the algorithm progressively identifies compact biomarker panels capturing cross-modal complementary signals. We benchmark five Sweeping* strategies, including hierarchical and concatenation-based variants, using survival prediction on three TCGA cohorts. Each strategy jointly optimizes predictive accuracy and set size, measured via the concordance index and root-leanness. Overall performance and estimation error are assessed through cross hypervolume and Pareto delta under 5-fold cross-validation. Our results show that Sweeping* can improve the accuracy-complexity trade-off when sufficient survival signal is present and that integrating omic layers can enhance survival prediction beyond clinical-only models, although benefits remain cohort-dependent. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.29727 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2603.29727v2 Announce Type: replace Abstract: Drug discovery relies on iterative expert workflows that are slow to parallelize and difficult to scale. Here we introduce Latent-Y, an AI agent that autonomously executes complete antibody design campaigns from text prompts, covering literature review, target analysis, epitope identification, candidate design, computational validation, and selection of lab-ready sequences. Latent-Y is integrated into the Latent Labs Platform, where it operates in the same environment as drug-discovery experts with access to bioinformatics tools, biological databases, and scientific literature. The agent can run fully autonomously end-to-end, or collaboratively, where researchers review progress, provide feedback, and direct subsequent steps. Candidate antibodies are generated using Latent-X2, our frontier generative model for drug-like antibody design. We demonstrate the agent's capability across three distinct campaign types: epitope discovery guided by therapeutic specifications, cross-species binder design, and autonomous design from a scientific publication targeting human transferrin receptor for blood-brain barrier crossing. Across nine targets, Latent-Y produced lab-confirmed nanobody binders against six, achieving a 67% target-level success rate with binding affinities reaching the single-digit nanomolar range, without human filtering or intervention. In user studies, experts working with Latent-Y completed design campaigns 56 times faster than independent expert time estimates, compressing weeks of work into hours. Because Latent-X2 is a general-purpose atomic-level model for biologics design, the same agent architecture naturally extends to macrocyclic peptide and mini-binder design campaigns, broadening autonomous discovery across therapeutic modalities. Latent-Y is available to selected partners at https://platform.latentlabs.com. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2604.01182 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.01182v1 Announce Type: cross Abstract: Optical biosensors are indispensable in medical and environmental diagnostics, yet existing approaches are fundamentally limited in their sensitivity due to ensemble-averaged measurements. Digital biosensing has emerged as a promising solution for resolving individual binding events, thereby providing signals at very low analyte concentrations down to the single-molecule level. Here, we present a novel concept for digital optical biosensing empowered by dielectric Mie voids, combining nanoparticle-based contrast enhancement and deep learning for ultrasensitive biomarker detection. The resonantly trapped light in the air cavities of the periodic Mie void arrays ensures strong overlap between the near-fields and the single gold nanoparticles that are captured on the surface in the presence of the protein biomarker. Remarkably, this strong interaction creates high-contrast digital signals for the precise counting of single nanoparticles located both within and outside the voids, yielding efficient use of the entire sensor area for high sensitivity. We employ deep-ultraviolet (DUV) lithography for the scalable and low-cost production of Mie voids in silicon wafers and automated image analysis with a convolutional neural network for robust nanoparticle counting. As a proof of our concept, we demonstrate the detection of an important disease biomarker, interleukin-6 (IL-6), from small sample volumes at concentrations as low as 1.84 pg/ml, within the physiological range of healthy individuals. Owing to its scalability, precision, and adaptability, our digital nanophotonic biosensing approach based on silicon Mie voids establishes a versatile route for applications ranging from bioanalytics to health and environmental monitoring. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2604.01169 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.01169v1 Announce Type: cross Abstract: A fundamental challenge in science and engineering is the simulation-to-experiment gap. While we often possess prior knowledge of physical laws, these physical laws can be too difficult to solve exactly for complex systems. Such systems are commonly modeled using simulators, which impose computational approximations. Meanwhile, experimental measurements more faithfully represent the real world, but experimental data typically consists of observations that only partially reflect the system's full underlying state. We propose a data-driven distribution alignment framework that bridges this simulation-to-experiment gap by pre-training a generative model on fully observed (but imperfect) simulation data, then aligning it with partial (but real) observations of experimental data. While our method is domain-agnostic, we ground our approach in the physical sciences by introducing Adversarial Distribution Alignment (ADA). This method aligns a generative model of atomic positions -- initially trained on a simulated Boltzmann distribution -- with the distribution of experimental observations. We prove that our method recovers the target observable distribution, even with multiple, potentially correlated observables. We also empirically validate our framework on synthetic, molecular, and experimental protein data, demonstrating that it can align generative models with diverse observables. Our code is available at https://kaityrusnelson.com/ada/. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2604.00580 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.00580v1 Announce Type: cross Abstract: Molecular dynamics simulations provide detailed trajectories at the atomic level, but extracting interpretable and robust insights from these high-dimensional data remains challenging. In practice, analyses typically rely on a single representation. Here, we show that representation choice is not neutral: it fundamentally shapes the conformational organization, similarity relationships, and apparent transitions inferred from identical simulation data. To complement existing representations, we introduce Orientation features, a geometrically grounded, rotation-aware encoding of protein backbone. We compare it against common descriptions across three dynamical regimes: fast-folding proteins, large-scale domain motions, and protein-protein association. Across these systems, we find that different representations emphasize complementary aspects of conformational space, and that no single representation provides a complete picture of the underlying dynamics. To facilitate systematic comparison, we developed ManiProt, a library for efficient computation and analysis of multiple protein representations. Our results motivate a comparative, representation-aware framework for the interpretation of molecular dynamics simulations. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2604.00470 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.00470v1 Announce Type: cross Abstract: The bacterial flagellar motor (BFM) is a rotary molecular machine driven by the ion electrochemical potential across the cell membrane. Recent cryo-EM structures reveal a cogwheel-like architecture in which multiple stators engage a large rotor. A longstanding puzzle is the directional asymmetry of its torque-speed relation: concave in counterclockwise (CCW) rotation but nearly linear in clockwise (CW) rotation. Here, we develop a stochastic mechanochemical model that explicitly incorporates rotor-stator coupling and detailed ion translocation kinetics. By integrating physiological torque-speed data with recent measurements of rotor-stator relative motion, we show that under physiological conditions the motor operates in a tight engagement regime, rendering the torque-speed relation largely insensitive to the specific form of mechanical interactions. This finding rules out differences in rotor-stator mechanics as the origin of CW-CCW asymmetry. Guided by cryo-EM structures, we propose a contact-dependent gating mechanism in which the MotA-FliG interaction modulates the ion release rate of the MotB subunit proximal to the FliG ring. Molecular dynamics simulations indicate tighter MotA-FliG contact in the CW motor, implying a reduced ion release rate compared to CCW. Our model demonstrates that differential gating strength accounts for the observed asymmetry: stronger gating in CCW shortens torque-free waiting phases, enhances torque generation, and produces a concave torque-speed curve, whereas weaker gating in CW yields lower torque and a linear relation. This structure-based framework quantitatively links molecular asymmetry to motor function and identifies specific interfaces for targeted perturbation and mutational studies. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2604.00602 Thu, 02 Apr 2026 00:00:00 -0400 arXiv:2604.00602v1 Announce Type: cross Abstract: Natural genomes sometimes encode two different proteins in staggered reading frames of the same DNA sequence. Despite the prevalence of these 'overlapping genes' across the tree of life, it remains unknown whether arbitrary protein pairs can overlap, to what extent such overlaps are feasible, or what design principles govern them. Here, we study compatibility, frustration, and connectivity in the fitness landscape of overlapping genes. We computationally design sequences de novo that satisfy the dual functional constraints of two distinct protein families. The joint fitness landscape, inferred via Potts models from multiple sequence alignments, reveals a fundamental trade-off between the two proteins and provides a simple criterion for when overlap is feasible. We find widespread compatibility between protein families, with one class of reading frames markedly more permissible than others. By exploring alternative genetic codes, we find that the natural genetic code is uniquely well-suited to support overlapping genes. Constructing mutational paths between sequences, we find that sequence-diverse overlapped genes can be connected via a network of near-neutral mutations. Overall, our results suggest that protein fitness landscapes are sufficiently flexible so as to accommodate the stringent, orthogonal requirements of overlapping genes. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2512.15534 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2512.15534v2 Announce Type: replace Abstract: Discrete dynamical models underpin systems biology, but we still lack substrate-agnostic diagnostics for when such models can sustain genuinely open-ended evolution (OEE): the continual production of novel phenotypes rather than eventual settling. We introduce a simple, model-independent metric, {\Omega}, that quantifies OEE as the residence-time-weighted average of attractor cycle lengths across the sequence of attractors realized over time. {\Omega} is zero for single-attractor dynamics and grows with the number and persistence of distinct cyclic phenotypes, separating enduring innovation from transient noise. Using Random Boolean Networks (RBNs) as a unifying testbed, we compare classical Boolean dynamics with biologically motivated non-classical mechanisms (probabilistic context switching, annealed rule mutation, paraconsistent logic, modal necessary/possible gating, and quantum-inspired superposition/paired-state coupling) under homogeneous and heterogeneous updating schemes. Our results support the view that undecidability-adjacent, state-dependent mechanisms -- implemented as probabilistic context switching, modal necessity/possibility gating, paraconsistent logic (controlled contradictions), or quantum-inspired superposition/paired-state coupling (correlated branching) -- are enabling conditions for sustained novelty. At the end of our manuscript we outline a practical extension of {\Omega} to continuous/hybrid state spaces, positioning {\Omega} as a portable benchmark for OEE in discrete biological modeling and a guide for engineering evolvable synthetic circuits. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2512.11164 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2512.11164v2 Announce Type: replace Abstract: Evolutionary graph theory (EGT) studies the effect of population structure on evolutionary dynamics. The vertices of the graph represent the $N$ individuals. The edges denote interactions for competitive replacement. Two standard update rules are death-Birth (dB) and Birth-death (Bd). Under dB, an individual is chosen uniformly at random to die, and its neighbors compete to fill the vacancy proportional to their fitness. Under Bd, an individual is chosen for reproduction proportional to fitness, and its offspring replaces a randomly chosen neighbor. Here we study mixed updating between those two scenarios. In each time step, with probability $\delta$ the update is dB and with remaining probability it is Bd. We study fixation probabilities and times as functions of $\delta$ under neutral evolution and constant selection. Despite the fact that fixation probabilities and times can be increasing, decreasing, or non-monotonic in $\delta$, we prove nearly all unweighted undirected graphs have short fixation times and provide an efficient algorithm to estimate their fixation probabilities. Finally, we prove exact formulas for fixation probabilities on cycles, stars, and more complex structures and classify their sensitivities to $\delta$. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.29398 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2603.29398v1 Announce Type: new Abstract: The spread of infectious disease and the evolution of antigenically distinct strains are often modeled separately, despite strong feedbacks mediated by host immune memory and heterogeneous contacts. To tackle this challenging problem, we introduce a coevolutionary framework in which transmission occurs on a metapopulation network while mutational exploration of strain space follows a mutation network. In this multiscale model, cross-immunity is encoded by similarity in the latent diffusion geometry of the strain network, so that nearby strains confer partial immune protection. We first identify an effective critical region that controls the transition between extinction, recurrent outbreak episodes, and long-lived endemic persistence, thus characterizing the resulting strain-turnover dynamics. We then derive a replicator-mutator-like equation for strain composition and an explicit dynamical evolutionary landscape induced by the coupling of mutation and transmission. Finally, allowing host heterogeneity to modulate the local mutation structure, we show that spreading across demes can effectively connect otherwise disconnected components of strain space, increasing long-term endemic diversity while producing a non-monotonic change in overall prevalence. Together, our results isolate minimal mechanisms by which immune-mediated competition and network structure can shape antigenic diversification. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2508.20125 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2508.20125v2 Announce Type: replace-cross Abstract: Purpose: Spiking neural networks (SNNs) have recently gained attention as energy-efficient, biologically plausible alternatives to conventional deep learning models. Their application in high-stakes biomedical imaging remains almost entirely unexplored. Methods: This study introduces SNNDeep, the first tailored SNN specifically optimized for binary classification of liver health status from computed tomography (CT) features. To ensure clinical relevance and broad generalizability, the model was developed and evaluated using the Task03\Liver dataset from the Medical Segmentation Decathlon (MSD), a standardized benchmark widely used for assessing performance across diverse medical imaging tasks. We benchmark three fundamentally different learning algorithms, namely Surrogate Gradient Learning, the Tempotron rule, and Bio-Inspired Active Learning across three architectural variants: a fully customized low-level model built from scratch, and two implementations using leading SNN frameworks, i.e., snnTorch and SpikingJelly. Hyperparameter optimization was performed using Optuna. Results: Our results demonstrate that the custom-built SNNDeep consistently outperforms framework-based implementations, achieving a maximum validation accuracy of 98.35%, superior adaptability across learning rules, and significantly reduced training overhead. Conclusion:This study provides the first empirical evidence that low-level, highly tunable SNNs can surpass standard frameworks in medical imaging, especially in data-limited, temporally constrained diagnostic settings, thereby opening a new pathway for neuro-inspired AI in precision medicine. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.30004 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2603.30004v1 Announce Type: new Abstract: This study examines the evolution of Intelligent and Secure Smart Hospital Ecosystems using a Scoping Review with Bibliometric Analysis (ScoRBA) to map research patterns, identify gaps, and derive policy implications. Analyzing 891 journal articles from Scopus (2006-2025) through co-occurrence analysis, network visualization, overlay analysis, and the Enhanced Strategic Diagram (ESD), the study applies the PAGER framework to link Patterns, Advances, Gaps, Research directions, and Evidence-based policy implications. Findings reveal three interrelated clusters: AI-driven intelligent healthcare systems, decentralized privacy-preserving digital health ecosystems, and scalable cloud-edge infrastructures, showing a convergence toward integrated ecosystem architectures where intelligence, trust, and infrastructure reinforce each other. Despite progress in AI, blockchain, and cloud computing, gaps remain in interoperability, real-world implementation, governance, and cross-layer integration. Emerging themes such as explainable AI, federated learning, and privacy mechanisms highlight areas needing further research. Policy-relevant recommendations focus on coordinated governance, scalable infrastructure, and secure data ecosystems, particularly for developing country contexts. The study bridges bibliometric evidence with actionable policies, supporting informed decision-making in smart hospital development. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.29903 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2603.29903v1 Announce Type: new Abstract: Brain connectomics is still largely dominated by pairwise-based models, such as graphs, which cannot represent circulatory or higher-order functional interactions. In this paper, we propose a multimodal framework based on Topological Signal Processing (TSP) that models the brain as a higher-order topological domain and treats functional interactions as discrete vector fields. We integrate diffusion MRI and resting-state fMRI to learn subject-specific brain cell complexes, where statistically validated structural connectivity defines a sparse scaffold and phase-coupling functional edge signals drive the inference of higher-order interactions (HOIs). Using Hodge-theoretic tools, spectral filtering, and sparse signal representations, our framework disentangles brain connectivity into divergence (source-sink organization), gradient (potential-driven coordination), and curl (circulatory HOIs), enabling the characterization of temporal dynamics through the lens of discrete vector calculus. Across 100 healthy young adults from Human Connectome Project, node-based HOIs are highly individualized, yet robust mesoscale structure emerges under functional-system aggregation. We identify a distributed default mode network-centered gradient backbone and limbic-centered rotational flows; divergence polarization and curl profiles defining circulation regimes with insightful occupancy and dwell-time statistics. These topological signatures yield significant brain-behavior associations, revealing a relevant higher-order organization intrinsic to edge-based models. By making divergence, circulation, and recurrent mesoscale coordination directly measurable, this work enables a principled and interpretable topological phenotyping of brain function. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.29843 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2603.29843v1 Announce Type: new Abstract: Causal inference in brain networks has traditionally relied on regression-based models such as Granger causality, structural equation modeling, and dynamic causal modeling. While effective for identifying directed associations, these methods remain descriptive and acyclic, leaving open the fundamental question of intervention: what would the causal organization become if a pathway were disrupted or externally modulated? We introduce a unified framework for counterfactual causal analysis that models both pathological disruptions and therapeutic interventions as an energy-perturbation problem on network flows. Grounded in Hodge theory, directed communication is decomposed into dissipative and persistent (harmonic) components, enabling systematic analysis of how causal organization reconfigures under hypothetical perturbations. This formulation provides a principled foundation for quantifying network resilience, compensation, and control in complex brain systems. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.29617 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2603.29617v1 Announce Type: new Abstract: Understanding how the brain processes linguistic constructions is a central challenge in cognitive neuroscience and linguistics. Recent computational studies show that artificial neural language models spontaneously develop differentiated representations of Argument Structure Constructions (ASCs), generating predictions about when and how construction-level information emerges during processing. The present study tests these predictions in human neural activity using electroencephalography (EEG). Ten native English speakers listened to 200 synthetically generated sentences across four construction types (transitive, ditransitive, caused-motion, resultative) while neural responses were recorded. Analyses using time-frequency methods, feature extraction, and machine learning classification revealed construction-specific neural signatures emerging primarily at sentence-final positions, where argument structure becomes fully disambiguated, and most prominently in the alpha band. Pairwise classification showed reliable differentiation, especially between ditransitive and resultative constructions, while other pairs overlapped. Crucially, the temporal emergence and similarity structure of these effects mirror patterns in recurrent and transformer-based language models, where constructional representations arise during integrative processing stages. These findings support the view that linguistic constructions are neurally encoded as distinct form-meaning mappings, in line with Construction Grammar, and suggest convergence between biological and artificial systems on similar representational solutions. More broadly, this convergence is consistent with the idea that learning systems discover stable regions within an underlying representational landscape - recently termed a Platonic representational space - that constrains the emergence of efficient linguistic abstractions. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.29597 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2603.29597v1 Announce Type: new Abstract: Reservoirs, typically implemented as recurrent neural networks with fixed random connection weights, can be combined with a simple trained readout layer to perform a wide range of computational tasks. However, increasing the magnitude of reservoir connection weights to exploit nonlinear dynamics can cause the network to develop strong spontaneous activity that drives neurons into saturation, dramatically degrading performance. In this work, we investigate two distinct countermeasures against such runaway excitation. The first approach introduces a subtle non-homogeneous structure into the matrix of connection weigths $w_{ij}$, without altering the overall probability distribution $p(w)$. We identify several favorable structuring principles, such as creating a small subset of neurons with weaker-than-average input connections. Even if the rest of the reservoir falls into runaway saturating behavior, this weakly coupled subset remains in a mildly nonlinear regime whose dynamics can still be exploited by the readout layer. The second approach implements a form of automatic gain control, in which a dedicated control unit dynamically regulates the reservoir's average global activation toward an optimal setpoint. Although the control unit modulates the excitability of the reservoir only via a global gain factor, this mechanism substantially enlarges the dynamical regime favorable for computation and renders performance largely independent of the underlying connection statistics. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2505.07638 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2505.07638v3 Announce Type: replace-cross Abstract: Biochemical reaction networks are widely applied across scientific disciplines to model complex dynamic systems. We investigate the diffusion approximation of reaction networks with mass-action kinetics, focusing on the identifiability of the stochastic differential equations associated to the reaction network. We derive conditions under which the law of the diffusion approximation is identifiable and provide theorems for verifying identifiability in practice. Notably, our results show that some reaction networks have non-identifiable reaction rates, even when the law of the corresponding stochastic process is completely known. Moreover, we show that reaction networks with distinct graphical structures can generate the same diffusion law under specific choices of reaction rates. Finally, we compare our framework with identifiability results in the deterministic ODE setting and the discrete continuous-time Markov chain models for reaction networks. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2412.11338 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2412.11338v3 Announce Type: replace Abstract: Arabidopsis root hair patterning is controlled by a complex transcription factor network containing positive and negative feedback loops, epidermal cell-cell signalling, and positional signalling from underlying tissue. Recently, several long accepted regulatory interactions within the network have been revised, and while there are extensive data regarding individual components, the complexity of the network has made it difficult to understand how these components combine to ensure correct and robust epidermal patterning. Here, mathematical modelling was used to integrate the wealth of experimental data into a single transcription factor network model. Current understanding of the epidermal patterning network was found to be insufficient to reproduce experimental data, and thus an additional negative feedback loop was hypothesized which enabled the model to reproduce both wildtype and mutant data. The negative feedback was supported by sequence analysis of candidate regulators. Modelling investigations uncovered interactions, mechanisms, and constraints essential for patterning, and revealed how a recently redefined reaction functions to produce mutant data while contributing to network robustness in wildtype. When analysed together, these results provide a holistic understanding of epidermal cell fate determination in Arabidopsis, shown here to be governed by a spontaneously patterning reaction-diffusion network containing combined activator-inhibitor and substrate depletion mechanisms. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2510.00027 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2510.00027v3 Announce Type: replace-cross Abstract: Accurate and scalable machine-learned inter-atomic potentials (MLIPs) are essential for molecular simulations ranging from drug discovery to new material design. Current state-of-the-art models enforce roto-translational symmetries through equivariant neural network architectures, a hard-wired inductive bias that can often lead to reduced flexibility, computational efficiency, and scalability. In this work, we introduce TransIP: Transformer-based Inter-Atomic Potentials, a novel training paradigm for interatomic potentials achieving symmetry compliance without explicit architectural constraints. Our approach guides a generic non-equivariant Transformer-based model to learn SO(3)-equivariance by optimizing its representations in the embedding space. Trained on the recent Open Molecules (OMol25) collection, a large and diverse molecular dataset built specifically for MLIPs and covering different types of molecules (including small organics, biomolecular fragments, and electrolyte-like species), TransIP attains comparable performance in machine-learning force fields versus state-of-the-art equivariant baselines. Further, compared to a data augmentation baseline, TransIP achieves 40% to 60% improvement in performance across varying OMol25 dataset sizes. More broadly, our work shows that learned equivariance can be a powerful and efficient alternative to equivariant or augmentation-based MLIP models. Our code is available at: https://github.com/Ahmed-A-A-Elhag/TransIP. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.29916 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2603.29916v1 Announce Type: cross Abstract: We propose new analytical tools for describing growth-rate distributions generated by stationary time-series. Our analysis shows how deviations from normality are not pathological behaviour, as suggested by some traditional views, but instead can be accounted for by clean and general statistical considerations. In contrast, strict normality is the effect of specific modelling choices. Systems characterized by stationary Gamma or heavy-tailed abundance distributions produce log-growth-rate distributions well described by a generalized logistic distribution, which can describe tent-shaped or nearly normal datasets and serves as a useful null model for these observables. These results prove that, for large enough time lags, in practice, growth-rate distributions cease to be time-dependent and exhibit finite variance. Based on this analysis, we identify some key stylized macroecological patterns and specific stochastic differential equations capable of reproducing them. A pragmatic workflow for heuristic selection between these models is then introduced. This approach is particularly useful for systems with limited data-tracking quality, where applying sophisticated inference methods is challenging. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.29529 Wed, 01 Apr 2026 00:00:00 -0400 arXiv:2603.29529v1 Announce Type: cross Abstract: We investigate the parameter space of transformer models trained on protein sequence data using a statistical mechanics framework, sampling the loss landscape at varying temperatures by Langevin dynamics to characterize the low-loss manifold and understand the mechanisms underlying the superior performance of transformers in protein structure prediction. We find that, at variance with feedforward networks, the lack of a first--order--like transition in the loss of the transformer produces a range of intermediate temperatures with good learning properties. We show that the parameters of most layers are highly conserved at these temperatures if the dimension of the embedding is optimal, and we provide an operative way to find this dimension. Finally, we show that the attention matrix is more predictive of the contact maps of the protein at higher temperatures and for higher dimensions of the embedding than those optimal for learning. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.14691 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.14691v3 Announce Type: replace-cross Abstract: The branching geometry of biological transport networks is characterized by a diameter scaling exponent $\alpha$. Two structural attractors compete: impedance matching ($\alpha \sim 2$) for pulsatile flow and viscous-metabolic minimization ($\alpha = 3$) for steady flow. Neither predicts the empirically observed $\alpha_{\mathrm{exp}} = 2.70 \pm 0.20$ in mammalian arterial trees. Incorporating sub-linear vessel-wall scaling $h(r) \propto r^p$ ($p = 0.77$) into a three-term metabolic cost rigorously breaks Murray's cubic law -- via Cauchy's functional equation -- bounding the static optimum to $\alpha_t \in [2.90, 2.94]$. We formulate a unified network-level Lagrangian balancing wave-reflection penalties against transport-metabolic costs. Because the operational duty cycle $\eta$ is uncertain over developmental timescales, we cast the optimization as a zero-sum game between network architecture and environment. Von Neumann's minimax theorem -- proved via strict monotonicity of the cost curves -- yields a unique saddle point $(\alpha^, \eta^)$ satisfying an exact equal-cost condition. We further prove $N = 2$ uniquely maximizes the network stiffness ratio $\kappa_{\mathrm{eff}}(N)$, deriving binary branching as a structural consequence of the framework. For the porcine coronary tree ($G = 11$ generations), $\alpha^* = 2.72$, within $0.1\sigma$ of morphometric data. Sensitivity analysis confirms $|\Delta\alpha^*| < 0.01$ across physiological metabolic ranges; the prediction depends critically only on the histological exponent $p$ -- a zero-parameter derivation from fundamental scaling principles that simultaneously recovers a cumulative wave dissipation of 6.3%, consistent with independent clinical estimates. Quantitative_Biology/q-bio.TO_(Tissues_and_Organs) https://arxiv.org/abs/2511.09588 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2511.09588v2 Announce Type: replace-cross Abstract: Medical image segmentation using deep learning (DL) has enabled the development of automated analysis pipelines for large-scale population studies. However, state-of-the-art DL methods are prone to hallucinations, which can result in anatomically implausible segmentations. With manual correction impractical at scale, automated quality control (QC) techniques have to address the challenge. While promising, existing QC methods are organ-specific, limiting their generalizability and usability beyond their original intended task. To overcome this limitation, we propose no-new Quality Control (nnQC), a robust QC framework based on a diffusion-generative paradigm that self-adapts to any input organ dataset. Central to nnQC is a novel Team of Experts (ToE) architecture, where two specialized experts independently encode 3D spatial awareness, represented by the relative spatial position of an axial slice, and anatomical information derived from visual features from the original image. A weighted conditional module dynamically combines the pair of independent embeddings, or opinions to condition the sampling mechanism within a diffusion process, enabling the generation of a spatially aware pseudo-ground truth for predicting QC scores. Within its framework, nnQC integrates fingerprint adaptation to ensure adaptability across organs, datasets, and imaging modalities. We evaluated nnQC on seven organs using twelve publicly available datasets. Our results demonstrate that nnQC consistently outperforms state-of-the-art methods across all experiments, including cases where segmentation masks are highly degraded or completely missing, confirming its versatility and effectiveness across different organs. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2508.01277 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2508.01277v2 Announce Type: replace-cross Abstract: Automated bioacoustic analysis is essential for biodiversity monitoring and conservation, requiring advanced deep learning models that can adapt to diverse bioacoustic tasks. This article presents a comprehensive review of large-scale pretrained bioacoustic foundation models and systematically investigates their transferability across multiple bioacoustic classification tasks. We overview bioacoustic representation learning by analysing pretraining data sources and benchmarks. On this basis, we review bioacoustic foundation models, dissecting the models' training data, preprocessing, augmentations, architecture, and training paradigm. Additionally, we conduct an extensive empirical study of selected models on the BEANS and BirdSet benchmarks, evaluating generalisability under linear and attentive probing. Our experimental analysis reveals that Perch~2.0 achieves the highest BirdSet score (restricted evaluation) and the strongest linear probing result on BEANS, building on diverse multi-taxa supervised pretraining; that BirdMAE is the best model among probing-based strategies on BirdSet and second on BEANS after BEATs$_{NLM}$, the encoder of NatureLM-audio; that attentive probing is beneficial to extract the full performance of transformer-based models; and that general-purpose audio models trained with self-supervised learning on AudioSet outperform many specialised bird sound models on BEANS when evaluated with attentive probing. These findings provide valuable guidance for practitioners selecting appropriate models to adapt them to new bioacoustic classification tasks via probing. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2502.07297 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2502.07297v3 Announce Type: replace-cross Abstract: High failure rates in cardiac drug development necessitate virtual clinical trials via electrocardiogram (ECG) generation to reduce risks and costs. However, existing ECG generation models struggle to balance morphological realism with pathological flexibility, fail to disentangle demographics from genuine drug effects, and are severely bottlenecked by early-phase data scarcity. To overcome these hurdles, we propose the Multimodal Drug-Aware Diffusion Model (MM-DADM), the first generative framework for generating individualized drug-induced ECGs. Specifically, our proposed MM-DADM integrates a Dynamic Cross-Attention (DCA) module that adaptively fuses External Physical Knowledge (EPK) to preserve morphological realism while avoiding the suppression of complex pathological nuances. To resolve feature entanglement, a Causal Feature Encoder (CFE) actively filters out demographic noise to extract pure pharmacological representations. These representations subsequently guide a Causal-Disentangled ControlNet (CDC-Net), which leverages counterfactual data augmentation to explicitly learn intrinsic pharmacological mechanisms despite limited clinical data. Extensive experiments on $9,443$ ECGs across $8$ drug regimens demonstrate that MM-DADM outperforms $10$ state-of-the-art ECG generation models, improving simulation accuracy by at least $6.13\%$ and recall by $5.89\%$, while providing highly effective data augmentation for downstream classification tasks. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2410.11328 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2410.11328v3 Announce Type: replace-cross Abstract: For decades since the development of phase-contrast optical microscopy, an analogous approach has been sought for maximizing the image contrast of weakly-scattering objects in transmission electron microscopy (TEM). The recent development of the laser phase plate (LPP) has demonstrated that an amplified, focused laser standing wave provides stable, tunable phase shift to the high-energy electron beam, achieving phase-contrast TEM. Building on proof-of-concept experimental demonstrations, this paper explores design improvements tailored to biological imaging. In particular, we introduce the approach of crossed laser phase plates (XLPP): two laser standing waves intersecting in the diffraction plane of the TEM, rather than a single beam as in the current LPP. We provide a theoretical model for the XLPP inside the microscope and use simulations to quantify its effect on image formation. Using simulations, we find that the XLPP increases information transfer at low spatial frequencies while also suppressing the ghost images formed by Kapitza-Dirac diffraction of the electron beam by the laser beam. We also present a simple acquisition scheme, enabled by the XLPP, which dramatically suppresses unwanted diffraction effects. Finally, we discuss important practical considerations of XLPP design and show experimental results from a prototype. The results of this study chart the course for future developments of LPP hardware. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2511.15839 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2511.15839v4 Announce Type: replace Abstract: Mathematical models support inference and forecasting in ecology and epidemiology, but results depend on the estimation framework. We compare Bayesian and Frequentist approaches across three biological models using four datasets: Lotka-Volterra predator-prey dynamics (Hudson Bay), a generalized logistic model (lung injury and 2022 U.S. mpox), and an SEIUR epidemic model (COVID-19 in Spain). Both approaches use a normal error structure to ensure a fair comparison. We first assessed structural identifiability to determine which parameters can theoretically be recovered from the data. We then evaluated practical identifiability and forecasting performance using four metrics: mean absolute error (MAE), mean squared error (MSE), 95 percent prediction interval (PI) coverage, and weighted interval score (WIS). For the Lotka-Volterra model with both prey and predator data, we analyzed three scenarios: prey only, predator only, and both. The Frequentist workflow used QuantDiffForecast (QDF) in MATLAB, which fits ODE models via nonlinear least squares and quantifies uncertainty through parametric bootstrap. The Bayesian workflow used BayesianFitForecast (BFF), which employs Hamiltonian Monte Carlo sampling via Stan to generate posterior distributions and diagnostics such as the Gelman-Rubin R-hat statistic. Results show that Frequentist inference performs best when data are rich and fully observed, while Bayesian inference excels when latent-state uncertainty is high and data are sparse, as in the SEIUR COVID-19 model. Structural identifiability clarifies these patterns: full observability benefits both frameworks, while limited observability constrains parameter recovery. This comparison provides guidance for choosing inference frameworks based on data richness, observability, and uncertainty needs. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.27303 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27303v1 Announce Type: cross Abstract: Protein scientific discovery is bottlenecked by the manual orchestration of information and algorithms, while general agents are insufficient in complex domain projects. VenusFactory2 provides an autonomous framework that shifts from static tool usage to dynamic workflow synthesis via a self-evolving multi-agent infrastructure to address protein-related demands. It outperforms a set of well-known agents on the VenusAgentEval benchmark, and autonomously organizes the discovery and optimization of proteins from a single natural language prompt. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.26994 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.26994v1 Announce Type: cross Abstract: T cells are a critical component of the adaptive immune system, playing a role in infectious disease, autoimmunity, and cancer. T cell function is mediated by the T cell receptor (TCR) protein, a highly diverse receptor targeting specific peptides presented by the major histocompatibility complex (pMHCs). Predicting the specificity of TCRs for their cognate pMHCs is central to understanding adaptive immunity and enabling personalized therapies. However, accurate prediction of this protein-protein interaction remains challenging due to the extreme diversity of both TCRs and pMHCs. Here, we present ImmSET (Immune Synapse Encoding Transformer), a novel sequence-based architecture designed to model interactions among sets of variable-length biological sequences. We train this model across a range of dataset sizes and compositions and study the resulting models' generalization to pMHC targets. We describe a failure mode in prior sequence-based approaches that inflates previously reported performance on this task and show that ImmSET remains robust under stricter evaluation. In systematically testing the scaling behavior of ImmSET with training data, we show that performance scales consistently with data volume across multiple data types and compares favorably with the pre-trained protein language model ESM2 fine-tuned on the same datasets. Finally, we demonstrate that ImmSET can outperform AlphaFold2 and AlphaFold3-based pipelines on TCR-pMHC specificity prediction when provided sufficient training data. This work establishes ImmSET as a scalable modeling paradigm for multi-sequence interaction problems, demonstrated in the TCR-pMHC setting but generalizable to other biological domains where high-throughput sequence-driven reasoning complements structure prediction and experimental mapping. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.27787 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27787v1 Announce Type: new Abstract: Cardiovascular-Kidney-Metabolic (CKM) syndrome represents a growing public health crisis, yet the subclinical heterogeneity of its component systems remains underexplored. Early detection of physiological deviation is critical for preventing irreversible organ damage and mortality. Here, we characterize the prevalence and interplay of CKM impairment in a US cohort (N=841) by integrating continuous wearable data with clinical biomarkers. We assessed cardiovascular, kidney via clinical biomarkers, namely Chol/HDL, eGFR, as well as metabolic health risk through Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). We show that while metabolic and cardiovascular disruptions are significantly associated (r=0.26, p<0.001), early-stage kidney impairment manifests independently. Utilizing a normalized deviance score, we identified significant health impairments in 29.0% of the cohort. Cardiovascular deviation was the most prevalent singular phenotype (13.3%), followed by metabolic (9.1%) and renal (6.25%) deviations, with dual metabolic-cardiovascular impairment occurring in only 2.2% of participants. These findings suggest that high system-specific deviance may serve as an indicator for accelerated physiological aging within the respective organ system. Furthermore, feature ablation analysis revealed that step count, Active Zone Minutes, and resting heart rate are the most potent wearable-derived predictors of cardiovascular and metabolic decline. These findings underscore the necessity of a multi-system subtyping approach, demonstrating that wearable-derived phenotypes can facilitate the early, targeted interventions required to manage the complex landscape of CKM syndrome. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.27484 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27484v1 Announce Type: new Abstract: Quantitatively mapping three-dimensional (3D) flow, diffusion, and particle density in crowded living cells remains challenging because most dynamic optical microscopy measurements are effectively planar and existing analysis methods struggle with dense, noisy volumetric data. We introduce volumetric spatio-temporal image correlation spectroscopy (vSTICS), a framework that recovers voxel-resolved flow, diffusion coefficients, and particle densities from 3D fluorescence time series. Growing Camellia japonica pollen tubes were imaged with field-synthesis lattice light-sheet microscopy, and localized 3D spatio-temporal correlation analysis was applied to overlapping volumetric samples to generate maps of velocity, diffusion, and density. Validation with synthetic flow-diffusion simulations showed accurate recovery of seeded transport parameters, including velocities near $3$ $\mu$m s$^{-1}$ and diffusion near $10^{-3}$ $\mu$m$^2$ s$^{-1}$. Fluorescent microsphere experiments verified particle number and point spread function readouts and measured diffusion coefficients of $0.3 \pm 0.1$ $\mu$m$^2$ s$^{-1}$ in gel, consistent with imaging-FCS measurements of $0.5 \pm 0.2$ $\mu$m$^2$ s$^{-1}$. Applied to mitochondria in pollen tubes, vSTICS resolved a bidirectional reverse-fountain pattern with slower anterograde transport ($0.1$-$1$ $\mu$m s$^{-1}$) and faster retrograde motion peaking near $3$ $\mu$m s$^{-1}$, plus a retrograde corridor about $2$ $\mu$m wide. Density and diffusion maps indicated a denser, more advective core and higher peripheral diffusion. High-density sub-diffraction vesicle mapping produced similar velocity landscapes with about ten-fold higher particle densities. These results establish vSTICS as a practical method for quantitative 3D mapping of intracellular transport and refines the reverse-fountain model by revealing asymmetric, predominantly transverse circulation. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.27104 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27104v1 Announce Type: new Abstract: Background: Medical Digital Twins (MDTs) are computational representations of individual patients that integrate clinical, genomic, and physiological data to support diagnosis, treatment planning, and outcome prediction. However, most MDTs remain static or passively updated, creating a critical synchronization gap, especially in rare genetic disorders where phenotypes, genomic interpretations, and care guidelines evolve over time. Methods: We propose an agent-orchestrated digital twin framework using OpenClaw's proactive "heartbeat" mechanism and modular Agent Skills. This Autonomous Agent-orchestrated Digital Twin (AADT) system continuously monitors local and external data streams (e.g., patient-reported phenotypes and updates in variant classification databases) and executes automated workflows for data ingestion, normalization, state updates, and trigger-based analysis. Results: A prototype implementation demonstrates that agent orchestration can continuously synchronize MDT states with both longitudinal phenotype updates and evolving genomic knowledge. In rare disease settings, this enables earlier diagnosis and more accurate modeling of disease progression. We present two case studies, including variant reinterpretation and longitudinal phenotype tracking, highlighting how AADTs support timely, auditable updates for both research and clinical care. Conclusion: The AADT framework addresses the key bottleneck of real-time synchronization in MDTs, enabling scalable and continuously updated patient models. We also discuss data security considerations and mitigation strategies through human-in-the-loop system design. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.27017 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27017v1 Announce Type: new Abstract: Body Mass Index (BMI) is a widely accessible but imprecise proxy of cardiometabolic health. While assessing true body composition is superior, gold-standard methods like Dual-Energy X-ray Absorptiometry (DXA) are not scalable. We address this gap by developing and validating "PhotoScan," a method to estimate body composition from smartphone imagery. We pretrained a deep learning model on UK Biobank participants (N=35,323) and fine-tuned on a newly recruited clinical cohort (PhotoBIA cohort, N=677) with diverse ethnicity, age, and body fat distribution, achieving high accuracy against DXA for total body fat percentage (BF%, MAE = 2.15%), Android-to-Gynoid fat ratio (A/G, MAE = 0.11), and visceral-to-subcutaneous fat area ratio (V/S, MAE = 0.09). Generalizability of the model was demonstrated on an independent metabolic health study cohort (MetabolicMosaic cohort, N=132 participants), achieving MAEs of 2.13% for BF%, 0.09 for A/G, and 0.09 for V/S. We then evaluated the clinical utility of these metrics in the MetabolicMosaic cohort by predicting insulin resistance (IR). Adding PhotoScan-derived body composition metrics to baseline demographics model (Age, Sex, BMI) significantly improved insulin resistance classification (Area Under the Receiver Operating Characteristic Curve "AUROC" 76.0% vs 69.2%, DeLong test p=0.002, Net Reclassification Index "NRI" 0.593). Crucially, this accessible smartphone method achieved performance nearly equivalent to adding clinical-grade DXA data to baseline demographics model (AUROC 77.3% vs 69.2%, DeLong test p=0.004, NRI 0.748). These findings demonstrate that smartphone-based phenotyping captures clinically meaningful risk signals missed by BMI and anthropometrics, offering a scalable alternative to DXA for cardiometabolic risk stratification. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2602.11478 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2602.11478v3 Announce Type: replace Abstract: Mental events are considered to supervene on physical events. A supervenient event does not change without a corresponding change in the underlying subvenient physical events. Since wholes and their parts exhibit the same supervenience-subvenience relations, inter-level causation has been expected to serve as a model for mental causation. We proposed an inter-level causation mechanism to construct a model of consciousness and an agent's self-determination. However, a significant gap exists between this mechanism and cognitive functions. Here, we demonstrate how to integrate the inter-level causation mechanism with the widely known dual-process theories. We assume that the supervenience level is composed of multiple supervenient functions (i.e., neural networks), and we argue that inter-level causation can be achieved by controlling the feedback error defined through changing algebraic expressions combining these functions. Using inter-level causation allows for a dual laws model in which each level possesses its own distinct dynamics. In this framework, the feedback error is determined independently by two processes: (1) the selection of equations combining supervenient functions, and (2) the negative feedback error reduction to satisfy the equations through adjustments of neurons and synapses. We interpret these two independent feedback controls as Type 1 and Type 2 processes in the dual process theories. As a result, theories of consciousness, agency, and dual process theory are unified into a single framework, and the characteristic features of Type 1 and Type 2 processes are naturally derived. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.27716 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27716v1 Announce Type: cross Abstract: Neuromorphic engineering has matured over the past four decades and is currently experiencing explosive growth with the potential to transform biomedical engineering and neurotechnologies. Participants at the Neuromorphic Principles in Biomedicine and Healthcare (NPBH) Workshop (October 2024) -- representing a broad cross-section of the community, including early-career and established scholars, engineers, scientists, clinicians, industry, and funders -- convened to discuss the state of the field, current and future challenges, and strategies for advancing neuromorphic research and development for biomedical applications. Publicly approved recordings with transcripts (https://2024.neuro-med.org/program/session-video-and-transcripts) and slides (https://2024.neuro-med.org/program/session-slides) can be found at the workshop website. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.27611 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27611v1 Announce Type: cross Abstract: When a cognitive system modifies its own functioning, what exactly does it modify: a low-level rule, a control rule, or the norm that evaluates its own revisions? Cognitive science describes executive control, metacognition, and hierarchical learning with precision, but lacks a formal framework distinguishing these targets of transformation. Contemporary artificial intelligence likewise exhibits self-modification without common criteria for comparison with biological cognition. We show that the question of what counts as a self-modifying system entails a minimal structure: a hierarchy of rules, a fixed core, and a distinction between effective rules, represented rules, and causally accessible rules. Four regimes are identified: (1) action without modification, (2) low-level modification, (3) structural modification, and (4) teleological revision. Each regime is anchored in a cognitive phenomenon and a corresponding artificial system. Applied to humans, the framework yields a central result: a crossing of opacities. Humans have self-representation and causal power concentrated at upper hierarchical levels, while operational levels remain largely opaque. Reflexive artificial systems display the inverse profile: rich representation and causal access at operational levels, but none at the highest evaluative level. This crossed asymmetry provides a structural signature for human-AI comparison. The framework also offers insight into artificial consciousness, with higher-order theories and Attention Schema Theory as special cases. We derive four testable predictions and identify four open problems: the independence of transformativity and autonomy, the viability of self-modification, the teleological lock, and identity under transformation. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.27597 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27597v1 Announce Type: cross Abstract: Recent work on artificial consciousness shifts evaluation from behaviour to internal architecture, deriving indicators from theories of consciousness and updating credences accordingly. This is progress beyond naive Turing-style tests. But the indicator-based programme remains epistemically under-calibrated: consciousness science is theoretically fragmented, indicators lack independent validation, and no ground truth of artificial phenomenality exists. Under these conditions, probabilistic consciousness attribution to current AI systems is premature. A more defensible near-term strategy is to redirect effort toward biologically grounded engineering -- biohybrid, neuromorphic, and connectome-scale systems -- that reduces the gap with the only domain where consciousness is empirically anchored: living systems. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.27188 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27188v1 Announce Type: cross Abstract: Dissipative cognitive architectures maintain computation through continuous energy expenditure, where units that exhaust their energy are stochastically replaced with fresh random state. This creates a fundamental challenge: how can persistent, context-specific memory survive when all learnable state is periodically destroyed? Existing memory mechanisms -- including elastic weight consolidation, synaptic intelligence, and surprise-driven gating -- rely on gradient computation and are inapplicable to non-gradient dissipative systems. We introduce Deep Memory (DM), a non-gradient persistent memory mechanism operating through a triple-loop consolidation cycle: (1) recording of expert-specific content centroids, (2) seeding of replaced units with stored representations, and (3) stabilization through continuous re-entry. We demonstrate that discrete expert routing via Mixture-of-Experts (MoE) gating is a causal prerequisite for DM, preventing centroid convergence that would render stored memories identical. Across ${\sim}970$ simulation runs spanning thirteen experimental blocks: (i) discrete routing is causally necessary for specialization ($\text{MI}=1.10$ vs. $0.001$; $n=91$); (ii) DM achieves $R=0.984$ vs. $0.385$ without memory ($n=16$); (iii) continuous seeding reconstructs representations after interference ($R_\mathrm{recon}=0.978$; one-shot fails; $n=30$); (iv) the mechanism operates within a characterized $(K,p)$ envelope ($n=350$); (v) recording $\times$ seeding is the minimal critical dyad ($n=40$); (vi) DM outperforms non-gradient baselines (Hopfield, ESN) under matched turnover ($n=370$). These results establish DM as a falsifiable mechanism for persistent memory in non-gradient cognitive systems, with functional parallels to hippocampal consolidation. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.26811 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.26811v1 Announce Type: cross Abstract: Implicit neural representations (INRs) offer continuous coordinate-based encodings for atlas registration, cross-modality resampling, sparse-view completion, and compact sharing of neuroanatomical data. Yet reproducible evaluation is lacking for high-resolution larval zebrafish microscopy, where preserving neuropil boundaries and fine neuronal processes is critical. We present a reproducible INR benchmark for the MapZebrain larval zebrafish brain atlas. Using a unified, seed-controlled protocol, we compare SIREN, Fourier features, Haar positional encoding, and a multi-resolution grid on 950 grayscale microscopy images, including atlas slices and single-neuron projections. Images are normalized with per-image (1,99) percentiles estimated from 10% of pixels in non-held-out columns, and spatial generalization is tested with a deterministic 40% column-wise hold-out along the X-axis. Haar and Fourier achieve the strongest macro-averaged reconstruction fidelity on held-out columns (about 26 dB), while the grid is moderately behind. SIREN performs worse in macro averages but remains competitive on area-weighted micro averages in the all-in-one regime. SSIM and edge-focused error further show that Haar and Fourier preserve boundaries more accurately. These results indicate that explicit spectral and multiscale encodings better capture high-frequency neuroanatomical detail than smoother-bias alternatives. For MapZebrain workflows, Haar and Fourier are best suited to boundary-sensitive tasks such as atlas registration, label transfer, and morphology-preserving sharing, while SIREN remains a lightweight baseline for background modelling or denoising. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.26707 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.26707v1 Announce Type: cross Abstract: This paper documents and theorises a self-reinforcing dynamic between two measurable trends: the exponential expansion of large language model (LLM) context windows and the secular contraction of human sustained-attention capacity. We term the resulting asymmetry the Cognitive Divergence. AI context windows have grown from 512 tokens in 2017 to 2,000,000 tokens by 2026 (factor ~3,906; fitted lambda = 0.59/yr; doubling time ~14 months). Over the same period, human Effective Context Span (ECS) -- a token-equivalent measure derived from validated reading-rate meta-analysis (Brysbaert, 2019) and an empirically motivated Comprehension Scaling Factor -- has declined from approximately 16,000 tokens (2004 baseline) to an estimated 1,800 tokens (2026, extrapolated from longitudinal behavioural data ending 2020 (Mark, 2023); see Section 9 for uncertainty discussion). The AI-to-human ratio grew from near parity at the ChatGPT launch (November 2022) to 556--1,111x raw and 56--111x quality-adjusted, after accounting for retrieval degradation (Liu et al., 2024; Chroma, 2025). Beyond documenting this divergence, the paper introduces the Delegation Feedback Loop hypothesis: as AI capability grows, the cognitive threshold at which humans delegate to AI falls, extending to tasks of negligible demand; the resulting reduction in cognitive practice may further attenuate the capacities already documented as declining (Gerlich, 2025; Kim et al., 2026; Kosmyna et al., 2025). Neither trend reverses spontaneously. The paper characterises the divergence statistically, reviews neurobiological mechanisms across eight peer-reviewed neuroimaging studies, presents empirical evidence bearing on the delegation threshold, and proposes a research agenda centred on a validated ECS psychometric instrument and longitudinal study of AI-mediated cognitive change. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.28600 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.28600v1 Announce Type: new Abstract: The dynamics of simple two-alternative forced-choice (2AFC) decisions are well-modeled by a class of random walk models (e.g. Laming, 1968; Ratcliff, 1978; Usher & McClelland, 2001; Bogacz et al., 2006). However, in real-life, even simple decisions involve dynamically changing influence of additional information. In this work, we describe a computational theory of decision making from multiple sources of information, grounded in Bayesian inference and consistent with a simple neural network. This Contextual Diffusion Decision Model (CDDM) is a formal generalization of the Diffusion Decision Model (DDM), a popular existing model of fixed-context decision making (Ratcliff, 1978), and shares with it both a mechanistic and a probabilistic motivation. Just as the DDM is a model for a variety of simple two-alternative forced-choice (2AFC) decision making tasks, we demonstrate that the CDDM supports a variety of simple context-dependent tasks of longstanding interest in psychology, including the Flanker (Eriksen & Eriksen, 1974), AX-CPT (Servan-Schreiber et al., 1996), Stop-Signal (Logan & Cowan, 1984), Cueing (Posner, 1980), and Prospective Memory paradigms (Einstein & McDaniel, 2005). Further, we use the CDDM to perform a number of normative rational analyses exploring optimal response and memory allocation policies. Finally, we show how the use of a consistent model across tasks allows us to recover consistent qualitative data patterns in multiple tasks, using the same model parameters. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.27926 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27926v1 Announce Type: new Abstract: This report presents three proofs showing that idealized architectures capable of navigation guided by allocentric maps with landmark structure can be computationally universal. The navigation may occur either online (in the environment) or offline (in the animal's head). The first proof proceeds from a universal two-counter machine by encoding counters as the positions of two movable markers on orthogonal coordinate axes. The second proof directly simulates an ordinary one-tape Turing machine by using a writable tape-path embedded in the map. The third proof strengthens locality by replacing the globally designated path with a two-dimensional field of landmarks that carries only local predecessor/successor information. These constructions are mathematically close to classical graph-based models in computability theory, including Kolmogorov-Uspensky machines, storage-modification machines, graph Turing machines, and related navigation-on-graphs models. Accordingly, the bare universality results are mathematically unsurprising. Nevertheless, the present treatment is, as far as I know, the first self-contained reconstruction of such universality demonstrations in the idiom of allocentric cognitive maps and offline navigation, that is, within an architecture whose core representational and computational primitives are drawn from a body of empirical and theoretical work on spatial navigation. The report therefore reframes known computability-theoretic ideas to show that an allocentric navigation-based architecture can be computationally universal. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.27644 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27644v1 Announce Type: new Abstract: Understanding how the human brain instantiates distinct emotional states is a key challenge in affective neuroscience. While network-based approaches have advanced emotion processing research,they remain largely descriptive,leaving the dynamical stability of emotional brain states unquantified.This study introduces a novel framework to quantify this stability by applying Hopfield network energy to empirically derived functional connectivity. High density EEG was recorded from 20 healthy adults during a happy versus sad facial expression discrimination task. Functional connectivity was estimated using the weighted Phase Lag Index to obtain artifact-robust,frequency-specific matrices, which served as coupling weights in a continuous Hopfield energy model to calculate a scalar energy value per trial. Statistical comparisons showed sad emotional processing was associated with significantly lower(more negative) energy in delta,theta,and alpha bands,with the strongest effect in the alpha band (Cohen's d =0.83). Energy correlated strongly negatively with global efficiency(r=-0.72),indicating hyperconnected,efficient networks correspond to more stable states.Additionally, alpha-band energy correlated positively with reaction time during sad trials(r=0.61),linking deeper network stability to increased cognitive effort. These findings demonstrate emotional valence corresponds to distinct attractor basins in the brain's functional landscape, with sadness occupying a deeper,more stable configuration than happiness.The Hopfield energy metric provides a principled, quantifiable measure of emotional brain state stability, opening new avenues for understanding affective dynamics in health and disease. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.27410 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27410v1 Announce Type: new Abstract: People infer rich social information from others' actions. These inferences are often constrained by the physical world: what agents can do, what obstacles permit, and how the physical actions of agents causally change an environment and other agents' mental states and behavior. We propose that such rich social perception is more than visual pattern matching, but rather a reasoning process grounded in an integration of intuitive psychology with intuitive physics. To test this hypothesis, we introduced PHASE (PHysically grounded Abstract Social Events), a large dataset of procedurally generated animations, depicting physically simulated two-agent interactions on a 2D surface. Each animation follows the style of the Heider and Simmel movie, with systematic variation in environment geometry, object dynamics, agent capacities, goals, and relationships (friendly/adversarial/neutral). We then present a computational model, SIMPLE, a physics-grounded Bayesian inverse planning model that integrates planning, probabilistic planning, and physics simulation to infer agents' goals and relations from their trajectories. Our experimental results showed that SIMPLE achieved high accuracy and agreement with human judgments across diverse scenarios, while feedforward baseline models -- including strong vision-language models -- and physics-agnostic inverse planning failed to achieve human-level performance and did not align with human judgments. These results suggest that our model provides a computational account for how people understand physically grounded social scenes by inverting a generative model of physics and agents. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.25240 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.25240v1 Announce Type: cross Abstract: Modeling cellular states and predicting their responses to perturbations are central challenges in computational biology and the development of virtual cells. Existing foundation models for single-cell transcriptomics provide powerful static representations, but they do not explicitly model the distribution of cellular states for generative simulation. Here, we introduce Lingshu-Cell, a masked discrete diffusion model that learns transcriptomic state distributions and supports conditional simulation under perturbation. By operating directly in a discrete token space that is compatible with the sparse, non-sequential nature of single-cell transcriptomic data, Lingshu-Cell captures complex transcriptome-wide expression dependencies across approximately 18,000 genes without relying on prior gene selection, such as filtering by high variability or ranking by expression level. Across diverse tissues and species, Lingshu-Cell accurately reproduces transcriptomic distributions, marker-gene expression patterns and cell-subtype proportions, demonstrating its ability to capture complex cellular heterogeneity. Moreover, by jointly embedding cell type or donor identity with perturbation, Lingshu-Cell can predict whole-transcriptome expression changes for novel combinations of identity and perturbation. It achieves leading performance on the Virtual Cell Challenge H1 genetic perturbation benchmark and in predicting cytokine-induced responses in human PBMCs. Together, these results establish Lingshu-Cell as a flexible cellular world model for in silico simulation of cell states and perturbation responses, laying the foundation for a new paradigm in biological discovery and perturbation screening. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.27465 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.27465v1 Announce Type: new Abstract: Genomic foundation models trained on DNA sequences have demonstrated remarkable capabilities across diverse biological tasks, from variant effect prediction to genome design. These models are typically trained on massive, publicly sourced genomic datasets comprising trillions of nucleotide tokens, which renders them intrinsically susceptible to errors, artifacts, and adversarial issues embedded in the training data. Unlike natural language, DNA sequences lack the semantic transparency that might allow model makers to filter out corrupted entries, making genomic training corpora particularly susceptible to undetected manipulation. While training data poisoning has been established as a credible threat to large language models, its implications for genomic foundation models remain unexplored. Here, we present the first systematic investigation of training data poisoning in genomic language models. We demonstrate two complementary attack vectors. First, we show that adversarially crafted sequences can selectively degrade generative behavior on targeted genomic contexts, with backdoor activation following a sigmoidal dose-response relationship and full implantation achieved at 1 percent cumulative poison exposure. Second, targeted label corruption of downstream training data can selectively compromise clinically relevant variant classification, demonstrated using BRCA1 variant effect prediction. Our results reveal that genomic foundation models are vulnerable to targeted data poisoning attacks, underscoring the need for data provenance tracking, integrity verification, and adversarial robustness evaluation in the genomic foundation model development pipeline. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2511.12931 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2511.12931v3 Announce Type: replace-cross Abstract: Cryo-electron microscopy (cryo-EM) enables the atomic-resolution visualization of biomolecules; however, modern direct detectors generate data volumes that far exceed the available storage and transfer bandwidth, thereby constraining practical throughput. We introduce cryoSENSE, the computational realization of a hardware-software co-designed framework for compressive cryo-EM sensing and acquisition. We show that cryo-EM images of proteins lie on low-dimensional manifolds that can be independently represented using sparse priors in predefined bases and generative priors captured by a denoising diffusion model. cryoSENSE leverages these low-dimensional manifolds to enable faithful image reconstruction from spatial and Fourier-domain undersampled measurements while preserving downstream structural resolution. In experiments, cryoSENSE increases acquisition throughput by up to 2.5$\times$ while retaining the original 3D resolution, offering controllable trade-offs between the number of masked measurements and the level of downsampling. Sparse priors favor faithful reconstruction from Fourier-domain measurements and moderate compression, whereas generative diffusion priors achieve accurate recovery from pixel-domain measurements and more severe undersampling. Project website: https://cryosense.github.io. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2508.15603 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2508.15603v2 Announce Type: replace-cross Abstract: Biology stores information and computes at the molecular scale, yet the ways in which it does so are often distinct from human-engineered computers. Mapping biological computation onto architectures familiar to computer science remains an outstanding challenge. Here, inspired by Crick's proposal for molecular memory, we analyse a thermodynamically-consistent model of a protein complex subject to driven, nonequilibrium enzymatic reactions. In the strongly driven limit, we find that the system maps onto a stochastic, asynchronous variant of cellular automata, where each rule corresponds to a different set of enzymes being present. We find a broad class of phenomena in these 'molecular automata' that can be exploited for molecular computation, including error-tolerant memory via multistable attractors, and long transients that can be used as molecular stopwatches. By systematically enumerating all possible dynamical rules, we identify those that allow molecular automata to implement simple computational architectures such as finite-state machines. Overall, our results provide a framework for engineering synthetic molecular automata, and offer a route to building protein-based computation in living cells. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.26974 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.26974v1 Announce Type: new Abstract: While experiments and computer simulations to study biological phenomena are usually performed in diluted in vitro conditions, such phenomena happen inside the cellular cytoplasm, an environment densely packed with diverse macromolecules. Here, we revise recent computational methods to investigate crowded and cellular environments. Protein crowders, inert crowders and small molecules were used to mimic crowding. Simulations were performed for models of the cytoplasm. New methods were developed to simulate crowded systems. Apart from the challenges, modeling and simulations to investigate biological phenomena inside cells is a growing field, and has a lot of potential to improve our understanding of how such phenomena happen in vivo. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/1904.03236 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:1904.03236v5 Announce Type: replace Abstract: We report the emergence of Log-normal Superstatistics in the collective motion of ants confined in a quasi-2D arena and exposed to a panic-inducing stimulus. A data-driven superstatistical Langevin model accurately reproduces the transition from stationary behavior to an organized escape response, characterized by non-Gaussian velocity distributions and a stochastic diffusion coefficient. Our findings show that danger information propagates via a memory-limited, cascade-like mechanism, resulting in a stable cluster formation despite individual memory constraints. These results indicate that a slowly varying diffusivity arises from the multiplicative combination of interaction-mediated processes under confinement, leading naturally to Log-normal fluctuations. The persistence of this statistical structure under panic reveals a form of collective resilience, establishing a mechanistic bridge between Superstatistics and living active matter in confined environments. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.28200 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.28200v1 Announce Type: cross Abstract: Guiding collective motion in biological groups is a fundamental challenge in understanding social interaction rules and developing automated systems for animal management. In this study, we propose a deep reinforcement learning (RL) framework for the closed-loop guidance of fish schools using virtual agents. These agents are controlled by policies trained via Proximal Policy Optimization (PPO) in simulation and deployed in physical experiments with rummy-nose tetras (Petitella bleheri), enabling real-time interaction between artificial agents and live individuals. To cope with the stochastic behavior of live individuals, we design a composite reward function to balance directional guidance with social cohesion. Our systematic evaluation of visual parameters shows that a white background and larger stimulus sizes maximize guidance efficacy in physical trials. Furthermore, evaluation across group sizes revealed that while the system demonstrates effective guidance for groups of five individuals, this capability markedly degrades as group size increases to eight. This study highlights the potential of deep RL for automated guidance of biological collectives and identifies challenges in maintaining artificial influence in larger groups. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.26708 Tue, 31 Mar 2026 00:00:00 -0400 arXiv:2603.26708v1 Announce Type: cross Abstract: Classical compartmental models of epidemiology rely on well-mixed, local interaction approximations that fail to capture the heavy-tailed burst dynamics and long-range spatial correlations observed in real-world outbreaks. While fractional calculus is frequently employed to model these anomalous behaviors, fractional operators are introduced phenomenologically. In this work, we demonstrate that fractional space-time epidemic dynamics emerge naturally and rigorously from first principles using a non-equilibrium quantum field theory model. By mapping the stochastic contagion process to a gauge-mediated field theory via the Doi-Peliti formalism, we go beyond the static mean-field approximation to compute the full dynamical one-loop vacuum polarization. We prove that integrating out a dynamically fluctuating host vacuum generates anomalous momentum and frequency scaling. Transitioning back to coordinate space, this derives a coupled space-time fractional integro-differential equations, where the non-linear transmission vertex is governed by parabolic Riesz potentials and Riemann-Liouville time derivatives. We show that in the anomalous regime ($\alpha < 2$), local Debye screening is modified, facilitating L\'evy flight super-spreading and temporal avalanches. Consequently, the effective reproductive number ($R_{eff}$) ceases to be a scalar, transforming into a spectral dispersion relation bounded strictly by the ultraviolet spatial cutoff. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.26544 Mon, 30 Mar 2026 00:00:00 -0400 arXiv:2603.26544v1 Announce Type: cross Abstract: Background: The identification of optimal signal detection methods is hindered by the lack of reliable reference datasets. Existing datasets do not capture when adverse events (AEs) are officially recognized by regulatory authorities, preventing restriction of analyses to pre-confirmation periods and limiting evaluation of early detection performance. This study addresses this gap by developing a time-indexed reference dataset for the European Union (EU), incorporating the timing of AE inclusion in product labels along with regulatory metadata. Methods: Current and historical Summaries of Product Characteristics (SmPCs) for all centrally authorized products (n=1,513) were retrieved from the EU Union Register of Medicinal Products (data lock: 15 December 2025). Section 4.8 was extracted and processed using DeepSeek V3 to identify AEs. Regulatory metadata, including labelling changes, were programmatically extracted. Time indexing was based on the date of AE inclusion in the SmPC. Results: The database includes 17,763 SmPC versions spanning 1995-2025, comprising 125,026 drug-AE associations. The time-indexed reference dataset, restricted to active products, included 1,479 medicinal products and 110,823 drug-AE associations. Most AEs were identified pre-marketing (74.5%) versus post-marketing (25.5%). Safety updates peaked around 2012. Gastrointestinal, skin, and nervous system disorders were the most represented System Organ Classes. Drugs had a median of 48 AEs across 14 SOCs. Conclusions: The proposed dataset addresses a critical gap in pharmacovigilance by incorporating temporal information on AE recognition for the EU, supporting more accurate assessment of signal detection performance and facilitating methodological comparisons across analytical approaches. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.26110 Mon, 30 Mar 2026 00:00:00 -0400 arXiv:2603.26110v1 Announce Type: new Abstract: The rapid scaling of Protein Language Models (PLMs) has unlocked unprecedented accuracy in protein structure prediction and design, but the quadratic memory growth of the Key-Value (KV) cache during inference remains a prohibitive barrier for single-GPU deployment and high-throughput generation. While 8-bit quantization is now standard, 3-bit quantization remains elusive due to severe numerical outliers in activations. This paper presents TurboESM, an adaptation of Google's TurboQuant to the PLM domain. We solve the fundamental incompatibility between Rotary Position Embeddings (RoPE) and orthogonal transformations by deriving a RoPE-first rotation pipeline. We introduce a head-wise SVD calibration method tailored to the amino acid activation manifold, a dual look-up table (LUT) strategy for asymmetric K/V distributions, and a 1-bit Quantized Johnson-Lindenstrauss (QJL) residual correction. All experiments are conducted on ESM-2 650M, where our implementation achieves a 7.1x memory reduction (330 MB to 47 MB) while maintaining cosine similarity > 0.96 in autoregressive decoding across diverse protein families, including short peptides, transmembrane helices, enzyme active site fragments, and intrinsically disordered regions. We further implement a Triton-based fused decode attention kernel that eliminates intermediate dequantization memory allocations, achieving a 1.96x speedup over the PyTorch two-step path for the KV fetch operation alone; however, TurboESM incurs a prefill overhead of 21-27 ms relative to the original model due to KV quantization and packing, making it most suitable for memory-bound scenarios rather than latency-critical short-sequence workloads. Analysis reveals that PLMs exhibit sharper outlier profiles than large language models (LLMs) due to amino acid vocabulary sparsity, and our method effectively addresses these distributions. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2507.03005 Mon, 30 Mar 2026 00:00:00 -0400 arXiv:2507.03005v2 Announce Type: replace-cross Abstract: Computational phylogenetics has become an established tool in historical linguistics, with many language families now analyzed using likelihood-based inference. However, standard approaches rely on expert-annotated cognate sets, which are sparse, labor-intensive to produce, and limited to individual language families. This paper explores alternatives by comparing the established method to two fully automated methods that extract phylogenetic signal directly from lexical data. One uses automatic cognate clustering with unigram/concept features; the other applies multiple sequence alignment (MSA) derived from a pair-hidden Markov model. Both are evaluated against expert classifications from Glottolog and typological data from Grambank. Also, the intrinsic strengths of the phylogenetic signal in the characters are compared. Results show that MSA-based inference yields trees more consistent with linguistic classifications, better predicts typological variation, and provides a clearer phylogenetic signal, suggesting it as a promising, scalable alternative to traditional cognate-based methods. This opens new avenues for global-scale language phylogenies beyond expert annotation bottlenecks. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2405.16885 Mon, 30 Mar 2026 00:00:00 -0400 arXiv:2405.16885v3 Announce Type: replace-cross Abstract: Real world spatio-temporal datasets, and phenomena related to them, are often challenging to visualise or gain a general overview of. In order to summarise information encompassed in such data, we combine two well known statistical modelling methods. To account for the spatial dimension, we use the intrinsic modification of the conditional autoregression, and incorporate it with the hidden Markov model, allowing the spatial patterns to vary over time. We apply our method to parish register data considering deaths caused by measles in Finland in 1750-1850, and gain novel insight of previously undiscovered infection dynamics. Five distinctive, reoccurring states, describing spatially and temporally differing infection burden and potential routes of spread, are identified. We also find that there is a change in the occurrences of the most typical spatial patterns circa 1812, possibly due to changes in communication networks after major administrative transformations in Finland. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2507.09011 Mon, 30 Mar 2026 00:00:00 -0400 arXiv:2507.09011v2 Announce Type: replace-cross Abstract: A rapidly alternating red and black display known as Ganzflicker induces visual hallucinations that reflect the generative capacity of the visual system. Individuals vary in their degree of visual imagery, ranging from absent to vivid imagery. Recent proposals suggest that differences in the visual system along this imagery spectrum should also influence the complexity of other internally generated visual experiences. Here, we used tools from natural language processing to analyze free-text descriptions of hallucinations from over 4,000 participants, asking whether people with different imagery phenotypes see different things in their mind's eye during Ganzflicker-induced hallucinations. Topic modeling of descriptions revealed that strong imagers described complex, naturalistic content, while weak imagers reported simple geometric patterns. Using crowd-sourced sensorimotor norms, we also found that participants with stronger imagery used language with richer perceptual associations. These findings may reflect individual variation in coordination between early visual areas and higher-order regions relevant for the imagery spectrum. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.26506 Mon, 30 Mar 2026 00:00:00 -0400 arXiv:2603.26506v1 Announce Type: new Abstract: Connectivity structure shapes neural computation, but inferring this structure from population recordings is degenerate: multiple connectivity structures can generate identical dynamics. Recent work uses low-rank recurrent neural networks (lrRNNs) to infer low-dimensional latent dynamics and connectivity structure from observed activity, enabling a mechanistic interpretation of the dynamics. However, standard approaches for training lrRNNs can recover spurious structures irrelevant to the underlying dynamics. We first characterize the identifiability of connectivity structures in lrRNNs and determine conditions under which a unique solution exists. Then, to find such solutions, we develop an inference framework based on maximum entropy and continuous normalizing flows (CNFs), trained via flow matching. Instead of estimating a single connectivity matrix, our method learns the maximally unbiased distribution over connection weights consistent with observed dynamics. This approach captures complex yet necessary distributions such as heavy-tailed connectivity found in empirical data. We validate our method on synthetic datasets with connectivity structures that generate multistable attractors, limit cycles, and ring attractors, and demonstrate its applicability in recordings from rat frontal cortex during decision-making. Our framework shifts circuit inference from recovering connectivity to identifying which connectivity structures are computationally required, and which are artifacts of underconstrained inference. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.26267 Mon, 30 Mar 2026 00:00:00 -0400 arXiv:2603.26267v1 Announce Type: new Abstract: This work analyzes the RAID dataset to evaluate human responses to affine image distortions, including rotation, translation, scaling, and Gaussian noise. Using Mean Squared Error (MSE), the study establishes human detection thresholds for these distortions, enabling comparison across types. Statistical analysis with ANOVA and Tukey Kramer tests reveals that observers are significantly more sensitive to Gaussian noise, which consistently produced the lowest detection thresholds. Fourier analysis further shows that high-frequency components act as a visual mask for Gaussian noise, demonstrating a strong correlation between high frequency energy and detection thresholds. Additionally, spectral orientation influences the perception of rotation. Finally, the study employs the PixelCNN model to show that image probability significantly correlates with detection thresholds for most distortions, suggesting that statistical likelihood affects human visual tolerance. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2512.05245 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2512.05245v2 Announce Type: replace Abstract: Accurate prediction of protein function is essential for elucidating molecular mechanisms and advancing biological and therapeutic discovery. Yet experimental annotation lags far behind the rapid growth of protein sequence data. Computational approaches address this gap by associating proteins with Gene Ontology (GO) terms, which encode functional knowledge through hierarchical relations and textual definitions. However, existing models often emphasize one modality over the other, limiting their ability to generalize, particularly to unseen or newly introduced GO terms that frequently arise as the ontology evolves, and making the previously trained models outdated. We present STAR-GO, a Transformer-based framework that jointly models the semantic and structural characteristics of GO terms to enhance zero-shot protein function prediction. STAR-GO integrates textual definitions with ontology graph structure to learn unified GO representations, which are processed in hierarchical order to propagate information from general to specific terms. These representations are then aligned with protein sequence embeddings to capture sequence-function relationships. STAR-GO achieves state-of-the-art performance and superior zero-shot generalization, demonstrating the utility of integrating semantics and structure for robust and adaptable protein function prediction. Code is available at https://github.com/boun-tabi-lifelu/stargo. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.25417 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2603.25417v1 Announce Type: new Abstract: We present efficient approaches for extracting spaced k-mers from nucleotide sequences. They are based on bit manipulation instructions at CPU level, making them both simpler to implement and up to an order of magnitude faster than existing methods. We further evaluate common pitfalls in k-mer processing, which can cause major inefficiencies. Combined, our approaches allow the utilization of spaced k-mers in high-performance bioinformatics applications without major performance degradation, offering a throughput of up to 750MB of sequence data per second per core. Availability: The implementation in C++20 is published under the MIT license, and freely available at https://github.com/lczech/fisk Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.24783 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2603.24783v1 Announce Type: cross Abstract: Causal discovery aims to infer causal relationships among variables from observational data, typically represented by a directed acyclic graph (DAG). Most existing methods assume independent and identically distributed observations, an assumption often violated in modern applications. In addition, many datasets contain a mixture of continuous and discrete variables, which further complicates causal modeling when dependence across samples is present. To address these challenges, we propose a de-correlation framework for causal discovery from dependent mixed data. Our approach formulates a structural equation model with latent variables that accommodates both continuous and discrete variables while allowing correlated Gaussian errors across units. We estimate the dependence structure among samples via a pairwise maximum likelihood estimator for the covariance matrix and develop an EM algorithm to impute latent variables underlying discrete observations. A de-correlation transformation of the recovered latent data enables the use of standard causal discovery algorithms to learn the underlying causal graph. Simulation studies demonstrate that the proposed method substantially improves causal graph recovery compared with applying standard methods directly to the original dependent data. We apply our approach to single-cell RNA sequencing data to infer gene regulatory networks governing embryonic stem cell differentiation. The inferred regulatory networks show significantly improved predictive likelihood on test data, and many high-confidence edges are supported by known regulatory interactions reported in the literature. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.25628 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2603.25628v1 Announce Type: cross Abstract: Short tandem repeats (STRs) are low-entropy regions in the genome, consisting of a short (1-6 bp) unit that is consecutively repeated multiple times. They are known for high mutational instability, due to so-called stutter-mutations, in which the number of units in the run increases or descreases. In particular, STRs with repeat unit length of 1-2 bp are prone to mutate even within several cell divisions. The extremely rapid accumulation of variation makes them interesting phylogenetic markers for retrospective single-cell lineage reconstruction. Here we model their mutational dynamics at the level of individual repeat unit type and then aggregate length variations over many STR loci with the aim of obtaining a very fast ``molecular clock''. We calibrate our model based on several datasets with known lineage structure prepared from cultured cells. We find that the mutational dynamics of STRs are reasonably consistent for a given cell line, but vary among different ones. This suggests that the dynamics are not entirely explained by mutations in caretaker genes, rather, various other factors play a role -- possibly tissue origin and differentiation state. Further data and research is necessary to asses their relative effects. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2506.14861 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2506.14861v2 Announce Type: replace Abstract: Transcriptomic foundation models pretrained with masked language modeling can achieve low pretraining loss yet produce poor cell representations for downstream tasks. We introduce whole-cell expression decoding (WCED), where models reconstruct the entire gene vocabulary from a single CLS token embedding, even with limited inputs, creating a maximally informative bottleneck. WCED consistently outperforms MLM on all downstream metrics despite higher reconstruction error during training. Gene-level error tracking reveals that both methods preferentially learn genes whose expression co-varies with stable transcriptional programs rather than those driven by transient factors. We further add hierarchical cross-entropy loss that exploits Cell Ontology structure for zero-shot annotation at multiple granularity levels. Models trained with these objectives achieve best overall performance across CZI benchmarks, on zero-shot batch integration and linear probing cell-type annotation. Methods are implemented in biomed-multi-omic ( https://github.com/BiomedSciAI/biomed-multi-omic ), an open-source framework for transcriptomic foundation model development. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.23361 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2603.23361v2 Announce Type: replace-cross Abstract: Biological AI models increasingly predict complex cellular responses, yet their learned representations remain disconnected from the molecular processes they aim to capture. We present CDT-III, which extends mechanism-oriented AI across the full central dogma: DNA, RNA, and protein. Its two-stage Virtual Cell Embedder architecture mirrors the spatial compartmentalization of the cell: VCE-N models transcription in the nucleus and VCE-C models translation in the cytosol. On five held-out genes, CDT-III achieves per-gene RNA r=0.843 and protein r=0.969. Adding protein prediction improves RNA performance (r=0.804 to 0.843), demonstrating that downstream tasks regularize upstream representations. Protein supervision sharpens DNA-level interpretability, increasing CTCF enrichment by 30%. Analysis of experimentally measured mRNA and protein responses reveals that the majority of genes with observable mRNA changes show opposite protein-level changes (66.7% at |log2FC|>0.01, rising to 87.5% at |log2FC|>0.02), exposing a fundamental limitation of RNA-only perturbation models. Despite this pervasive direction discordance, CDT-III correctly predicts both mRNA and protein responses. Applied to in silico CD52 knockdown approximating Alemtuzumab, the model predicts 29/29 protein changes correctly and rediscovers 5 of 7 known clinical side effects without clinical data. Gradient-based side effect profiling requires only unperturbed baseline data (r=0.939), enabling screening of all 2,361 genes without new experiments. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.25713 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2603.25713v1 Announce Type: new Abstract: High-resolution brain imaging can now capture not just synapse locations but their molecular composition, with the cost of such mapping falling exponentially. Yet such ultrastructural data has so far told us little about local neuronal physiology - specifically, the parameters (e.g., synaptic efficacies, local conductances) that govern neural dynamics. We propose to translate molecularly annotated ultrastructure into physiology, introducing the concept of an ultrastructure-to-dynamics compiler: a learned mapping from molecularly annotated ultrastructure to simulator-ready, uncertainty-aware physiological parameters. The requirement is paired training data, with jointly acquired ultrastructure from imaging, and dynamical responses to perturbations from physiological experiments. With this data we can train models that predict local physiology directly from structure. Such a compiler would support biophysical simulations by turning anatomical maps into models of circuit dynamics, shifting structure-to-function from a descriptive program to a predictive one and opening routes to understanding neural computation and forecasting intervention effects. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2509.14418 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2509.14418v2 Announce Type: replace Abstract: In attitude theory, formal theoretical predictions come largely from the simulation of computational models. We argue that to push attitude theory further, we should employ mathematical analysis/analytic methods alongside of computational simulation, something that other sciences and engineering consider standard practice. Our work first attempts to portray the complementary nature of mathematical analysis along side of computational simulation using as an example the Causal Attitude Network model of attitudes (Dalege et al., 2016). We then introduce a mathematical theory, Graph Dynamical Systems (GDS), as a broad theoretical framework for network models of attitudes. We illustrate the use of GDS, in the context of the Attitudes as Constraint Satistfaction (ACS) theory of attitude dynamics (Monroe & Read, 2008), as a generator of precise, quantitative theoretical predictions. We conclude by pointing out the value of improved attitude theory for the so-called replication crisis in psychology. KEYWORDS: attitudes, neural networks, dynamical systems, psychological networks Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2511.04454 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2511.04454v2 Announce Type: replace-cross Abstract: We consider the problem of fitting a reinforcement learning (RL) model to some given behavioral data under a multi-armed bandit environment. These models have received much attention in recent years for characterizing human and animal decision making behavior. We provide a generic mathematical optimization problem formulation for the fitting problem of a wide range of RL models that appear frequently in scientific research applications. We then provide a detailed theoretical analysis of its convexity properties. Based on the theoretical results, we introduce a novel solution method for the fitting problem of RL models based on convex relaxation and optimization. Our method is then evaluated in several simulated and real-world bandit environments to compare with some benchmark methods that appear in the literature. Numerical results indicate that our method achieves comparable performance to the state-of-the-art, while significantly reducing computation time. We also provide an open-source Python package for our proposed method to empower researchers to apply it in the analysis of their datasets directly, without prior knowledge of convex optimization. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.25283 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2603.25283v1 Announce Type: cross Abstract: Gait is increasingly recognized as a vital sign, yet current approaches treat it as a symptom of specific pathologies rather than a systemic biomarker. We developed a gait foundation model for 3D skeletal motion from 3,414 deeply phenotyped adults, recorded via a depth camera during five motor tasks. Learned embeddings outperformed engineered features, predicting age (Pearson r = 0.69), BMI (r = 0.90), and visceral adipose tissue area (r = 0.82). Embeddings significantly predicted 1,980 of 3,210 phenotypic targets; after adjustment for age, BMI, VAT, and height, gait provided independent gains in all 18 body systems in males and 17 of 18 in females, and improved prediction of clinical diagnoses and medication use. Anatomical ablation revealed that legs dominated metabolic and frailty predictions while torso encoded sleep and lifestyle phenotypes. These findings establish gait as an independent multi-system biosignal, motivating translation to consumer-grade video and its integration as a scalable, passive vital sign. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.25455 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2603.25455v1 Announce Type: cross Abstract: In a dataset of 423 patients who had had radical prostatectomy for localised prostate cancer we estimated the apparent Shannon information (ASI) about time to biochemical recurrence in various subsets of the available pre-op variables using a Bayesian Gamma-power-mixture survival regression model. In all the subsets examined the ASI was positive with posterior probability greater than 0.975 . Using only age and results of pre-operative blood tests (PSA and biomarkers) we achieved 0.232 (0.180 to 0.290) nats ASI (0.335 (0.260 to 0.419) bits) (posterior mean and equitailed 95% posterior confidence intervals). This is more than double the mean posterior ASI previously achieved on the same dataset by a subset of the current authors using a log-skew-Student-mixture model, and is greater than that previous value with posterior probability greater than 0.99 . Additionally using pre- or post-operative Gleason grades, operative findings, clinical stage, and presence or absence of extraprostatic extension or seminal vesicle invasion did not increase the ASI extracted. However removing the blood-based biomarkers and replacing them with either pre-operative Gleason grades or findings available from MRI scanning greatly reduced the available ASI to respectively 0.077 (0.038 to 0.120) and 0.088 (0.045 to 0.132) nats (both less than the values using blood-based biomarkers with posterior probability greater than 0.995). A greedy approach to selection of the best biomarkers gave TGFbeta1, VCAM1, IL6sR, and uPA in descending order of importance from those examined. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2509.08013 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2509.08013v2 Announce Type: replace Abstract: Patients with rare types of melanoma such as acral, mucosal, or uveal melanoma, have lower survival rates than patients with cutaneous melanoma; these lower survival rates reflect the lower objective response rates to immunotherapy compared to cutaneous melanoma. Understanding tumor-immune dynamics in rare melanomas is critical for the development of new therapies and for improving response rates to current cancer therapies. Progress has been hindered by the lack of clinical data and the need for better preclinical models of rare melanomas. Canine melanoma provides a valuable comparative oncology model for rare types of human melanomas. We analyzed RNA sequencing data from canine melanoma patients and combined this with literature information to create a novel mechanistic mathematical model of melanoma-immune dynamics. Sensitivity analysis of the mathematical model indicated influential pathways in the dynamics, providing support for potential new therapeutic targets and future combinations of therapies. We share our learnings from this work, to help enable the application of this proof-of-concept workflow to other rare disease settings with sparse available data. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2408.05696 Fri, 27 Mar 2026 00:00:00 -0400 arXiv:2408.05696v2 Announce Type: replace-cross Abstract: In drug discovery, predicting the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of small-molecule drugs is critical for ensuring safety and efficacy. However, the process of accurately predicting these properties is often resource-intensive and requires extensive experimental data. To address this challenge, we propose SMILES-Mamba, a two-stage model that leverages both unlabeled and labeled data through a combination of self-supervised pretraining and fine-tuning strategies. The model first pre-trains on a large corpus of unlabeled SMILES strings to capture the underlying chemical structure and relationships, before being fine-tuned on smaller, labeled datasets specific to ADMET tasks. Our results demonstrate that SMILES-Mamba exhibits competitive performance across 22 ADMET datasets, achieving the highest score in 14 tasks, highlighting the potential of self-supervised learning in improving molecular property prediction. This approach not only enhances prediction accuracy but also reduces the dependence on large, labeled datasets, offering a promising direction for future research in drug discovery. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2511.04854 Thu, 26 Mar 2026 00:00:00 -0400 arXiv:2511.04854v2 Announce Type: replace-cross Abstract: Determining the binding pose of a ligand to a protein, known as molecular docking, is a fundamental task in drug discovery. Generative approaches promise faster, improved, and more diverse pose sampling than physics-based methods, but are often hindered by chemically implausible outputs, poor generalisability, and high computational cost. To address these challenges, we introduce a novel fragmentation scheme, leveraging inductive biases from structural chemistry, to decompose ligands into rigid-body fragments. Building on this decomposition, we present SigmaDock, an SE(3) Riemannian diffusion model that generates poses by learning to reassemble these rigid bodies within the binding pocket. By operating at the level of fragments in SE(3), SigmaDock exploits well-established geometric priors while avoiding overly complex diffusion processes and unstable training dynamics. Experimentally, we show SigmaDock achieves state-of-the-art performance, reaching Top-1 success rates (RMSD<2 & PB-valid) above 79.9% on the PoseBusters set, compared to 12.7-30.8% reported by recent deep learning approaches, whilst demonstrating consistent generalisation to unseen proteins. SigmaDock is the first deep learning approach to surpass classical physics-based docking under the PB train-test split, marking a significant leap forward in the reliability and feasibility of deep learning for molecular modelling. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2602.01496 Thu, 26 Mar 2026 00:00:00 -0400 arXiv:2602.01496v2 Announce Type: replace Abstract: The NBSS (normalized biomass size spectrum) is a common, intuitive approach for the study of natural ecosystems. However, very few studies have been dedicated to verifying possible flaws and paradoxes in this widely used method. Evident points of concern of the NBSS method are 1.) the loss of variability due to binning and 2.) the use of intriguing non-biomass units (such as abundance units) on biomass spectra. The main objectives of this study were to verify, test and analyze the procedures involved in transformations that lead to the NBSS plot, and to check for the correctness of currently used units, while testing the hypothesis that NBSS indeed represents biomass, not abundance or biomass flux (dB/dM), while developing i.) a new conceptual framework, ii.) new terminology, iii.) a novel back-transformation method, iv.) high-resolution kernel density estimation (KDE) plots of the density distribution shape, and v.) a new calculation method for numerical values, dimensions, and units. Extensive tests with in situ and synthetic (simulated) data were used to compare the original biomass distributions with binned outputs. Original biomass units and dimensions are retained in the proposed robust 'bootstrapped, backtransformed, and normalized biomass spectrum' (bNBS). The combination of quantitative binning and non-parametric KDE intends to address the importance of intuitive, high-resolution, simple plotting methods and the relevance of avoiding binning artifacts and oversimplifications. If a standardized binning vector and units are used, the proposed bNBS may allow for a new approach of robust size spectra science, that allows for quantitative inter-comparisons of biomass across regions and time periods. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2502.14915 Thu, 26 Mar 2026 00:00:00 -0400 arXiv:2502.14915v2 Announce Type: replace Abstract: We develop a novel ultrasound nasogastric tube (UNGT) dataset to address the lack of public nasogastric tube datasets. The UNGT dataset includes 493 images gathered from 110 patients with an average image resolution of approximately 879 $\times$ 583. Four structures, encompassing the liver, stomach, tube, and pancreas, are precisely annotated. Besides, we propose a semi-supervised adaptive-weighting aggregation medical segmenter to address data limitation and imbalance concurrently. The introduced adaptive weighting approach tackles the severe unbalanced challenge by regulating the loss across varying categories as training proceeds. The presented multiscale attention aggregation block bolsters the feature representation by integrating local and global contextual information. With these, the proposed AAMS can emphasize sparse or small structures and feature enhanced representation ability. We perform extensive segmentation experiments on our UNGT dataset, and the results show that AAMS outperforms existing state-of-the-art approaches to varying extents. In addition, we conduct comprehensive classification experiments across varying state-of-the-art methods and compare their performance. The dataset and code will be available upon publication at https://github.com/NUS-Tim/UNGT. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2503.14637 Thu, 26 Mar 2026 00:00:00 -0400 arXiv:2503.14637v3 Announce Type: replace-cross Abstract: How do humans move? Advances in reinforcement learning (RL) have produced impressive results in capturing human motion using physics-based humanoid control. However, torque-controlled humanoids fail to model key aspects of human motor control such as biomechanical joint constraints & non-linear and overactuated musculotendon control. We present KINESIS, a model-free motion imitation framework that tackles these challenges. KINESIS is trained on 1.8 hours of locomotion data and achieves strong motion imitation performance on unseen trajectories. Through a negative mining approach, KINESIS learns robust locomotion priors that we leverage to deploy the policy on several downstream tasks such as text-to-control, target point reaching, and football penalty kicks. Importantly, KINESIS learns to generate muscle activity patterns that correlate well with human EMG activity. We show that these results scale seamlessly across biomechanical model complexity, demonstrating control of up to 290 muscles. Overall, the physiological plausibility makes KINESIS a promising model for tackling challenging problems in human motor control. Code, videos and benchmarks are available at https://github.com/amathislab/Kinesis. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.22705 Thu, 26 Mar 2026 00:00:00 -0400 arXiv:2603.22705v2 Announce Type: replace Abstract: Background: Autism spectrum disorder (ASD) is characterized by significant clinical and biological heterogeneity. Conventional group-mean analyses of eye movements often mask individual atypicalities, potentially overlooking critical pathological signatures. This study aimed to identify idiosyncratic oculomotor patterns in ASD using an "outlier analysis" of smooth pursuit eye movement (SPEM). Methods: We recorded SPEM during a slow Lissajous pursuit task in 18 adults with ASD and 39 typically developed (TD) individuals. To quantify individual deviations, we derived an "outlier score" based on the Mahalanobis distance. This score was calculated from a feature vector, optimized via Principal Component Analysis (PCA), comprising the temporal lag ($\Delta$t) and the spatial deviation ($\Delta$s). An outlier was statistically defined as a score exceeding $\sqrt{10}$ (approximately 3.16$\sigma$) relative to the TD normative distribution. Results: While the TD group exhibited a low outlier rate of 5.1%, the ASD group demonstrated a significantly higher prevalence of 38.9% (7/18) (binomial P = 0.0034). Furthermore, the mean outlier score was significantly elevated in the ASD group (3.00 $\pm$ 2.62) compared to the TD group (1.52 $\pm$ 0.80; P = 0.002). Notably, these extreme deviations were captured even when conventional mean-based comparisons showed limited sensitivity. Conclusions: Our outlier analysis successfully visualized the high degree of idiosyncratic atypicality in ASD oculomotor control. By shifting the focus from group averages to individual deviations, this approach provides a sensitive metric for capturing the inherent heterogeneity of ASD, offering a potential baseline for identifying clinical subtypes. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.24356 Thu, 26 Mar 2026 00:00:00 -0400 arXiv:2603.24356v1 Announce Type: new Abstract: We derive a Riemannian metric on three-dimensional color space from the Fisher information of neural population codes in the visual pathway. Photoreceptor adaptation, retinal opponent channels, and cortical population encoding each map onto a geometric construction, producing a metric tensor whose components correspond to measurable neural quantities. The resulting 17-parameter model is fitted jointly to four independent threshold datasets: MacAdam's (1942) chromaticity ellipses, the Koenderink et al. (2026) three-dimensional ellipsoids, Wright's (1941) wavelength discrimination function, and the Huang et al. (2012) threshold color difference ellipses, covering 96 independently measured discrimination conditions across varied chromaticities and luminances. The joint fit achieves STRESS of 23.9 on MacAdam, 20.8 on Koenderink et al., 30.1 on Wright, and 30.8 on Huang et al. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.07137 Thu, 26 Mar 2026 00:00:00 -0400 arXiv:2603.07137v3 Announce Type: replace Abstract: Fossil DNA preservation varies with depositional environments and diagenesis, producing fragments of heterogeneous origins and degradation states. We use first-principles biomolecular analysis to classify fossil molecular environments into four system types, distinguished by three orthogonal indicators: origin (H/h: host/heterologous), deamination status (D/d), and similarity ratio (S/s). Conventional aDNA pipelines assume a binary mix of endogenous host DNA and modern contaminants, overlooking multisource complexity from multiple species and time-averaged deposits. This leads to bias: authentic signals suppressed during enrichment, alignment, or damage filtering, and exogenous/ancient admixed fragments misassigned as endogenous, particularly in open systems. We introduce the HSF (Host/Species-specific Fragment) posterior traceability framework to address this. It treats fragments as primary units, maximizes source diversity, detects isolated sequences, defers lineage assignment to preserve uncertainty, and applies phylogenetic consistency to discriminate origins. Combined with preservation characterization (e.g., 3D imaging and volumetric openness assessment), it improves authenticity evaluation and reduces misassignment in mixed-signal samples. Case studies identify novel fossil DNA patterns (CRSRR and SRRA) and demonstrate superior performance compared with conventional methods. The HSF framework enhances aDNA reliability, extends molecular archaeology to challenging contexts, and aids genome evolution and lineage reconstruction. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2510.02578 Thu, 26 Mar 2026 00:00:00 -0400 arXiv:2510.02578v5 Announce Type: replace Abstract: We present FLOWR.root, an SE(3)-equivariant flow-matching model for pocket-aware 3D ligand generation with joint potency and binding affinity prediction and confidence estimation. The model supports de novo generation, interaction- and pharmacophore-conditional sampling, fragment elaboration and replacement, and multi-endpoint affinity prediction (pIC50, pKi, pKd, pEC50). Training combines large-scale ligand libraries with mixed-fidelity protein-ligand complexes, refined on curated co-crystal datasets and adapted to project-specific data through parameter-efficient finetuning. The base FLOWR.root model achieves state-of-the-art performance in unconditional 3D molecule and pocket-conditional ligand generation. On HiQBind, the pre-trained and finetuned model demonstrates highly accurate affinity predictions, and outperforms recent state-of-the-art methods such as Boltz-2 on the FEP+/OpenFE benchmark with substantial speed advantages. However, we show that addressing unseen structure-activity landscapes requires domain adaptation; parameter-efficient LoRA finetuning yields marked improvements on diverse proprietary datasets and PDE10A. Joint generation and affinity prediction enable inference-time scaling through importance sampling, steering design toward higher-affinity compounds. Case studies validate this: selective CK2$\alpha$ ligand generation against CLK3 shows significant correlation between predicted and quantum-mechanical binding energies. Scaffold elaboration on ER$\alpha$, TYK2, and BACE1 demonstrates strong agreement between predicted affinities and QM calculations while confirming geometric fidelity. By integrating structure-aware generation, affinity estimation, property-guided sampling, and efficient domain adaptation, FLOWR.root provides a comprehensive foundation for structure-based drug design from hit identification through lead optimization. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.23775 Thu, 26 Mar 2026 00:00:00 -0400 arXiv:2603.23775v1 Announce Type: new Abstract: A major barrier to decentralized, near-patient diagnostics is the lack of a signal transduction modality that is both analytically precise and accessible at the point of care. Optical readouts remain instrument-dependent and difficult to miniaturize, while compact electrochemical readouts are prone to matrix-derived signal distortion, limiting their biomarker coverage in real clinical settings. Here, we define interfacial potential transduction as a standardized electrical modality for portable, clinical-grade diagnostics across diverse assay formats. A mechanistic framework identifying key sample matrix parameters within the interfacial potentials transduction system enables control of biofluid-derived interference, and is demonstrated in a widely accessible lateral flow immunoassay format through quantitative detection of estradiol, progesterone, and luteinizing hormone in human plasma with high correlation (r2 > 0.97) to clinical analyzers. Broader applicability across representative diagnostic sectors is further demonstrated through exceptional performance including glucose quantification for biochemical analysis with limit of detection (LOD) of 0.92 ug/dL, HIV p24 capsid protein under an immunomagnetic separation workflow (LOD = 44.8 fg/mL), and hepatitis B virus detection within 5 min via loop-mediated isothermal amplification for molecular diagnostics. Together, these results establish interfacial potentials transduction as a unified diagnostic paradigm for near-patient deployment beyond optical and electrochemical approaches. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2512.01074 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2512.01074v2 Announce Type: replace-cross Abstract: Accurate and reliable forecasting models are critical for guiding public health responses and policy decisions during pandemics such as COVID-19. Retrospective evaluation of model performance is essential for improving epidemic forecasting capabilities. In this study, we used COVID-19 wastewater data from CDC's National Wastewater Surveillance System to generate sequential weekly retrospective forecasts for the United States from March 2022 through September 2024, both at the national level and for four major regions (Northeast, Midwest, South, and West). We produced 133 weekly forecasts using 11 models, including ARIMA, generalized additive models (GAM), simple linear regression (SLR), Prophet, and the n-sub-epidemic framework (top-ranked, weighted-ensemble, and unweighted-ensemble variants). Forecast performance was assessed using mean absolute error (MAE), mean squared error (MSE), weighted interval score (WIS), and 95% prediction interval coverage. The n-sub-epidemic unweighted ensembles outperformed all other models at 3-4-week horizons, particularly at the national level and in the Midwest and West. ARIMA and GAM performed best at 1-2-week horizons in most regions, whereas Prophet and SLR consistently underperformed across regions and horizons. These findings highlight the value of region-specific modeling strategies and demonstrate the utility of the n-sub-epidemic framework for real-time outbreak forecasting using wastewater surveillance data. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2511.05688 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2511.05688v2 Announce Type: replace Abstract: Waning immunity and reinfection are critical features of many infectious diseases, but epidemiological models often fail to capture the intricate interaction between an individual's history of immunity and their current infection status; when they do, the approach is usually overly simplistic. We develop a novel dual-age structured model that simultaneously tracks immunity age (time since the last recovery from infection) and infection age (time since infection) to analyze epidemic dynamics under conditions of waning immunity and reinfection. The model is formulated as a system of age-structured partial differential equations that describe susceptible and infected populations stratified by both immunity and infection ages. We derive basic reproduction numbers associated with the model and numerically solve the system using a second-order Runge-Kutta scheme along the characteristic lines. We further extend the model to explore vaccination interventions, specifically targeting individuals according to their immunity age. Numerical results reveal that higher contact rates produce larger amplitude oscillations with longer interepidemic periods. The relationship between initial infection levels and long-term epidemic behavior is nonmonotonic. Vaccination efficiency depends critically on the viral load profile across immunity and infection age, with more pronounced viral load distributions requiring higher vaccination rates for disease elimination. Most efficient vaccination strategies begin with intermediate immunity ages rather than targeting only fully susceptible individuals. The structured dual-age framework provides a flexible approach to analyzing the dynamics of reinfection and evaluating targeted vaccination strategies based on the history of immunity. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.22680 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2603.22680v1 Announce Type: new Abstract: Musculoskeletal injuries (MSI) in Thoroughbred racehorses are a leading cause of death and premature retirement in racehorses and are heavily influenced by training practices. Greater distances of high-speed galloping accumulated during racing campaigns are associated with MSI. Bone injury is the most common MSI, and understanding how training practices influence bone damage accumulation is critical for improving both horse welfare and racing outcomes. This study builds on an existing mathematical model of bone adaptation and damage to investigate the impact of different training programs on bone injury risk. Several training programs (three progressive, four race-fit, six rest programs and two with rest replaced by low-intensity training) were constructed to reflect representative practices undertaken by professional trainers in Victoria, Australia. Training programs varied in training volume, rest frequency and program duration. Lower volume training programs that included high-speed training, achieved sufficient bone adaptation with less accumulation of bone damage, and subsequently lower risk of bone failure. In addition, incorporating more frequent rests (at least 2 per year) and/or longer rest periods (at least 6 weeks) reduced bone damage due to the extended opportunity to remove and repair bone damage. These results provide an in-silico mathematical model of the bone response to training, demonstrating the effects of training programs on bone adaptation, damage formation and repair. The findings can guide the design of training programs that balance both bone adaptation and bone health throughout horses racing career. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.22858 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2603.22858v1 Announce Type: cross Abstract: We introduce the Dual-View Pheromone Pathway Network (DPPN), an architecture that routes sparse attention through a persistent pheromone field over latent slot transitions, and use it to discover two independent requirements for persistent structural memory in neural networks. Through five progressively refined experiments using up to 10 seeds per condition across 5 model variants and 4 transfer targets, we identify a core principle: persistent memory requires a stable coordinate system, and any coordinate system learned jointly with the model is inherently unstable. We characterize three obstacles -- pheromone saturation, surface-structure entanglement, and coordinate incompatibility -- and show that neither contrastive updates, multi-source distillation, Hungarian alignment, nor semantic decomposition resolves the instability when embeddings are learned from scratch. Fixed random Fourier features provide extrinsic coordinates that are stable, structure-blind, and informative, but coordinate stability alone is insufficient: routing-bias pheromone does not transfer (10 seeds, p>0.05). DPPN outperforms transformer and random sparse baselines for within-task learning (AULC 0.700 vs 0.680 vs 0.670). Replacing routing bias with learning-rate modulation eliminates negative transfer: warm pheromone as a learning-rate prior achieves +0.003 on same-family tasks (17 seeds, p<0.05) while never reducing performance. A structure completion function over extrinsic coordinates produces +0.006 same-family bonus beyond regularization, showing the catch-22 between stability and informativeness is partially permeable to learned functions. The contribution is two independent requirements for persistent structural memory: (a) coordinate stability and (b) graceful transfer mechanism. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.23358 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2603.23358v1 Announce Type: new Abstract: This proof-of-concept study introduces a novel multimodal framework combining synchronized EEG-fNIRS modalities with neuronal avalanche analysis to identify early network dysfunction in Alzheimer's disease. The approach leverages complementary neural signals to examine motor network dynamics during execution and imagery tasks within an interactive task environment. Preliminary analysis of a small pilot cohort (N=4 subjects, including one with Mild Cognitive Impairment) validated the technical feasibility of the multimodal framework and revealed observable condition-dependent patterns in network organization. Two primary observations emerged: a reduced neural contrast between motor execution and imagery states, and increased trial-to-trial variability in network organization in the MCI participant. These initial results successfully validate the technical pipeline and provide hypothesis-generating observations for future statistically powered studies. The convergence of findings across modalities suggests that multimodal assessment of network flexibility may help detect functional changes in early Alzheimer's continuum, supporting the future development of this BCI-inspired framework into an engaging diagnostic tool. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.23233 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2603.23233v1 Announce Type: new Abstract: The disjunction effect in human decision making is often taken to show that the classical law of total probability is violated, motivating quantum-like models. We re-examine this claim for the Prisoner's Dilemma disjunction effect. Under the mental-event reading of the opponent-choice events, the conventional classical decision-process model implicitly builds in a certainty-only premise: its standard partition assumptions leave no room for ambiguity, forcing every participant to be certain that the opponent will defect or will cooperate. We relax this by introducing a new classical model in which each participant carries a continuous expectation parameter representing the anticipated likelihood of opponent defection, and the participant pool is partitioned by expectation level; the resulting ambiguity set is precisely the union of the interior expectation bins. In contrast, under the quantum-like event semantics, ambiguous pure states are generic (dense and of full unitarily invariant measure on the unit sphere), so "certainty states" are mathematically exceptional. We prove that an instance of our classical model can realize any empirically observed triple of defection rates across the three information conditions, including strong disjunction-effect patterns, while strictly obeying the classical law of total probability. We further prove that for any such triple produced by a standard quantum-like model of the same experiment, there exists a classical instance reproducing it exactly. In this sense, classical and quantum-like approaches have the same observable-rate expressiveness; their substantive difference lies in how ambiguity is represented and in their respective event semantics, not in a breakdown of classical probability. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.23082 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2603.23082v1 Announce Type: new Abstract: Alzheimer's disease (AD) develops over a prolonged preclinical phase, during which neuropathological changes accumulate long before cognitive symptoms appear. Identifying cognitive functions affected at early stages is critical for the preclinical detection of asymptomatic individuals at-risk of AD. Early risk identification could enable timely interventions aimed at mitigating the development of significant future cognitive impairment. While episodic memory decline typically appears after substantial medial temporal lobe damage, spatial navigation has emerged as a particularly sensitive cognitive function in preclinical AD. In this review, we provide an overview of spatial navigation computations and the tasks used to assess them, highlighting how spatial navigation relies on neural circuits corresponding to the earliest sites of AD pathology. We synthesize evidence from cognitively unimpaired individuals with AD biomarkers, i.e. individuals at-risk of AD, and discuss future research directions. Overall, performance on spatial navigation tasks, particularly path integration and wayfinding, correlates with plasma and CSF biomarkers of AD pathology, notably p-tau. Spatial navigation assessment can represent a sensitive and scalable approach for early detection of individuals at-risk of AD in preclinical stages, and will inform future interventions to mitigate the progression toward clinically significant cognitive impairment. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.22933 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2603.22933v1 Announce Type: new Abstract: The incorporation of neuroimaging techniques such as electroenchephalography (EEG) and functional near-infrared spectroscopy (fNIRS) has provided new opportunities for the analysis of dynamic brain processes involved in cognitive and motor functions. Despite the great contribution of the open-access neuroimaging datasets to neuroscience studies, they have mainly remained on a single modality and isolated task paradigms performed in a controlled environments. These limitations restrict the analysis of multi-task effects in real-world applications, thus creating a gap in the understanding of how cognitive and motor processes interact in daily life activities. To address these limitations, we present a multi-modal dataset containing neurophysiological (EEG, fNIRS), physiological (ECG), behavioral, and subjective measures collected from 30 healthy participants over three sessions. This dataset includes a hierarchical series of seven tasks ranging from single cognitive and motor activities, such as N-back, motor, passive motor, mental arithmetic and motor imagery, to combined cognitive-motor interactions simulating real life scenarios. This raw dataset provides a resource for developing advanced preprocessing methods and analysis pipelines, with potential applications in brain-computer interfaces, neurorehabilitation, and other fields requiring an understanding of multi-tasks brain dynamics. https://doi.org/10.18112/openneuro.ds007554.v1.0.0 Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.22357 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2603.22357v1 Announce Type: new Abstract: Aphasia, a language impairment primarily resulting from stroke or brain injury, profoundly disrupts communication and everyday functioning. Despite advances in speech therapy, barriers such as limited therapist availability and the scarcity of personalized, culturally relevant tools continue to hinder optimal rehabilitation outcomes. This paper reviews recent developments in neurocognitive research and language technologies that contribute to the diagnosis and therapy of aphasia. Drawing on findings from our ethnographic field study, we introduce two digital therapy prototypes designed to reflect local linguistic diversity and enhance patient engagement. We also show how insights from neuroscience and the local context guided the design of these tools to better meet patient and therapist needs. Our work highlights the potential of adaptive, AI-enhanced assistive technologies to complement conventional therapy and broaden access to therapy. We conclude by outlining future research directions for advancing personalized and scalable aphasia rehabilitation. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2504.16956 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2504.16956v4 Announce Type: replace-cross Abstract: Single-cell RNA sequencing (scRNA-seq) enables high-resolution analysis of cellular heterogeneity, but its complexity, which is marked by high dimensionality, sparsity, and batch effects, which poses major computational challenges. Transformer-based models have made significant advances in this domain but are often limited by their quadratic complexity and suboptimal handling of long-range dependencies. In this work, we introduce GeneMamba, a scalable and efficient foundation model for single-cell transcriptomics built on state space modeling. Leveraging the Bi-Mamba architecture, GeneMamba captures bidirectional gene context with linear-time complexity, offering substantial computational gains over transformer baselines. The model is pretrained on nearly 30 million cells and incorporates biologically informed objectives, including pathway-aware contrastive loss and rank-based gene encoding. We evaluate GeneMamba across diverse tasks, including multi-batch integration, cell type annotation, and gene-gene correlation, demonstrating strong performance, interpretability, and robustness. These results position GeneMamba as a practical and powerful alternative to transformer-based methods, advancing the development of biologically grounded, scalable tools for large-scale single-cell data analysis. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2412.05430 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2412.05430v3 Announce Type: replace-cross Abstract: Recent advances in self-supervised models for natural language, vision, and protein sequences have inspired the development of large genomic DNA language models (DNALMs). These models aim to learn generalizable representations of diverse DNA elements, potentially enabling various genomic prediction, interpretation and design tasks. Despite their potential, existing benchmarks do not adequately assess the capabilities of DNALMs on key downstream applications involving an important class of non-coding DNA elements critical for regulating gene activity. In this study, we introduce DART-Eval, a suite of representative benchmarks specifically focused on regulatory DNA to evaluate model performance across zero-shot, probed, and fine-tuned scenarios against contemporary ab initio models as baselines. Our benchmarks target biologically meaningful downstream tasks such as functional sequence feature discovery, predicting cell-type specific regulatory activity, and counterfactual prediction of the impacts of genetic variants. We find that current DNALMs exhibit inconsistent performance and do not offer compelling gains over alternative baseline models for most tasks, while requiring significantly more computational resources. We discuss potentially promising modeling, data curation, and evaluation strategies for the next generation of DNALMs. Our code is available at https://github.com/kundajelab/DART-Eval. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2509.02060 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2509.02060v4 Announce Type: replace Abstract: Peptide self-assembly prediction offers a powerful bottom-up strategy for designing biocompatible, low-toxicity materials for large-scale synthesis in a broad range of biomedical and energy applications. However, screening the vast sequence space for categorization of aggregate morphology remains intractable. We introduce PepMorph, an end-to-end peptide discovery pipeline that generates novel sequences that are not only prone to aggregate but whose self-assembly is steered toward fibrillar or spherical morphologies by conditioning on isolated peptide descriptors that serve as morphology proxies. To this end, we compiled a new dataset by leveraging existing aggregation propensity datasets and extracting geometric and physicochemical descriptors. This dataset is then used to train a Transformer-based Conditional Variational Autoencoder with a masking mechanism, which generates novel peptides under arbitrary conditioning. After filtering to ensure design specifications and validation of generated sequences through coarse-grained molecular dynamics (CG-MD) simulations, PepMorph yielded 83% success rate under our CG-MD validation protocol and morphology criterion for the targeted class, showcasing its promise as a framework for application-driven peptide discovery. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2303.15604 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2303.15604v2 Announce Type: replace Abstract: Publicly available collections of drug-like molecules have grown to comprise 10s of billions of possibilities in recent history due to advances in chemical synthesis. Traditional methods for identifying "hit" molecules from a large collection of potential drug-like candidates have relied on biophysical theory to compute approximations to the Gibbs free energy of the binding interaction between the drug to its protein target. A major drawback of the approaches is that they require exceptional computing capabilities to consider for even relatively small collections of molecules. Hyperdimensional Computing (HDC) is a recently proposed learning paradigm that is able to leverage low-precision binary vector arithmetic to build efficient representations of the data that can be obtained without the need for gradient-based optimization approaches that are required in many conventional machine learning and deep learning approaches. This algorithmic simplicity allows for acceleration in hardware that has been previously demonstrated for a range of application areas. We consider existing HDC approaches for molecular property classification and introduce two novel encoding algorithms that leverage the extended connectivity fingerprint (ECFP) algorithm. We show that HDC-based inference methods are as much as 90 times more efficient than more complex representative machine learning methods and achieve an acceleration of nearly 9 orders of magnitude as compared to inference with molecular docking. We demonstrate multiple approaches for the encoding of molecular data for HDC and examine their relative performance on a range of challenging molecular property prediction and drug-protein binding classification tasks. Our work thus motivates further investigation into molecular representation learning to develop ultra-efficient pre-screening tools. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.22399 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2603.22399v1 Announce Type: cross Abstract: The development of new drugs is a tedious, time-consuming, and expensive process, for which the average costs are estimated to be up to around $2.5 billion. The first step in this long process is the design of the new drug, for which de novo drug design, assisted by artificial intelligence, has blossomed in recent years and revolutionized the field. In particular, generative artificial intelligence has delivered promising results in drug discovery and development, reducing costs and the time to solution. However, classical generative models, such as generative adversarial networks (GANs), are difficult to train due to barren plateaus and prone to mode collapse. Quantum computing may be an avenue to overcome these issues and provide models with fewer parameters, thereby enhancing the generalizability of GANs. We propose a new style-based quantum GAN (QGAN) architecture for drug design that implements noise encoding at every rotational gate of the circuit and a gradient penalty in the loss function to mitigate mode collapse. Our pipeline employs a variational autoencoder to represent the molecular structure in a latent space, which is then used as input to our QGAN. Our baseline model runs on up to 15 qubits to validate our architecture on quantum simulators, and a 156-qubit IBM Heron quantum computer in the five-qubit setup is used for inference to investigate the effects of using real quantum hardware on the analysis. We benchmark our results against classical models as provided by the MOSES benchmark suite. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.22311 Wed, 25 Mar 2026 00:00:00 -0400 arXiv:2603.22311v1 Announce Type: new Abstract: Fluorescence-based Ca$^{2+}$-imaging is a powerful tool for studying localized neuronal activity, including miniature Synaptic Calcium Transients, providing real-time insights into synaptic activity. These transients induce only subtle changes in the fluorescence signal, often barely above baseline, which poses a significant challenge for automated synaptic transient detection and segmentation. Detecting astronomical transients similarly requires efficient algorithms that will remain robust over a large field of view with varying noise properties. We leverage techniques used in astronomical transient detection for miniature Synaptic Calcium Transient detection in fluorescence microscopy. We present Astro-BEATS, an automatic miniature Synaptic Calcium Transient segmentation algorithm that incorporates image estimation and source-finding techniques used in astronomy and designed for Ca$^{2+}$-imaging videos. Astro-BEATS outperforms current threshold-based approaches for synaptic Ca$^{2+}$ transient detection and segmentation. The produced segmentation masks can be used to train a supervised deep learning algorithm for improved synaptic Ca$^{2+}$ transient detection in Ca$^{2+}$-imaging data. The speed of Astro-BEATS and its applicability to previously unseen datasets without re-optimization makes it particularly useful for generating training datasets for deep learning-based approaches. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.20469 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.20469v1 Announce Type: new Abstract: This research reports the entropy and information transfer throughout seven different enzymatic systems, namely, TIM-Barrel, Human Lysozyme, Ribonuclease A1, Pepsin , b-lactamase, Human Glucokinase and Carbonic anhydrase II. A general trend is detected: entropy and information is transported form the peripherical regions towards the catalytic site of the analyzed enzymatic systems. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.21503 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.21503v1 Announce Type: new Abstract: Accurate prediction of protein-ligand binding affinity remains a central challenge in structure-based drug discovery. The effectiveness of machine learning models critically depends on the quality of molecular descriptors, for which advanced mathematical frameworks provide powerful tools. In this work, we employ a novel mathematical theory, termed the persistent local Laplacian (PLL), to construct molecular descriptors that capture localized geometric and topological features of biomolecular structures. The PLL framework addresses key limitations of traditional topological data analysis methods, such as persistent homology and the persistent Laplacian, which are often insensitive to local structural variations, while maintaining high computational efficiency. The resulting molecular descriptors are integrated with advanced machine learning algorithms to develop accurate predictive models for protein-ligand binding affinity. The proposed models are systematically evaluated on three well-established benchmark datasets, demonstrating consistently strong and competitive predictive performance. Computational results show that the PLL-based models outperform existing approaches, highlighting their potential as a powerful tool for drug discovery, protein engineering, and broader applications in science and engineering. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.22269 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.22269v1 Announce Type: new Abstract: RNA binding proteins play a crucial role in post-transcriptional gene regulation by controlling the transport, processing, and translation of their target RNAs. Post-transcriptional gene regulation leads to the differential expression of genetic material and loss of regulation or over-regulation relates to a large range of cancers and diseases - many of which have directly been associated with RNA binding proteins and their target RNAs. To understand RNA, RNA binding proteins, and how they function in gene expression, it is essential to characterize how RNA binding proteins interact with their target RNAs. Here, we aim to assess the potential for single molecule force spectroscopy experiments to be used in the characterization of RNA-protein binding by investigating to what extent a change of extension due to RNA-protein binding is experimentally measurable and what aspects of the interaction can be deduced from such measurements. We predict the effect of protein binding on RNA force extension measurements via the open-source ViennaRNA package, which we have modified to simultaneously consider an external force, protein binding, and RNA secondary structure. From this work, we see protein concentration-dependent responses to external forces with discernable differences in predicted extensions around biologically relevant concentrations and a connection to protein binding domain geometry for several RNA binding proteins. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2212.07826 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2212.07826v2 Announce Type: replace-cross Abstract: In molecular research, the modelling and analysis of molecules through simulation is an important part that has a direct influence on medical development, material science and drug discovery. The processing power required to design protein chains with hundreds of peptides is huge. Classical computing techniques, including state-of-the-art machine learning models being deployed on classical computing machines, have proven to be inefficient in this task, though they have been successful in a limited way. Moreover, current practical implementations, as opposed to purely theoretical modelling, are often infeasible in terms of both time and cost. One of the major areas where quantum machine learning is expected to have a profound advantage over classical algorithms is drug discovery. Quantum generative models have given some promising benefits in recent studies. This paper introduces three novel quantum generative adversarial network (QGAN) architecture variants resulting from different configurations, various quantum circuit layers and patched ansatz. A quantum simulator from Xanadu's PennyLane was utilized for executing the QGAN models trained on the QM9 dataset. Upon evaluation, one of the models, namely the QWGAN-HG-GP (Wasserstein distance with gradient penalty) model, outperformed the other QGAN models in different drug molecule property metrics. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2505.15054 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2505.15054v4 Announce Type: replace-cross Abstract: Precise recognition, editing, and generation of molecules are essential prerequisites for both chemists and AI systems tackling various chemical tasks. We present MolLangBench, a comprehensive benchmark designed to evaluate fundamental molecule-language interface tasks: language-prompted molecular structure recognition, editing, and generation. To ensure high-quality, unambiguous, and deterministic outputs, we construct the recognition tasks using automated cheminformatics tools, and curate editing and generation tasks through rigorous expert annotation and validation. MolLangBench supports the evaluation of models that interface language with different molecular representations, including linear strings, molecular images, and molecular graphs. Evaluations of state-of-the-art models reveal significant limitations: the strongest model (GPT-5) achieves $86.2\%$ and $85.5\%$ accuracy on recognition and editing tasks, which are intuitively simple for humans, and performs even worse on the generation task, reaching only $43.0\%$ accuracy. These results highlight the shortcomings of current AI systems in handling even preliminary molecular recognition and manipulation tasks. We hope MolLangBench will catalyze further research toward more effective and reliable AI systems for chemical applications.The dataset and code can be accessed at https://huggingface.co/datasets/ChemFM/MolLangBench and https://github.com/TheLuoFengLab/MolLangBench, respectively. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.20420 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.20420v1 Announce Type: new Abstract: Nanopore sequencing can read substantially longer sequences of nucleic acid molecules than other sequencing methods, which has led to advances in genomic analysis such as the gapless human genome assembly. By analyzing the raw electrical signal reads that nanopore sequencing generates from molecules, existing works can map these reads without translating them into DNA characters (i.e., basecalling), allowing for quick and efficient analysis of sequencing data. However, raw signals often contain errors due to noise and mistakes when processing them, which limits the overall accuracy of raw signal analysis. Our goal in this work is to detect and correct errors in raw signals to improve the accuracy of raw signal analyses. To this end, we propose CERN, a mechanism that trains and utilizes a Hidden Markov Model (HMM) to accurately correct signal errors. Our extensive evaluation on various datasets including E. coli, Fruit Fly, and Human genomes shows that CERN 1) consistently improves the overall mapping accuracy of the underlying raw signal analysis tools, 2) minimizes the burden on segmentation algorithm optimization with newer nanopore chemistries, and 3) functions without causing substantial computational overhead. We conclude that CERN provides an effective mechanism to systematically identify and correct the errors in raw nanopore signals before further analysis, which can enable the development of a new class of error correction mechanisms purely designed for raw nanopore signals. CERN is available at https://github.com/STORMgroup/CERN. We also provide the scripts to fully reproduce our results on our GitHub page. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.21201 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.21201v1 Announce Type: new Abstract: Polygenic risk score (PRS) tools differ substantially in statistical assumptions, input requirements, and implementation complexity, making direct comparison difficult. We developed a harmonized, implementation-aware benchmarking framework to evaluate 46 PRS tools across seven binary UK Biobank phenotypes and one continuous trait under three model configurations: null, PRS-only, and PRS plus covariates. The framework integrates standardized preprocessing, tool-specific execution, hyperparameter exploration, and unified downstream evaluation using five-fold cross-validation on high-performance computing infrastructure. In addition to predictive performance, we assessed runtime, memory use, input dependencies, and failure modes. A Friedman test across 40 phenotype--fold combinations confirmed significant differences in tool rankings ($\chi^2 = 102.29$, $p = 2.57 \times 10^{-11}$), with no single method universally optimal. These findings provide a reproducible framework for comparative PRS evaluation and demonstrate that tool performance is shaped not only by statistical methodology but also by phenotype architecture, preprocessing choices, covariate structure, computational demands, software robustness, and practical implementation constraints. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2412.15225 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2412.15225v2 Announce Type: replace Abstract: Biochemical and environmental modeling typically relies on reaction networks to represent complex transformations. While the Linkage Class Decomposition (LCD) partitions networks based on visual standard connectivity, it often misaligns with the algebraic properties governing long-term dynamics. This work establishes the Finest Decompositions' Architecture (FDA) framework by analyzing hierarchical relationships between the LCD and two algebraic structures: the Finest Independent Decomposition (FID) and the Finest Incidence-Independent Decomposition (FIID). These algebraic decompositions serve as the respective building blocks for characterizing general equilibria and complex-balanced equilibria of a reaction network. Under the partial order of "coarsens to," we categorize reaction networks into six architectures, distinguishing three subclasses of Independent Linkage Classes (ILC) from three subclasses of Dependent Linkage Classes (DLC). To facilitate the classification, we introduce the Deficiency Difference (Delta), measuring the discrepancy between total and subnetwork deficiencies, and the Common Complexes Cardinality CC of the FID. Results show that Delta uniquely identifies all the ILC classes and one DLC subclass, while CC distinguishes the remaining DLC subclasses. A number of results on mass action systems such as the Deficiency One Theorem as well as on power law systems essentially rely on the ILC property of the underlying networks. These suggest that the FDA classification of ILC and DLC networks signify a certain alignment of both structural and kinetic attributes. This work opens up direction for the study of the structure and equilibria analysis of reaction networks across diverse decomposition architectures. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2602.23624 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2602.23624v2 Announce Type: replace-cross Abstract: Sex chromosomes have evolved repeatedly across the Tree of Life, yet their evolutionary fates differ strikingly. In sharp contrast to mammals and birds with degenerated, stable Y/W chromosomes, in most amphibians, teleosts, non avian reptiles and flowering plants, sex chromosomes remain largely homomorphic and undergo frequently turnover. Explanations such as the evolutionary trap hypothesis, sexually antagonistic selection, mutation load, genetic drift and selfish genetic elements, focus on population genetic processes and do not fully explain this pattern. Here we propose the developmental gene regulatory network (GRN) lock in hypothesis. We compile case studies of turnover across vertebrates, synthesise comparative developmental data on sex determination and dosage regulation (DC). In mammals and birds, sex is determined by an early, initiation by somatic cells, fully penetrant master signal acting within a narrow, thermally buffered embryonic window. This signal operates within highly canalised GRNs, coupled to chromosome scale dosage compensation, with alternative splicing events playing little or no causal role in primary sex determination. This configuration makes it difficult for new master sex determining loci to invade without generating deleterious intermediate states. By contrast, many ectothermic vertebrates possess flexible, integrative threshold GRNs in which genetic, germ cells and environmental inputs interact over a prolonged sensitive embryonic period, with absent or largely gene-by-gene based DC and environmentally responsive splicing near key regulatory nodes, providing many entry points for sex determining loci to evolve. We outline empirical predictions and highlight how integrating developmental biology, molecular mechanisms and population genetics can yield testable models for when sex chromosomes become evolutionarily locked-in versus repeated turnover. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2603.20680 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.20680v1 Announce Type: new Abstract: Integrating structural and functional connectomes remains challenging because their relationship is non-linear and organized over nested modular hierarchies. We propose a hierarchical multiscale structure-function coupling framework for connectome integration that jointly learns individualized modular organization and hierarchical coupling across structural connectivity (SC) and functional connectivity (FC). The framework includes: (i) Prototype-based Modular Pooling (PMPool), which learns modality-specific multiscale communities by selecting prototypical ROIs and optimizing a differentiable modularity-inspired objective; (ii) an Attention-based Hierarchical Coupling Module (AHCM) that models both within-hierarchy and cross-hierarchy SC-FC interactions to produce enriched hierarchical coupling representations; and (iii) a Coupling-guided Clustering loss (CgC-Loss) that regularizes SC and FC community assignments with coupling signals, allowing cross-modal interactions to shape community alignment across hierarchies. We evaluate the model's performance across four cohorts for predicting brain age, cognitive score, and disease classification. Our model consistently outperforms baselines and other state-of-the-art approaches across three tasks. Ablation and sensitivity analyses verify the contributions of key components. Finally, the visualizations of learned coupling reveal interpretable differences, suggesting that the framework captures biologically meaningful structure-function relationships. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.20756 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.20756v1 Announce Type: new Abstract: This study aims to better understand the functional geometry of the motor cortex, starting from different sources of experimental evidence. Recent studies have proved that cells of the primary motor cortex (M1) are sensitive to short hand trajectories called fragments. Here, we propose a sub-Riemannian higher-dimensional geometry accounting for geometric and kinematic properties. Due to the constraints of the geometry, horizontal curves naturally satisfy a relation between geometric and kinematic properties experimentally observed. In the space of trajectories, we also apply a clustering algorithm based on the Wasserstein distance: we obtain a grouping which nicely fits the observed experimental data much more efficiently than the Sobolev distance. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.21542 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.21542v1 Announce Type: new Abstract: The human brain achieves its remarkable computational prowess not despite its inherent non-ideal factors noise, heterogeneity, structural irregularities, decentralized plasticity, systematic errors, and chaotic dynamics but precisely because of them. This paper systematically demonstrates that these traits, long dismissed as imperfections in classical neuroscience and eliminated in digital engineering, are evolutionary design principles that endow the brain with robustness, adaptability, and creativity. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.20246 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.20246v1 Announce Type: cross Abstract: Speech brain--computer interfaces require decoders that translate intracortical activity into linguistic output while remaining robust to limited data and day-to-day variability. While prior high-performing systems have largely relied on framewise phoneme decoding combined with downstream language models, it remains unclear what contextual sequence-to-sequence decoding contributes to sublexical neural readout, robustness, and interpretability. We evaluated a multitask Transformer-based sequence-to-sequence model for attempted speech decoding from area 6v intracortical recordings. The model jointly predicts phoneme sequences, word sequences, and auxiliary acoustic features. To address day-to-day nonstationarity, we introduced the Neural Hammer Scalpel (NHS) calibration module, which combines global alignment with feature-wise modulation. We further analyzed held-out-day generalization and attention patterns in the encoder and decoders. On the Willett et al. dataset, the proposed model achieved a state-of-the-art phoneme error rate of 14.3%. Word decoding reached 25.6% WER with direct decoding and 19.4% WER with candidate generation and rescoring. NHS substantially improved both phoneme and word decoding relative to linear or no day-specific transform, while held-out-day experiments showed increasing degradation on unseen days with temporal distance. Attention visualizations revealed recurring temporal chunking in encoder representations and distinct use of these segments by phoneme and word decoders. These results indicate that contextual sequence-to-sequence modeling can improve the fidelity of neural-to-phoneme readout from intracortical speech signals and suggest that attention-based analyses can generate useful hypotheses about how neural speech evidence is segmented and accumulated over time. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.20988 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.20988v1 Announce Type: cross Abstract: The cognitive sciences aim to understand intelligence by formalizing underlying operations as computational models. Traditionally, this follows a cycle of discovery where researchers develop paradigms, collect data, and test predefined model classes. However, this manual pipeline is fundamentally constrained by the slow pace of human intervention and a search space limited by researchers' background and intuition. Here, we propose a paradigm shift toward a fully automated, in silico science of the mind that implements every stage of the discovery cycle using Large Language Models (LLMs). In this framework, experimental paradigms exploring conceptually meaningful task structures are directly sampled from an LLM. High-fidelity behavioral data are then simulated using foundation models of cognition. The tedious step of handcrafting cognitive models is replaced by LLM-based program synthesis, which performs a high-throughput search over a vast landscape of algorithmic hypotheses. Finally, the discovery loop is closed by optimizing for ''interestingness'', a metric of conceptual yield evaluated by an LLM-critic. By enabling a fast and scalable approach to theory development, this automated loop functions as a high-throughput in-silico discovery engine, surfacing informative experiments and mechanisms for subsequent validation in real human populations. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2509.11545 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2509.11545v2 Announce Type: replace Abstract: Neural systems face the challenge of maintaining reliable representations amid variations from plasticity and spontaneous activity. In particular, the spontaneous dynamics in neuronal circuit is known to operate near a highly variable critical state, which intuitively contrasts with the requirement of reliable representation. It is intriguing to understand how reliable representation could be maintained or even enhanced by critical spontaneous states. We firstly examined the co-existence of the scale-free avalanche in the spontaneous activity of mouse visual cortex with restricted representational geometry manifesting representational reliability amid the representational drift with respect to the visual stimulus. To explore how critical spontaneous state influences the neural representation, we built an excitation-inhibition network with homeostatic plasticity, which self-organizes to the critical spontaneous state. This model successfully reproduced both representational drift and restricted representational geometry observed experimentally, in contrast with randomly shuffled plasticity which causes accumulated drift of representational geometry. We further showed that the self-organized critical state enhances the cross-session low-dimensional representation, comparing to the non-critical state, by restricting the synapse weight into a low variation space. Our findings suggest that spontaneous self-organized criticality serves not only as a ubiquitous property of neural systems but also as a functional mechanism for maintaining reliable information representation under continuously changing networks, providing a potential explanation how the brain maintains consistent perception and behavior despite ongoing synaptic rewiring. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.20480 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2601.20480v2 Announce Type: replace-cross Abstract: High-dimensional neuroimaging data presents challenges for assessing neurodegenerative diseases due to complex non-linear relationships. Variational Autoencoders (VAEs) can encode scans into lower-dimensional latent spaces capturing disease-relevant features. We propose a semi-supervised VAE framework with a flexible similarity regularization term that aligns selected latent variables with clinical or biomarker measures of dementia progression. This allows adapting the similarity metric and supervised variables to specific goals or available data. We demonstrate the approach using PET scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI), guiding the first latent dimension to align with a cognitive score. Using this supervised latent variable, we generate average reconstructions across levels of cognitive impairment. Voxel-wise GLM analysis reveals reduced metabolism in key regions, mainly the hippocampus, and within major Resting State Networks, particularly the Default Mode and Central Executive Networks. The remaining latent variables encode affine transformations and intensity variations, capturing confounds such as inter-subject variability and site effects. Our framework effectively extracts disease-related patterns aligned with established Alzheimer's biomarkers, offering an interpretable and adaptable tool for studying neurodegenerative progression. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.20707 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.20707v1 Announce Type: new Abstract: Many natural ecosystems harbor large numbers of coexisting species competing for far fewer distinct resources, in apparent defiance of the competitive exclusion principle. Various mechanisms have been proposed to explain this apparent paradox, among the most prominent being competition--colonization trade-offs, environmental heterogeneity, and ecological neutrality. We develop a unified stochastic model class that combines all three coexistence narratives in the context of propagule disperser communities and show that this setting encompasses several important classical models. We then prove a general theorem on coexistence at macroscopic equilibria and provide an algorithm that determines equilibrium coalitions solely from readily available matrix spectra, thereby bypassing the costly computation of exact equilibrium states. Using illustrative examples, we demonstrate the potential of this approach for quantifying the relative merits of different coexistence narratives and for studying their synergistic effects. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.20922 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.20922v1 Announce Type: new Abstract: We develop a unified spectral framework for finite ultrametric phylogenetic trees, grounding the analysis of phylogenetic structure in operator theory and stochastic dynamics in the finite setting. For a given finite ultrametric measure space $(X,d,m)$, we introduce the ultrametric Laplacian $L_X$ as the generator of a continuous time Markov chain with transition rate $q(x,y)=k(d(x,y))m(y)$. We establish its complete spectral theory, obtaining explicit closed-form eigenvalues and an eigenbasis supported on the clades of the tree. For phylogenetic applications, we associate to any ultrametric phylogenetic tree $\mathcal{T}$ a canonical operator $L_{\mathcal{T}}$, the ultrametric phylogenetic Laplacian, whose jump rates encode the temporal structure of evolutionary divergence. We show that the geometry and topology of the tree are explicitly encoded in the spectrum and eigenvectors of $L_{\mathcal{T}}$: eigenvalues aggregate branch lengths weighted by clade mass along ancestral paths, while eigenvectors are supported on the clades, with one eigenspace attached to each internal node. From this we derive three main contributions: a spectral reconstruction theorem with linear complexity $O(|X|)$; a rigorous geometric interpretation of the spectral gaps of $L_{\mathcal{T}}$ as detectors of distinct evolutionary modes, validated on an empirical primate phylogeny; an eigenmode decomposition of biological traits that resolves trait variance into contributions from individual splits of the phylogeny; and a closed-form centrality index for continuous-time Markov chains on ultrametric spaces, which we propose as a mathematically grounded measure of evolutionary distinctiveness. All results are exact and biologically interpretable, and are supported by numerical experiments on empirical primate data. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.21025 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.21025v1 Announce Type: new Abstract: The costly provision of public goods serves as a model problem for the evolution of cooperative behavior, presenting a social dilemma between the collective benefits of shared resources and the individual incentive to free-ride in resource production. The spatial structure of populations can also impact cooperation over public goods, as diffusion of public goods and intentional motion of individuals towards regions with greater resources can interact with population and public goods dynamics to produce heterogeneous patterns in the spatial distribution of strategies and resources. In this paper, we build off a model introduced by Young and Belmonte for the reaction dynamics of interacting individuals and explicit public good, deriving a system of PDEs that describes the spatial profiles of strategies and the public good in the presence of both diffusive motion of individuals and resources and chemotaxis-like directed motion of individuals in response to gradients in the concentration of public goods. Through linear stability analysis, we show that spatial patterns in strategic and public goods profiles can emerge due to either Turing instability with high defector diffusivity or a directed-motion instability through strong sensitivity of cooperators towards increasing resource concentration. We further explore the emergent spatial patterns with a mix of weakly nonlinear stability analysis and numerical simulation, showing that diffusion-driven instability appears to increase cooperation and public goods across the spatial domain, while directed motion of cooperators towards regions with great public goods provision tends to decrease cooperation and environmental quality across the environment. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.21634 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.21634v1 Announce Type: cross Abstract: We study population dynamics through a general growth/degrowth-fragmentation process, with resource consumption and unbounded growth/degrowth, birth and death rates. Our model is structured in a positive trait called energy (which is a proxy for any biological parameter such as size, age, mass, protein quantity...), and the jump rates of the process can be arbitrarily high depending on individual energies, which has not been considered yet in the literature. After a preliminary study to construct well-defined objects (which is necessary contrary to similar works, because of the explosion of individual rates), we consider a classical sequence of renormalizations of the underlying process and obtain a tightness result for the associated laws in large-population asymptotics. We characterize the accumulation points of this sequence as solutions of an integro-differential system of equations, which proves the existence of measure solutions to this system. Furthermore, if such a measure solution is unique, then our tightness result becomes a convergence result towards this unique process. We illustrate our work with the case of allometric rates (i.e. they are assumed to be power functions) and eventually present numerical simulations in this allometric setting. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2507.06358 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2507.06358v3 Announce Type: replace Abstract: Biodiversity assessments depend critically on the spatial scale at which species richness is measured. How species richness accumulates with sampling area is influenced by natural and anthropogenic processes whose effects vary across spatial scales. These accumulation dynamics, described by the species-area relationship (SAR), are challenging to assess because most biodiversity surveys cover sampling areas far smaller than the scales at which these processes operate. Here, we combine sampling theory with deep learning to estimate species richness at arbitrary spatial scales across geographic space from existing ecological surveys. We apply our model, named MuScaRi, to ~350k vegetation surveys across Europe. Validated against independent regional plant inventories, MuScaRi reduces root mean squared error of vascular plant richness estimates by 61% relative to conventional estimators, yields substantially less biased predictions, and produces multi-scale richness maps alongside spatially explicit estimates of the species accumulation rate, a key indicator for biodiversity conservation. By encompassing the full spectrum of ecologically relevant spatial scales within a single unified framework, MuScaRi provides an essential tool for robust biodiversity assessments and forecasts under global change. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2508.06719 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2508.06719v2 Announce Type: replace Abstract: Speciation is often associated with geographical barriers that limit gene flow. However, species can also emerge in continuous homogeneous environments through isolation by distance. When the environment is not homogeneous, natural selection contributes to differentiation by local adaptation and tends to facilitate speciation. To explore how isolation by distance and adaptation combine to determine species diversity, we implemented a model regulated by these two components. The first is implemented via mating restrictions on spatial proximity and genetic similarity. The second is realized by an ecological phenotype subjected to adaptation by natural selection. We consider scenarios where the environment is either homogeneous, with a single ecological optimum, or heterogeneous with two distinct optima. We show that the interplay between selection and isolation by distance affect not only species formation but also phenotypic distributions and speed of speciation. In homogeneous environment, speciation occurs only under restrictive mating, but it takes longer if selection is weak. In contrast, in heterogeneous environments with two local optima and strong selection, species well adapted to each of the optima emerge along the spatial structure, leading to the formation of groups with distinct phenotypes. Permissive mating leads to the formation of only two species, each occupying one of the optima; restrictive mating leads to several species per optimum, in a much faster speciation process. Interestingly, when selection is weak and mating is restrictive, several species form, but the process is slow. Moreover, species average phenotypes do not remain constant over generations, causing the phenotypic distribution to oscillate, never reaching a stationary pattern. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2409.18634 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2409.18634v2 Announce Type: replace-cross Abstract: Phylogenetic trees are leaf-labelled trees used to model the evolution of species. In practice it is not uncommon to obtain two topologically distinct trees for the same set of species, and this motivates the use of distance measures to quantify dissimilarity. A well-known measure is the maximum agreement forest (MAF): a minimum-size partition of the leaf labels which splits both trees into the same set of disjoint, leaf-labelled subtrees (up to isomorphism after suppressing degree-2 vertices). Computing such a MAF is NP-hard and so considerable effort has been invested in finding FPT algorithms, parameterised by $k$, the number of components of a MAF. The state of the art has been unchanged since 2015, with running times of $O^*(3^k)$ for unrooted trees and $O^*(2.3431^k)$ for rooted trees. In this work we present improved algorithms for both the unrooted and rooted cases, with runtimes $O^*(2.846^k)$ and $O^*(2.3391^k)$ respectively. The key to our improvement is a novel branching strategy in which we show that any overlapping components obtained on the way to a MAF can be `split' by a branching rule with favourable branching factor, and then the problem can be decomposed into disjoint subproblems to be solved separately. We expect that this technique may be more widely applicable to other problems in algorithmic phylogenetics. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2502.01178 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2502.01178v3 Announce Type: replace-cross Abstract: We study a population of $N$ individuals evolving according to a biparental Moran model with two types, one being advantaged compared to the other. The advantage is conferred by a Mendelian mutation, which reduces the death probability of individuals carrying it. We assume that a proportion $a$ of individuals initially carry this mutation, which therefore eventually gets fixed with high probability. After a long time, we sample a gene uniformly from the population, at a new locus, independent of the locus under selection, and calculate the probability that this gene originated from one of the initially advantaged individuals, when the population size is large. Our theorem provides quantitative insights, such as the observation that under strong viability selection, if only $1\%$ of the individuals are initially advantaged, up to $19\%$ of the population's genome will originate from them after a long time. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.19814 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.19814v2 Announce Type: replace-cross Abstract: Recent biological evidence suggests the presence of a two-phase ageing process in several species. We introduce a system of two age-structured partial differential equations (PDE) representing two phases of ageing of a wild population. The model includes a coupling of both equations through birth and transition between phases and non-linearities due to competition. We show the existence, positivity and uniqueness of weak solutions in a general setting. For a simplified system of ordinary differential equations (ODE), we show existence and uniqueness of a strictly positive steady state attracting all trajectories. We study another simplification, a coupled PDE-ODE model, for which we prove existence, uniqueness and local asymptotic stability of a strictly positive steady state. Under further assumptions, but without assuming weak non-linearities, we show the global asymptotic stability of that steady state. The uniqueness of steady states and absence of oscillations in these systems show that the proportion of individuals in each phase at equilibrium is a unique feature of the model. This paves the way to ecological applications as the experimental measure of such a proportion could help gain some insight on the health of a wild population. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.21020 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2603.21020v1 Announce Type: new Abstract: Finite element analysis of knee joint contact mechanics is computationally expensive, which has motivated the development of graph neural network surrogate models. However, effectively representing long-range dependencies in joint mechanical responses remains challenging. This study systematically compared topology diffusion, global routing, and their hybridization for surrogate modeling of knee joint contact mechanics. Using kinematic and force data from nine soccer players performing change-of-direction maneuvers, finite element simulations were used to generate graph-structured samples for training and evaluation under a grouped three-fold cross-subject evaluation framework. Five architectures were compared: standard MeshGraphNet, hierarchical MeshGraphNet, a routing-only transformer, a topology-biased routing transformer, and a hybrid model. The hybrid model achieved the best overall performance, yielding the lowest full-field error and peak stress error, together with the highest spatial agreement for high-risk regions. Among the non-hybrid models, the standard topology-diffusion model performed best overall, whereas routing-only strategies were less effective. These findings indicate that topology diffusion provides a robust basis for surrogate modeling of knee joint contact mechanics within the present benchmark, while the addition of global routing can further improve reconstruction of clinically relevant high-stress patterns. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2407.02771 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2407.02771v2 Announce Type: replace Abstract: For mathematical and experimental ease, models with time varying parameters are often simplified to assume constant parameters. However, this simplification can potentially lead to identifiability issues (lack of uniqueness of parameter estimates). Methods have been developed to algebraically and numerically determine the identifiability of a model, as well as resolve identifiability issues. This specific type of simplification presents an alternate opportunity to instead use this information to resolve the unidentifiability. Given that re-parameterizing, collecting more data, and adding inputs can be potentially costly or impractical, this could present new alternatives. We present a method for resolving unidentifiability in a system by introducing a new data stream correlated with a parameter of interest. First, we demonstrate how and when non-constant input data can be introduced into any rational function ODE system without worsening the model identifiability. Then, we prove when these input functions improve structural and potentially also practical identifiability for a given model and relevant data. By utilizing pre-existing data streams, these methods can potentially reduce experimental costs, while still answering key questions. By connecting mathematical proofs to application, our framework removes guesswork from when, where, and how researchers can best introduce new data to improve model outcomes. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2505.07140 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2505.07140v3 Announce Type: replace Abstract: In chemical safety assessment, validation studies rely on reference compound lists to evaluate the applicability of alternative methods prior to regulatory acceptance. These lists are expected to cover multiple aspects, including chemical structure, physicochemical properties, and toxicity profiles. In practice, however, trade-offs among these aspects are typically addressed implicitly through expert judgment, making them difficult to examine systematically. Here, we formulate reference compound selection for toxicity assay validation as an explicit multi-objective design problem. We define three interpretable objectives capturing structural, physicochemical, and toxicity diversity, and employ a genetic algorithm as an exploratory tool to examine the trade-off structure and resulting Pareto-optimal solutions. Rather than prescribing optimal or recommended compound sets, this formulation enables systematic exploration of designs and explicit comparison of their positions within a common design space. As an illustrative application, we link existing assay datasets with expert-curated validation lists by treating ``selected as a reference compound`` as an annotation on the underlying compound pool. We show that expert-selected, random, and algorithmically generated compound lists occupy distinct regions of the design space. Furthermore, under an illustrative fixed modeling setup, different regions of the design space were associated with different observed evaluation outcomes, supporting the view that reference compound selection constitutes a structured dimension of evaluation design. Together, these results provide a methodological perspective for treating reference compound selection as an analyzable design object, complementing established expert-driven practices. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2508.08441 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2508.08441v2 Announce Type: replace Abstract: Automated molecular structure elucidation remains challenging, as existing approaches often depend on pre-compiled databases or restrict themselves to single spectroscopic modalities. Here we introduce \textbf{SpectraLLM}, a large language model that performs end-to-end structure prediction by reasoning over one or multiple spectra. Unlike conventional spectrum-to-structure pipelines, SpectraLLM represents both continuous (IR, Raman, UV-Vis, NMR) and discrete (MS) modalities in a shared language space, enabling it to capture substructural patterns that are complementary across different spectral types. We pretrain and fine-tune the model on small-molecule domains and evaluate it on four public benchmark datasets. SpectraLLM achieves state-of-the-art performance, substantially surpassing single-modality baselines. Moreover, it demonstrates strong robustness in unimodal settings and further improves prediction accuracy when jointly reasoning over diverse spectra, establishing a scalable paradigm for language-based spectroscopic analysis. Code is available at https://github.com/OPilgrim/SpectraLLM. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2508.14936 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2508.14936v2 Announce Type: replace Abstract: Synthetic data holds substantial potential to address practical challenges in epidemiology due to restricted data access and privacy concerns. However, many current methods suffer from limited quality, high computational demands, and complexity for non-experts. Furthermore, common evaluation strategies for synthetic data often fail to directly reflect statistical utility and measure privacy risks sufficiently. Against this background, a critical underexplored question is whether synthetic data can reliably reproduce key findings from epidemiological research while preserving privacy. We propose adversarial random forests (ARF) as an efficient and convenient method for synthesizing tabular epidemiological data. To evaluate its performance, we replicated statistical analyses from six epidemiological publications covering blood pressure, anthropometry, myocardial infarction, accelerometry, loneliness, and diabetes, from the German National Cohort (NAKO Gesundheitsstudie), the Bremen STEMI Registry U45 Study, and the Guelph Family Health Study. We further assessed how dataset dimensionality and variable complexity affect the quality of synthetic data, and contextualized ARF's performance by comparison with commonly used tabular data synthesizers in terms of utility, privacy, generalisation, and runtime. Across all replicated studies, results on ARF-generated synthetic data consistently aligned with original findings. Even for datasets with relatively low sample size-to-dimensionality ratios, replication outcomes closely matched the original results across descriptive and inferential analyses. Reduced dimensionality and variable complexity further enhanced synthesis quality. ARF demonstrated favourable performance regarding utility, privacy preservation, and generalisation relative to other synthesizers and superior computational efficiency. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2511.06426 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2511.06426v2 Announce Type: replace Abstract: Understanding the growth and form of shapes is one of the most fundamental problems in biology. While many prior works have analyzed the beak shapes of Darwin's finches, other cranial features are relatively less explored. In this work, we develop geometric and statistical methods for analyzing the skull morphology of Darwin's finches and their relatives, focusing on the relationship between their skull dimensions, orbit curvature, and neurocranial geometries. Unlike traditional landmark-based approaches that scale linearly with human labor, our framework is fully unsupervised. Specifically, by utilizing tools in computational geometry, differential geometry, and numerical optimization, we develop efficient algorithms for quantifying various key geometric features of the skull. We then perform a statistical analysis and discover a strong correlation between skull size and orbit curvature. Based on our findings, we further establish a predictive model that can estimate the orbit curvature using easily obtainable linear skull measurements. Our results show that the predictive model is highly effective and capable of explaining 85.48\% of the variance in curvature with an average prediction error of only 6.35\%. Altogether, our work establishes a rigorous foundation for the digital estimation and high-throughput phenotyping of large-scale museum collections, overcoming the scalability bottlenecks of manual methods. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2511.17695 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2511.17695v4 Announce Type: replace Abstract: Drug synergy is profoundly influenced by cellular context, as variations in protein interaction landscapes and pathway activities across cell types reshape how drugs act in combination. Most existing models overlook this heterogeneity, relying on static or bulk-level protein-protein interaction (PPI) networks that ignore cell-specific molecular wiring. The availability of large-scale transcriptomic data now enables the reconstruction of cell-line-resolved interactomes, offering a new foundation for contextualized drug synergy modeling. Here we present SynCell, a Contextualized Drug Synergy framework that integrates drug-protein, protein-protein, and protein-cell line relations within a unified graph architecture. SynCell leverages cell-line-specific PPI networks to embed the molecular context in which drugs act, and employs graph convolutional learning to model how pharmacological effects propagate through cell-specific signaling networks. This formulation treats synergy prediction as a cell-line-contextualized drug-drug interaction problem. Across the large-scale DrugCombDB benchmark, SynCell consistently outperforms state-of-the-art baselines - including DeepSynergy, HypergraphSynergy, HERMES, BAITSAO, DTF, and NHP - particularly in predicting synergies involving unseen drugs or novel cell lines. When benchmarked against these seven methods, SynCell demonstrates substantial gains in generalization and biological interpretability, confirming that contextualizing PPIs with cell-line resolution is indispensable for accurate synergy prediction. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2509.19988 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2509.19988v2 Announce Type: replace-cross Abstract: Efficient design of genomic perturbation experiments is crucial for accelerating drug discovery and therapeutic target identification, yet exhaustive perturbation of the human genome remains infeasible due to the vast search space of potential genetic interactions and experimental constraints. Bayesian optimization (BO) has emerged as a powerful framework for selecting informative interventions, but existing approaches often fail to exploit domain-specific biological prior knowledge. We propose Biology-Informed Bayesian Optimization (BioBO), a method that integrates Bayesian optimization with multimodal gene embeddings and enrichment analysis, a widely used tool for gene prioritization in biology, to enhance surrogate modeling and acquisition strategies. BioBO combines biologically grounded priors with acquisition functions in a principled framework, which biases the search toward promising genes while maintaining the ability to explore uncertain regions. Through experiments on established public benchmarks and datasets, we demonstrate that BioBO improves labeling efficiency by 25-40%, and consistently outperforms conventional BO by identifying top-performing perturbations more effectively. Moreover, by incorporating enrichment analysis, BioBO yields pathway-level explanations for selected perturbations, offering mechanistic interpretability that links designs to biologically coherent regulatory circuits. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2602.15677 Tue, 24 Mar 2026 00:00:00 -0400 arXiv:2602.15677v3 Announce Type: replace-cross Abstract: Electrocardiograms (ECG) are electrical recordings of the heart that are critical for diagnosing cardiovascular conditions. ECG language models (ELMs) have recently emerged as a promising framework for ECG classification accompanied by report generation. However, current models cannot forecast future cardiac events despite the immense clinical value for planning earlier intervention. To address this gap, we propose CAMEL, the first ELM that is capable of inference over longer signal durations which enables its forecasting capability. Our key insight is a specialized ECG encoder which enables cross-understanding of ECG signals with text. We train CAMEL using established LLM training procedures, combining LoRA adaptation with a curriculum learning pipeline. Our curriculum includes ECG classification, metrics calculations, and multi-turn conversations to elicit reasoning. CAMEL demonstrates strong zero-shot performance across 6 tasks and 9 datasets, including ECGForecastBench, a new benchmark that we introduce for forecasting arrhythmias. CAMEL is on par with or surpasses ELMs and fully supervised baselines both in- and out-of-distribution, achieving SOTA results on ECGBench (+7.0% absolute average gain) as well as ECGForecastBench (+12.4% over fully supervised models and +21.1% over zero-shot ELMs). Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.20115 Mon, 23 Mar 2026 00:00:00 -0400 arXiv:2603.20115v1 Announce Type: cross Abstract: Protein sequence generation via stochastic attention produces plausible family members from small alignments without training, but treats all stored sequences equally and cannot direct generation toward a functional subset of interest. We show that a single scalar parameter, added as a bias to the sampler's attention logits, continuously shifts generation from the full family toward a user-specified subset, with no retraining and no change to the model architecture. A practitioner supplies a small set of sequences (for example, hits from a binding screen) and a multiplicity ratio that controls how strongly generation favors them. The method is agnostic to what the subset represents: binding, stability, specificity, or any other property. We find that the conditioning is exact at the level of the sampler's internal representation, but that the decoded sequence phenotype can fall short because the dimensionality reduction used to encode sequences does not always preserve the residue-level variation that defines the functional split. We term this discrepancy the calibration gap and show that it is predicted by a simple geometric measure of how well the encoding separates the functional subset from the rest of the family. Experiments on five Pfam families (Kunitz, SH3, WW, Homeobox, and Forkhead domains) confirm the monotonic relationship between separation and gap across a fourfold range of geometries. Applied to omega-conotoxin peptides targeting a calcium channel involved in pain signaling, curated seeding from 23 characterized binders produces over a thousand candidates that preserve the primary pharmacophore and all experimentally identified binding determinants. These results show that stochastic attention enables practitioners to expand a handful of experimentally characterized sequences into diverse candidate libraries without retraining a generative model. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2403.17210 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2403.17210v3 Announce Type: replace-cross Abstract: Examining Drug-Drug Interactions (DDIs) is a pivotal element in the process of drug development. DDIs occur when one drug's properties are affected by the inclusion of other drugs. Detecting favorable DDIs has the potential to pave the way for creating and advancing innovative medications applicable in practical settings. However, existing DDI prediction models continue to face challenges related to generalization in extreme cases, robust feature extraction, and real-life application possibilities. We aim to address these challenges by leveraging the effectiveness of context-aware deep graph learning by introducing a novel framework named CADGL. Based on a customized variational graph autoencoder (VGAE), we capture critical structural and physio-chemical information using two context preprocessors for feature extraction from two different perspectives: local neighborhood and molecular context, in a heterogeneous graphical structure. Our customized VGAE consists of a graph encoder, a latent information encoder, and an MLP decoder. CADGL surpasses other state-of-the-art DDI prediction models, excelling in predicting clinically valuable novel DDIs, supported by rigorous case studies. CADGL is vailable at: https://github.com/azminewasi/cadgl Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2603.19139 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2603.19139v1 Announce Type: cross Abstract: Learning systems must balance generalization across experiences with discrimination of task-relevant details. Effective learning therefore requires representations that support both. Online latent-cause models support incremental inference but assume flat partitions, whereas hierarchical Bayesian models capture multilevel structure but typically require offline inference. We introduce the Hierarchical Online Learning of Multiscale Experience Structure (HOLMES) model, a computational framework for hierarchical latent structure learning through online inference. HOLMES combines a variation on the nested Chinese Restaurant Process prior with sequential Monte Carlo inference to perform tractable trial-by-trial inference over hierarchical latent representations without explicit supervision over the latent structure. In simulations, HOLMES matched the predictive performance of flat models while learning more compact representations that supported one-shot transfer to higher-level latent categories. In a context-dependent task with nested temporal structure, HOLMES also improved outcome prediction relative to flat models. These results provide a tractable computational framework for discovering hierarchical structure in sequential data. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2505.24125 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2505.24125v2 Announce Type: replace Abstract: Human cognition is supported by brain structural connectivity wherein weak connectivity with weights several orders of magnitude smaller than those of strong connectivity, has been treated as noise and ignored from analysis over a long time. We here propose that weak connectivity plays roles to cognitive abilities by nonlinearly amplifying its small weights. Using the HCP dataset (n=999) and multiple tractography algorithms, we found that weak connectivity involves high individual variability and contributes to predictions of general cognitive ability and memory, and it is also critical for brain functional connectivity simulation and structure-function coupling. Importantly, we fused two post-tractography filtering methods to generate more reliable connectivity that preserves weak links and outperforms conventional thresholding. At the network level, we showed that weak connectivity expands the operational capacity of brain networks to enhance both global integration and fine-grained segregation, thereby supporting a functional balance essential for diverse cognitive abilities. Finally, we identified a specific type of weak connectivity mainly linking visual/motor to limbic areas with negative gene co-expression, which has a disproportionately large functional impact. Our findings demonstrate groundbreaking evidence of underestimated but crucial role of weak connectivity in human cognition, providing a refined approach to reliably reveal brain structural connectivity. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2507.11027 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2507.11027v4 Announce Type: replace Abstract: We explore a functionalist approach to emotion by employing an ansatz -- an initial set of assumptions -- that a hypothetical concept generation model incorporates unproven but biologically plausible traits. From these traits, we mathematically construct a theoretical reinforcement learning framework grounded in functionalist principles and examine how the resulting utility function aligns with emotional valence in biological systems. Our focus is on structuring the functionalist perspective through a conceptual network, particularly emphasizing the construction of the utility function, not to provide an exhaustive explanation of emotions. The primary emphasis is not of planning or action execution, but such factors are addressed when pertinent. Finally, we apply the framework to psychological phenomena such as humor, psychopathy, and advertising, demonstrating its breadth of explanatory power. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.06134 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2601.06134v2 Announce Type: replace-cross Abstract: Electroencephalography (EEG) foundation models hold significant promise for universal Brain-Computer Interfaces (BCIs). However, existing approaches often rely on end-to-end fine-tuning and exhibit limited efficacy under frozen-probing protocols, lacking the intrinsic universality required for broad generalization. This limitation stems from adapting general-purpose sequence architectures that overlook the biophysical and dynamical principles of neural activity. To bridge this gap, we propose DeeperBrain, a neuro-grounded foundation model integrating domain-specific inductive biases into its model design and learning objectives. Architecturally, DeeperBrain incorporates a volume conduction-aware channel encoding to model spatial mixing via 3D geometry, and a neurodynamics-aware temporal encoding capturing slow adaptations using oscillatory and exponential bases. For pretraining, we introduce a dual-objective strategy combining Masked EEG Reconstruction (MER) for local fidelity and Neurodynamics Statistics Prediction (NSP). NSP enforces alignment with macroscopic brain states by predicting interpretable order parameters, including spectral power, functional connectivity, cross-frequency coupling, and dynamic complexity. Extensive experiments demonstrate that DeeperBrain achieves state-of-the-art or highly competitive performance under end-to-end fine-tuning. Crucially, it maintains superior efficacy under a rigorous frozen-probing protocol, verifying that embedding neuroscientific first principles endows learned representations with the intrinsic universality essential for universal BCI. The code will be publicly available. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.18801 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2603.18801v1 Announce Type: new Abstract: The SIR model is the cornerstone model for mathematical epidemiology, explaining key epidemic features such as the second-order transition between disease-free and epidemic states, the initial exponential growth of outbreaks or the short-term benefits of control measures. Nonetheless, the classical SIR model assumes that pathogen traits remain fixed, thus neglecting viral evolution. Here we propose a minimal extension of the SIR model, allowing infectiousness to evolve. We show that such evolution can cause superexponential early growth of outbreaks, create abrupt epidemic transitions, and undermine the effectiveness of control policies, as lifting interventions too early can lead to worse epidemic scenarios than no action. We derive analytical expressions for the critical mutation rate and intervention time governing this behavior, and identify a strong asymmetry between control strategies: while shortening the infectious period hinders transmission without suppressing viral evolution, lowering transmission both reduces cases and slows down viral evolution. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.18249 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2603.18249v1 Announce Type: new Abstract: Spatial transcriptomics (ST) profiles gene expression across a tissue section while preserving the spatial coordinates. Because current ST technologies typically profile two-dimensional tissue slices, integrating and aligning slices from different regions of the same three-dimensional tissue or from samples under different conditions enables analyses that reveal 3D organization and condition-associated spatial patterns. Two major challenges remain. First, interpretable and flexible control over spatial distortion is needed because rigid transformations can be overly restrictive, whereas highly deformable mappings may arbitrarily distort spatial proximity. Second, biologically plausible matching is also needed, especially when the slices overlap partially. Here, we introduce RAFT-UP, a tool for robust ST alignment that provides explicit control over spatial distance preservation through a fused supervised Gromov-Wasserstein (FsGW) optimal transport framework. FsGW combines expression and spatial information, incorporates spot-wise constraints to discourage biologically implausible matches, and enforces a pairwise distance-consistency constraint that prevents mapping two pairs of spots when their spatial distances differ beyond a specified tolerance. We demonstrate that RAFT-UP accurately aligns slices from different regions of the same tissue and slices from different samples. Benchmarking shows that RAFT-UP improves spatial distance preservation while achieving spot label matching accuracy comparable to state-of-the-art methods. Finally, we demonstrate RAFT-UP on two spatially constrained downstream applications, including spatiotemporal mapping of developing mouse midbrain and comparative cross-slice analysis of cell-cell communication. RAFT-UP is available as open-source software. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.18497 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2603.18497v1 Announce Type: new Abstract: Inferring the connectivity of neural circuits from incomplete observations is a fundamental challenge in neuroscience. We present a covariance-based method for estimating the weight matrix of a recurrent neural network from sparse, partial measurements across multiple recording sessions. By accumulating pairwise covariance estimates across sessions where different subsets of neurons are observed, we reconstruct the full connectivity matrix without requiring simultaneous recording of all neurons. A Granger-causality refinement step enforces biological constraints via projected gradient descent. Through systematic experiments on synthetic networks modeling small brain circuits, we characterize a fundamental control-estimation tradeoff: stimulation aids identifiability but disrupts intrinsic dynamics, with the optimal level depending on measurement density. We discover that the ``incorrect'' linear approximation acts as implicit regularization -- outperforming the oracle estimator with known nonlinearity at all operating regimes -- and provide an exact characterization via the Stein--Price identity. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.18571 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2603.18571v1 Announce Type: cross Abstract: Subcellular localization is a crucial biological task for drug target identification and function annotation. Although it has been biologically realized that subcellular localization is closely associated with protein structure, no existing dataset offers comprehensive 3D structural information with detailed subcellular localization annotations, thus severely hindering the application of promising structure-based models on this task. To address this gap, we introduce a new benchmark called $\mathbf{CAPSUL}$, a $\mathbf{C}$omprehensive hum$\mathbf{A}$n $\mathbf{P}$rotein benchmark for $\mathbf{SU}$bcellular $\mathbf{L}$ocalization. It features a dataset that integrates diverse 3D structural representations with fine-grained subcellular localization annotations carefully curated by domain experts. We evaluate this benchmark using a variety of state-of-the-art sequence-based and structure-based models, showcasing the importance of involving structural features in this task. Furthermore, we explore reweighting and single-label classification strategies to facilitate future investigation on structure-based methods for this task. Lastly, we showcase the powerful interpretability of structure-based methods through a case study on the Golgi apparatus, where we discover a decisive localization pattern $\alpha$-helix from attention mechanisms, demonstrating the potential for bridging the gap with intuitive biological interpretability and paving the way for data-driven discoveries in cell biology. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2508.15034 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2508.15034v3 Announce Type: replace Abstract: Characterizing in-utero brain development is essential for understanding typical and atypical neurodevelopment. Building on prior spatiotemporal fetal brain MRI atlases, we present the CRL-2025 fetal brain atlas, a spatiotemporal (4D) atlas of the developing fetal brain between 21 and 37 gestational weeks. This atlas is constructed from MRI scans of 159 fetuses with typically developing brains using a diffeomorphic deformable registration framework integrated with kernel regression on age. CRL-2025 uniquely includes detailed tissue segmentations, transient white matter compartments, and parcellation into 126 anatomical regions. It offers significantly enhanced anatomical details over the CRL-2017 atlas and is presented along with a re-release of the CRL diffusion MRI atlas featuring newly created tissue segmentation and labels. We release de-identified, processed subject-level fetal MRI datasets used to generate CRL-2025, providing input-output transparency and reproducibility. We also provide FetalSEG, a deep learning-based multiclass segmentation tool to facilitate automatic fetal brain MRI segmentation. The CRL-2025 atlas and its tools enable scalable fetal brain MRI segmentation, analysis, and neurodevelopmental research for the broader community. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.17380 Fri, 20 Mar 2026 00:00:00 -0400 arXiv:2603.17380v2 Announce Type: replace-cross Abstract: Virtual cell models aim to enable in silico experimentation by predicting how cells respond to genetic, chemical, or cytokine perturbations from single-cell measurements. In practice, however, large-scale perturbation prediction remains constrained by three coupled bottlenecks: inefficient training and inference pipelines, unstable modeling in high-dimensional sparse expression space, and evaluation protocols that overemphasize reconstruction-like accuracy while underestimating biological fidelity. In this work we present a specialized large-scale foundation model SCALE for virtual cell perturbation prediction that addresses the above limitations jointly. First, we build a BioNeMo-based training and inference framework that substantially improves data throughput, distributed scalability, and deployment efficiency, yielding 12.51* speedup on pretrain and 1.29* on inference over the prior SOTA pipeline under matched system settings. Second, we formulate perturbation prediction as conditional transport and implement it with a set-aware flow architecture that couples LLaMA-based cellular encoding with endpoint-oriented supervision. This design yields more stable training and stronger recovery of perturbation effects. Third, we evaluate the model on Tahoe-100M using a rigorous cell-level protocol centered on biologically meaningful metrics rather than reconstruction alone. On this benchmark, our model improves PDCorr by 12.02% and DE Overlap by 10.66% over STATE. Together, these results suggest that advancing virtual cells requires not only better generative objectives, but also the co-design of scalable infrastructure, stable transport modeling, and biologically faithful evaluation. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.15080 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2603.15080v3 Announce Type: replace-cross Abstract: Biomedical knowledge is fragmented across siloed databases -- Reactome for pathways, STRING for protein interactions, ClinicalTrials.gov for study registries, DrugBank for drug vocabularies, DGIdb for drug-gene interactions, SIDER for side effects. We present three open-source biomedical knowledge graphs -- Pathways KG (118,686 nodes, 834,785 edges from 5 sources), Clinical Trials KG (7,774,446 nodes, 26,973,997 edges from 5 sources), and Drug Interactions KG (32,726 nodes, 191,970 edges from 3 sources) -- built on Samyama, a high-performance graph database written in Rust. Our contributions are threefold. First, we describe a reproducible ETL pattern for constructing large-scale KGs from heterogeneous public data sources, with cross-source deduplication, batch loading (Python Cypher and Rust native loaders), and portable snapshot export. Second, we demonstrate cross-KG federation: loading all three snapshots into a single graph tenant enables property-based joins across datasets. Third, we introduce schema-driven MCP server generation for LLM agent access, evaluated on a new BiomedQA benchmark (40 pharmacology questions): domain-specific MCP tools achieve 98% accuracy vs. 85% for schema-aware text-to-Cypher and 75% for standalone GPT-4o, with zero schema errors. All data sources are open-license. The combined federated graph (7.9M nodes, 28M edges) loads in approximately 3 minutes on commodity cloud hardware, with single-KG queries completing in 80-100ms and cross-KG federation joins in 1-4s Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.17247 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2603.17247v1 Announce Type: cross Abstract: We propose Q-BIOLAT, a framework for modeling and optimizing protein fitness landscapes in binary latent spaces. Starting from protein sequences, we leverage pretrained protein language models to obtain continuous embeddings, which are then transformed into compact binary latent representations. In this space, protein fitness is approximated using a quadratic unconstrained binary optimization (QUBO) model, enabling efficient combinatorial search via classical heuristics such as simulated annealing and genetic algorithms. On the ProteinGym benchmark, we demonstrate that Q-BIOLAT captures meaningful structure in protein fitness landscapes and enables the identification of high-fitness variants. Despite using a simple binarization scheme, our method consistently retrieves sequences whose nearest neighbors lie within the top fraction of the training fitness distribution, particularly under the strongest configurations. We further show that different optimization strategies exhibit distinct behaviors, with evolutionary search performing better in higher-dimensional latent spaces and local search remaining competitive in preserving realistic sequences. Beyond its empirical performance, Q-BIOLAT provides a natural bridge between protein representation learning and combinatorial optimization. By formulating protein fitness as a QUBO problem, our framework is directly compatible with emerging quantum annealing hardware, opening new directions for quantum-assisted protein engineering. Our implementation is publicly available at: https://github.com/HySonLab/Q-BIOLAT Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.17191 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2603.17191v1 Announce Type: cross Abstract: Accurate diagnosis of Alzheimer's disease (AD) requires handling tabular biomarker data, yet such data are often small and incomplete, where deep learning models frequently fail to outperform classical methods. Pretrained large language models (LLMs) offer few-shot generalization, structured reasoning, and interpretable outputs, providing a powerful paradigm shift for clinical prediction. We propose TAP-GPT Tabular Alzheimer's Prediction GPT, a domain-adapted tabular LLM framework built on TableGPT2 and fine-tuned for few-shot AD classification using tabular prompts rather than plain texts. We evaluate TAP-GPT across four ADNI-derived datasets, including QT-PAD biomarkers and region-level structural MRI, amyloid PET, and tau PET for binary AD classification. Across multimodal and unimodal settings, TAP-GPT improves upon its backbone models and outperforms traditional machine learning baselines in the few-shot setting while remaining competitive with state-of-the-art general-purpose LLMs. We show that feature selection mitigates degradation in high-dimensional inputs and that TAP-GPT maintains stable performance under simulated and real-world missingness without imputation. Additionally, TAP-GPT produces structured, modality-aware reasoning aligned with established AD biology and shows greater stability under self-reflection, supporting its use in iterative multi-agent systems. To our knowledge, this is the first systematic application of a tabular-specialized LLM to multimodal biomarker-based AD prediction, demonstrating that such pretrained models can effectively address structured clinical prediction tasks and laying the foundation for tabular LLM-driven multi-agent clinical decision-support systems. The source code is publicly available on GitHub: https://github.com/sophie-kearney/TAP-GPT. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.17765 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2603.17765v1 Announce Type: new Abstract: Automated radiology report generation has gained increasing attention with the rise of deep learning and large language models. However, fully generative approaches often suffer from hallucinations and lack clinical grounding, limiting their reliability in real-world workflows. In this study, we propose a multimodal retrieval-augmented generation (RAG) system for grounded drafting of chest radiograph impressions. The system combines contrastive image-text embeddings, case-based similarity retrieval, and citation-constrained draft generation to ensure factual alignment with historical radiology reports. A curated subset of the MIMIC-CXR dataset was used to construct a multimodal retrieval database. Image embeddings were generated using CLIP encoders, while textual embeddings were derived from structured impression sections. A fusion similarity framework was implemented using FAISS indexing for scalable nearest-neighbor retrieval. Retrieved cases were used to construct grounded prompts for draft impression generation, with safety mechanisms enforcing citation coverage and confidence-based refusal. Experimental results demonstrate that multimodal fusion significantly improves retrieval performance compared to image-only retrieval, achieving Recall@5 above 0.95 on clinically relevant findings. The grounded drafting pipeline produces interpretable outputs with explicit citation traceability, enabling improved trustworthiness compared to conventional generative approaches. This work highlights the potential of retrieval-augmented multimodal systems for reliable clinical decision support and radiology workflow augmentation Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.16984 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2603.16984v1 Announce Type: new Abstract: Many diatoms follow a size diminuation - size restoration cycle in their vegetative phase, leading to daughter cells that differ in size. For the diatom Seminavis robusta, we investigated by cell tracking over several generations whether the size difference reflects also in different intermitotic times or in the mobility of the cells. A tracking setup and machine-learning based detection algorithm was developed that revealed no significant difference in intermitotic times, a weak coupling to the day- night cycle, and a higher motility of the hypothecal, smaller daughter cell. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.16963 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2603.16963v1 Announce Type: new Abstract: Routine oncologic computed tomography (CT) presents an ideal opportunity for screening spinal instability, yet prophylactic stabilization windows are frequently missed due to the complex geometric reasoning required by the Spinal Instability Neoplastic Score (SINS). Automating SINS is fundamentally hindered by metastatic osteolysis, which induces topological ambiguity that confounds standard segmentation and black-box AI. We propose Topology-Guided Biomechanical Profiling (TGBP), an auditable white-box framework decoupling anatomical perception from structural reasoning. TGBP anchors SINS assessment on two deterministic geometric innovations: (i) canal-referenced partitioning to resolve posterolateral boundary ambiguity, and (ii) context-aware morphometric normalization via covariance-based oriented bounding boxes (OBB) to quantify vertebral collapse. Integrated with auxiliary radiomic and large language model (LLM) modules, TGBP provides an end-to-end, interpretable SINS evaluation. Validated on a multi-center, multi-cancer cohort ($N=482$), TGBP achieved 90.2\% accuracy in 3-tier stability triage. In a blinded reader study ($N=30$), TGBP significantly outperformed medical oncologists on complex structural features ($\kappa=0.857$ vs.\ $0.570$) and prevented compounding errors in Total Score estimation ($\kappa=0.625$ vs.\ $0.207$), democratizing expert-level opportunistic screening. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.17754 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2603.17754v1 Announce Type: new Abstract: Species sharing a habitat will co-evolve to make use of the available resources, as consumption is modulated by competition and negative feedback loops between consumers and resources. The dietary range of a given species determines the resources it has access to and thus the other species with which it competes. A narrow dietary range avoids competition at the cost of over-reliance on a small selection of resources; conversely a wide dietary range provides more alternatives but also more chance of competition with other species. Here, we investigate the evolution of dietary range within a mathematical model of niche formation. We find highly path dependent co-evolution dynamics characterised by long-lived quasi-stable states. Ultimately, stochastic effects drive the evolution of generalist diets, as we uncover in our analysis and simulations. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2511.12797 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2511.12797v3 Announce Type: replace-cross Abstract: In-context learning (ICL) -- the capacity of a model to infer and apply abstract patterns from examples provided within its input -- has been extensively studied in large language models trained for next-token prediction on human text. In fact, prior work often attributes this emergent behavior to distinctive statistical properties in human language. This raises a fundamental question: can ICL arise organically in other sequence domains purely through large-scale predictive training? To explore this, we turn to genomic sequences, an alternative symbolic domain rich in statistical structure. Specifically, we study the Evo2 genomic model, trained predominantly on next-nucleotide (A/T/C/G) prediction, at a scale comparable to mid-sized LLMs. We develop a controlled experimental framework comprising symbolic reasoning tasks instantiated in both linguistic and genomic forms, enabling direct comparison of ICL across genomic and linguistic models. Our results show that genomic models, like their linguistic counterparts, exhibit log-linear gains in pattern induction as the number of in-context demonstrations increases. To the best of our knowledge, this is the first evidence of organically emergent ICL in genomic sequences, supporting the hypothesis that ICL arises as a consequence of large-scale predictive modeling over rich data. These findings extend emergent meta-learning beyond language, pointing toward a unified, modality-agnostic view of in-context learning. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2503.21450 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2503.21450v2 Announce Type: replace-cross Abstract: AI-assisted protein design has emerged as a critical tool for advancing biotechnology, as deep generative models have demonstrated their reliability in this domain. However, most existing models primarily utilize protein sequence or structural data for training, neglecting the physicochemical properties of proteins.Moreover, they are deficient to control the generation of proteins in intuitive conditions. To address these limitations,we propose CMADiff here, a novel framework that enables controllable protein generation by aligning the physicochemical properties of protein sequences with text-based descriptions through a latent diffusion process. Specifically, CMADiff employs a Conditional Variational Autoencoder (CVAE) to integrate physicochemical features as conditional input, forming a robust latent space that captures biological traits. In this latent space, we apply a conditional diffusion process, which is guided by BioAligner, a contrastive learning-based module that aligns text descriptions with protein features, enabling text-driven control over protein sequence generation. Validated by a series of evaluations including AlphaFold3, the experimental results indicate that CMADiff outperforms protein sequence generation benchmarks and holds strong potential for future applications. The implementation and code are available at https://github.com/HPC-NEAU/PhysChemDiff. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.16957 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2603.16957v1 Announce Type: cross Abstract: Raman spectroscopy is a promising tool for microbial identification, yet its implementation in microbiology and clinical workflow is still restricted due to the accompanying additional preparation required to focus on microbial signals. Here, we demonstrate Raman-based bacterial identification directly from unopened, inverted agar plates, the same conditions used during incubation. Our approach enabled identification with single gene-level sensitivity using two Escherichia coli variants, differing only in green fluorescent protein (GFP) expression, across diverse media and substrate material conditions, despite the interrogation path traversing 3-4 mm thick background material. We integrated traditional density functional theory (DFT)-based material computation with machine learning analysis, achieving over 97.7% classification accuracy, surpassing the performance of standard measurements from opened plates by 10.8% higher mean accuracy and 0.76% less variance. We further demonstrated Raman mapping-based colony identification via Raman peaks characteristic to GFPmut3 chromophore structure generated by DFT. Our approach is robust to changes in algorithms or substrate materials and promises real-time, non-perturbative monitoring of bacterial growth, biofilm formation, and antimicrobial resistance development. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.17633 Thu, 19 Mar 2026 00:00:00 -0400 arXiv:2603.17633v1 Announce Type: new Abstract: Understanding the dynamic behavior of biomolecules is fundamental to elucidating biological function and facilitating drug discovery. While Molecular Dynamics (MD) simulations provide a rigorous physical basis for studying these dynamics, they remain computationally expensive for long timescales. Conversely, recent deep generative models accelerate conformation generation but are typically either failing to model temporal relationship or built only for monomeric proteins. To bridge this gap, we introduce ATMOS, a novel generative framework based on State Space Models (SSM) designed to generate atom-level MD trajectories for biomolecular systems. ATMOS integrates a Pairformer-based state transition mechanism to capture long-range temporal dependencies, with a diffusion-based module to decode trajectory frames in an autoregressive manner. ATMOS is trained across crystal structures from PDB and conformation trajectory from large-scale MD simulation datasets including mdCATH and MISATO. We demonstrate that ATMOS achieves state-of-the-art performance in generating conformation trajectories for both protein monomers and complex protein-ligand systems. By enabling efficient inference of atomic trajectory of motions, this work establishes a promising foundation for modeling biomolecular dynamics. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.12253 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.12253v2 Announce Type: replace Abstract: Absolute Binding Free Energy (ABFE) methods are among the most accurate computational techniques for predicting protein-ligand binding affinities, but their utility is limited by the need for many simulations of alchemically modified intermediate states. We propose Direct Binding Free Energy (DBFE), an end-state ABFE method in implicit solvent that requires no alchemical intermediates. DBFE outperforms OBC2 double decoupling on a host-guest benchmark and performs comparably to OBC2 MM/GBSA on a protein-ligand benchmark. Since receptor and ligand simulations can be precomputed and amortized across compounds, DBFE requires only one complex simulation per ligand compared to the many lambda windows needed for double decoupling, making it a promising candidate for virtual screening workflows. We publicly release the code for this method at https://github.com/molecularmodelinglab/dbfe. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.06819 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.06819v2 Announce Type: replace Abstract: Obesity does not emerge abruptly; rather, it develops gradually over extended periods. The gradual progression often prevents early recognition of physiological changes until excess adiposity is established. A common belief is that weight reduction can be achieved simply by "eating less and moving more". Although reductions in caloric intake and increases in physical activity are fundamental principles of weight management, this perspective oversimplifies a complex and adaptive biological system. Metabolic rate, hormonal regulation, behavioral factors, and compensatory physiological responses all influence the body's resistance to changes in weight. During weight loss, reduced metabolic rate and increased efficiency make maintaining a caloric deficit increasingly difficult. Conversely, during periods of overfeeding, resting metabolic rate, the thermic effect of food, and non-exercise activity thermogenesis increase with rising body weight, partially offsetting the caloric surplus and slowing weight gain. However, these compensatory responses are asymmetrical, with stronger and more persistent adaptations to underfeeding than to overfeeding. This asymmetry helps explain why weight gain often occurs gradually and why sustained weight loss is biologically challenging. In this work, we employ a lambda-omega model from dynamical systems theory to describe metabolic regulation in response to lifestyle perturbations. We introduce time-varying parameters that allow the regulatory coefficients to evolve gradually under sustained environmental and physiological stressors. By allowing lambda(t) and omega(t) to vary over time, the model captures progressive shifts in the metabolic set-point and deformation of the underlying dynamical landscape. This framework enables exploration of transitions between metabolic states and long-term adaptations that shape trajectories of weight gain and loss. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2211.13231 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2211.13231v3 Announce Type: replace Abstract: Heterogeneous molecular entities and their interactions, commonly depicted as a network, are crucial for advancing our systems-level understanding of biology. With recent advancements in high-throughput data generation and a significant improvement in computational power, graph neural networks (GNNs) have demonstrated their effectiveness in predicting biomedical interactions. Since GNNs follow a neighborhood aggregation scheme, the number of graph convolution (GC) layers (i.e., depth) determines the neighborhood orders from which they can aggregate information, thereby significantly impacting the model's performance. However, it often relies on heuristics or extensive experimentation to determine an appropriate GNN depth for a given biomedical network. These methods can be unreliable or result in expensive computational overhead. Moreover, GNNs with more GC layers tend to exhibit poor calibration, leading to high confidence in incorrect predictions. To address these challenges, we propose a Bayesian model selection framework to jointly infer the most plausible number of GC layers supported by the data, apply dropout regularization, and learn network parameters. Experiments on four biomedical interaction datasets demonstrate that our method achieves superior performance over competing methods, providing well-calibrated predictions by allowing GNNs to adapt their depths to accommodate interaction information from various biomedical networks. Source code and data is available at: https://github.com/kckishan/BBGCN-LP/tree/master Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.16789 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.16789v1 Announce Type: cross Abstract: We develop a conservative continuous-time stochastic control framework for treatment optimization from irregularly sampled patient trajectories. The unknown patient dynamics are modeled as a controlled stochastic differential equation with treatment as a continuous-time control. Naive model-based optimization can exploit model errors and propose out-of-support controls, so optimizing the estimated dynamics may not optimize the true dynamics. To limit extrapolation, we add a consistent signature-based MMD regularizer on path space that penalizes treatment plans whose induced trajectory distribution deviates from observed trajectories. The resulting objective minimizes a computable upper bound on the true cost. Experiments on benchmark datasets show improved robustness and performance compared to non-conservative baselines. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.16185 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.16185v1 Announce Type: cross Abstract: Predicting drug response in patients from preclinical data remains a major challenge in precision oncology due to the substantial biological gap between in vitro cell lines and patient tumors. Rather than aiming to improve absolute in vitro prediction accuracy, this work examines whether explicitly separating representation learning from task supervision enables more sample-efficient adaptation of drug-response models to patient data under strong biological domain shift. We propose a staged transfer-learning framework in which cellular and drug representations are first learned independently from large collections of unlabeled pharmacogenomic data using autoencoder-based representation learning. These representations are then aligned with drug-response labels on cell-line data and subsequently adapted to patient tumors using few-shot supervision. Through a systematic evaluation spanning in-domain, cross-dataset, and patient-level settings, we show that unsupervised pretraining provides limited benefit when source and target domains overlap substantially, but yields clear gains when adapting to patient tumors with very limited labeled data. In particular, the proposed framework achieves faster performance improvements during few-shot patient-level adaptation while maintaining comparable accuracy to single-phase baselines on standard cell-line benchmarks. Overall, these results demonstrate that learning structured and transferable representations from unlabeled molecular profiles can substantially reduce the amount of clinical supervision required for effective drug-response prediction, offering a practical pathway toward data-efficient preclinical-to-clinical translation. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.15711 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.15711v1 Announce Type: cross Abstract: Alkaptonuria (AKU) is an ultra-rare autosomal recessive metabolic disorder caused by mutations in the HGD (Homogentisate 1,2-Dioxygenase) gene, leading to a pathological accumulation of homogentisic acid (HGA) in body fluids and tissues. This leads to systemic manifestations, including premature spondyloarthropathy, renal and prostatic stones, and cardiovascular complications. Being ultra-rare, the amount of data related to the disease is limited, both in terms of clinical data and literature. Knowledge graphs (KGs) can help connect the limited knowledge about the disease (basic mechanisms, manifestations and existing therapies) with other knowledge; however, AKU is frequently underrepresented or entirely absent in existing biomedical KGs. In this work, we apply a text-mining methodology based on PubTator3 for large-scale extraction of biomedical relations. We construct two KGs of different sizes, validate them using existing biochemical knowledge and use them to extract genes, diseases and therapies possibly related to AKU. This computational framework reveals the systemic interactions of the disease, its comorbidities, and potential therapeutic targets, demonstrating the efficacy of our approach in analyzing rare metabolic disorders. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.16587 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.16587v1 Announce Type: new Abstract: We present HistoAtlas, a pan-cancer computational atlas that extracts 38 interpretable histomic features from 6,745 diagnostic H&E slides across 21 TCGA cancer types and systematically links every feature to survival, gene expression, somatic mutations, and immune subtypes. All associations are covariate-adjusted, multiple-testing corrected, and classified into evidence-strength tiers. The atlas recovers known biology, from immune infiltration and prognosis to proliferation and kinase signaling, while uncovering compartment-specific immune signals and morphological subtypes with divergent outcomes. Every result is spatially traceable to tissue compartments and individual cells, statistically calibrated, and openly queryable. HistoAtlas enables systematic, large-scale biomarker discovery from routine H&E without specialized staining or sequencing. Data and an interactive web atlas are freely available at https://histoatlas.com . Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.15175 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.15175v2 Announce Type: replace-cross Abstract: This lecture note provides a self-contained introduction to Bayesian inference and Markov Chain Monte Carlo (MCMC) methods for parameter estimation in epidemic models. Using the classical Susceptible-Infectious-Recovered (SIR) compartmental model as a running example, we derive the likelihood function from first principles, specify priors on the transmission and recovery parameters, and implement the Metropolis-Hastings algorithm to sample from the posterior distribution. The note is aimed at graduate students and researchers in mathematical epidemiology with limited prior exposure to Bayesian statistics. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.15217 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.15217v2 Announce Type: replace Abstract: Mathematical models of biological populations commonly use discrete structure classes to capture trait variation among individuals (e.g. age, size, phenotype, intracellular state). Upscaling these discrete models into continuum descriptions can improve analytical tractability and scalability of numerical solutions. Common upscaling approaches based solely on Taylor expansions may, however, introduce ambiguities in truncation order, uniform validity and boundary conditions. To address this, here we introduce a discrete multiscale framework to systematically derive continuum approximations of structured population models. Using the method of multiple scales and matched asymptotic expansions applied to discrete systems, we identify regions of structure space for which a continuum representation is appropriate and derive the corresponding partial differential equations. The leading-order dynamics are given by a nonlinear advection equation in the bulk domain and advection-diffusion processes in small inner layers about the leading wavefronts and stagnation point. We further derive discrete boundary layer descriptions for regions where a continuum representation is fundamentally inappropriate. Finally, we demonstrate the method on a simple lipid-structured model for early atherosclerosis and verify consistency between the discrete and continuum descriptions. The multiscale framework we present can be applied to other heterogeneous systems with discrete structure in order to obtain appropriate upscaled dynamics with asymptotically consistent boundary conditions. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2509.24657 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2509.24657v2 Announce Type: replace Abstract: West Nile virus (WNV) is a mosquito-borne virus in the genus Flavivirus that circulates between mosquitoes and birds, whereas humans, equids, and other mammals are dead-end hosts. Since its emergence in Germany in 2018, the virus has spread across the country, emphasising the need for effective intervention strategies. However, it remains unclear how different strategies should be combined and timed to effectively reduce WNV transmission under temperature-driven dynamics. In this study, we develop a temperature-dependent, process-based model to evaluate the effectiveness of WNV control strategies, such as mosquito reduction methods, equid vaccination, and the use of personal protective equipment (PPE). Human behavioural responses to infection risk are incorporated through imitation dynamics that capture how individuals adopt PPE based on perceived infection risk and social influence. An optimal control problem has been formulated and studied to determine the seasonal timing of mosquito controls under temperature forcing. Results suggest that mosquito control efforts initiated in early spring and intensified in early May, may reduce the August peak in the infectious bird population. Moreover, a combined scenario of mosquito control methods, human PPE adoption, and equid vaccination could be the best strategy among dead-end hosts. The analysis of various combinations of constant controls is available as an interactive application, allowing users to explore intervention strategies under different temperature projections corresponding to the low-mitigation (SSP126), intermediate (SSP245), and high-emission (SSP585) scenarios. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.16384 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.16384v1 Announce Type: cross Abstract: This study investigates a method to guide and control fish schools using virtual fish trained with reinforcement learning. We utilize 2D virtual fish displayed on a screen to overcome technical challenges such as durability and movement constraints inherent in physical robotic agents. To address the lack of detailed behavioral models for real fish, we adopt a model-free reinforcement learning approach. First, simulation results show that reinforcement learning can acquire effective movement policies even when simulated real fish frequently ignore the virtual stimulus. Second, real-world experiments with live fish confirm that the learned policy successfully guides fish schools toward specified target directions. Statistical analysis reveals that the proposed method significantly outperforms baseline conditions, including the absence of stimulus and a heuristic "stay-at-edge" strategy. This study provides an early demonstration of how reinforcement learning can be used to influence collective animal behavior through artificial agents. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.16773 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.16773v1 Announce Type: new Abstract: OBJECTIVE: To propose a new approach to analyze the age-distribution of reported cases for vector-transmitted infections. METHODS: Using officially reported number of cases of dengue, Zika, chikungunya, malaria and leishmaniasis for distinct geographical areas, in different periods. Data were treated in special but well-known procedure, transforming the raw data into a density age-dependent distribution and fitting a special continuous function to it. RESULTS: We found that the proportion of age-dependent cases with respect to the total number of cases in a given year (or any transmission season) is probably determined by the ecological interactions between vectors and hosts. The age-distribution of the proportion of cases for the three Aedes-related infections are essentially the same independently of the magnitude of the outbreak and the geographical region considered. On the other hand, for the infections transmitted by other vectors, the age-distributions of the proportion of cases are entirely different. CONCLUSIONS: During specific outbreaks, the ratio between the age distribution of the proportion of officially reported cases and the total number of cases for Aedes transmitted infections such as dengue, chikungunya and zika is independent of the size of the outbreak, the size of the studied population, the period when the outbreak occurs; and the geographical region considered. Our results also suggest that the age-distribution of cases is mainly due to the interaction between vectors and their hosts. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.12662 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.12662v3 Announce Type: replace Abstract: Objectively verifying the generative mechanism of consciousness is extremely difficult because of its subjective nature. As long as theories of consciousness focus solely on its generative mechanism, developing a theory remains challenging. We believe that broadening the theoretical scope and enhancing theoretical unification are necessary to establish a theory of consciousness. This study proposes seven questions that theories of consciousness should address: phenomena, self, causation, state, function, contents, and universality. The questions were designed to examine the functional aspects of consciousness and its applicability to system design. Next, we will examine how our proposed Dual-Laws Model (DLM) can address these questions. Based on our theory, we anticipate two unique features of a conscious system: autonomy in constructing its own goals and cognitive decoupling from external stimuli. We contend that systems with these capabilities differ fundamentally from machines that merely follow human instructions. This makes a design theory that enables high moral behavior indispensable. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2507.19416 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2507.19416v2 Announce Type: replace Abstract: Respiration is an essential involuntary function necessary for survival. This poses a challenge for the control of breathing. The preB\"otzinger complex (preB\"otC) is a heterogeneous neuronal network responsible for driving the inspiratory rhythm. While neuromodulators such as norepinephrine (NE) allow it to be both robust and flexible for all living beings to interact with their environment, the basis for how neuromodulation impacts neuron-specific properties remains poorly understood. In this work, we examine how NE influences different preB\"otC neuronal subtypes by modeling its effects through modulating two key parameters: calcium-activated nonspecific cationic current gating conductance ($g_{\rm CAN}$) and inositol-triphosphate ($\rm IP_3$), guided by experimental studies. Our computational model captures the experimentally observed differential effects of NE on distinct preB\"otC bursting patterns. We show that this dual mechanism is critical for inducing conditional bursting and identify specific parameter regimes where silent neurons remain inactive in the presence of NE. Furthermore, using methods of dynamical systems theory, we uncover the mechanisms by which NE differentially modulates burst frequency and duration in NaP-dependent and CAN-dependent bursting neurons. These results align well with previously reported experimental findings and provide a deeper understanding of cell-specific neuromodulatory responses within the respiratory network. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.16741 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.16741v1 Announce Type: cross Abstract: Objective. We establish a principled method for inferring mental health related psychometric variables from neural and behavioral data using the Implicit Association Test (IAT) as the data generation engine, aiming to overcome the limited predictive performance (typically under 0.7 AUC) of the gold-standard D-score method, which relies solely on reaction times. Approach. We propose a sparse hierarchical Bayesian model that leverages multi-modal data to predict experiences related to mental illness symptoms in new participants. The model is a multivariate generalization of the D-score with trainable parameters, engineered for parameter efficiency in the small-cohort regime typical of IAT studies. Data from two IAT variants were analyzed: a suicidality-related E-IAT ($n=39$) and a psychosis-related PSY-IAT ($n=34$). Main Results. Our approach overcomes a high inter-individual variability and low within-session effect size in the dataset, reaching AUCs of 0.73 (E-IAT) and 0.76 (PSY-IAT) in the best modality configurations, though corrected 95% confidence intervals are wide ($\pm 0.18$) and results are marginally significant after FDR correction ($q=0.10$). Restricting the E-IAT to MDD participants improves AUC to 0.79 $[0.62, 0.97]$ (significant at $q=0.05$). Performance is on par with the best reference methods (shrinkage LDA and EEGNet) for each task, even when the latter were adapted to the task, while the proposed method was not. Accuracy was substantially above near-chance D-scores (0.50-0.53 AUC) in both tasks, with more consistent cross-task performance than any single reference method. Significance. Our framework shows promise for enhancing IAT-based assessment of experiences related to entrapment and psychosis, and potentially other mental health conditions, though further validation on larger and independent cohorts will be needed to establish clinical utility. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.16281 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.16281v1 Announce Type: cross Abstract: Electroencephalography (EEG) is a widely used tool for studying brain function, with applications in clinical neuroscience, diagnosis, and brain-computer interfaces (BCIs). Recent EEG foundation models trained on large unlabeled corpora aim to learn transferable representations, but their effectiveness remains unclear; reported improvements over smaller task-specific models are often modest, sensitive to downstream adaptation and fine-tuning strategies, and limited under linear probing. We hypothesize that one contributing factor is the reliance on signal reconstruction as the primary self-supervised learning (SSL) objective, which biases representations toward high-variance artifacts rather than task-relevant neural structure. To address this limitation, we explore an SSL paradigm based on Joint Embedding Predictive Architectures (JEPA), which learn by predicting latent representations instead of reconstructing raw signals. While earlier JEPA-style methods often rely on additional heuristics to ensure training stability, recent advances such as LeJEPA provide a more principled and stable formulation. We introduce Laya, the first EEG foundation model based on LeJEPA. Across a range of EEG benchmarks, Laya demonstrates improved performance under linear probing compared to reconstruction-based baselines, suggesting that latent predictive objectives offer a promising direction for learning transferable, high-level EEG representations. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.16501 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.16501v1 Announce Type: new Abstract: Kangaroo mother care (KMC) is an intervention involving skin-to-skin contact that promotes physiological stability and supports long-term neurodevelopment in preterm infants. However, the underlying neurophysiological mechanisms remain unclear. We aimed to investigate the immediate effects of the first KMC on infants' brain function, mother-infant inter-brain synchrony, as well as their associations. Fifty-eight preterm infants (gestational age < 32 weeks or birth weight < 1500 g) and their mothers underwent synchronous dual-electroencephalography recording before and during the first KMC session. Infant brain function was assessed via power spectrum energy and graph theory-based network metrics, and mother-infant inter-brain synchrony was quantified using phase-locking value (PLV), from which inter-brain density and inter-brain strength were calculated. Correlation analyses were performed between infant intra-brain metrics and inter-brain synchrony indicators.During the first KMC, preterm infants showed enhanced theta, alpha, and beta power alongside reduced relative delta power, while brain network topological metrics remained stable. Concurrently, mother-infant inter-brain synchrony was significantly enhanced across all frequency bands, as evidenced by increased inter-brain density and strength (all p < .001). Furthermore, in the alpha band, inter-brain strength correlated positively with infant local efficiency and clustering coefficient, and in the beta band, it was positively correlated with infant small-worldness. The first KMC session can immediately enhance both preterm infant single-brain activity and mother-infant inter-brain synchrony. The strength of inter-brain synchrony is associated with the infant's intra-brain network organization, suggesting that KMC may promote intra-brain development in preterm infants via enhancing mother-infant inter-brain synchrony. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.16288 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.16288v1 Announce Type: new Abstract: Pain is strongly influenced by expectations and learning from previous experience, such as in classical conditioning. Conditioned responses and expectations can generalize to perceptually and conceptually related cues, but how generalization influences pain experience and the neurobiological processing of pain remains unclear. We used fMRI and multilevel mediation analyses to address this question. Thirty-six human participants first learned to associate two visual cues from distinct conceptual categories (e.g., animals vs. vehicles) with high or low levels of heat pain. In a subsequent phase, they were presented novel cues (images, drawings, or words) not previously paired with pain, but which shared the conceptual category of the initial pain-predictive cues. Participants who developed explicit expectations during learning reported greater pain in response to stimuli conceptually related to high-vs. low-pain cues ('generalization stimuli'), demonstrating generalization of cue influences on pain. This effect was mediated by increased pain-related activity to generalization stimuli in the hippocampus, which correlated with individual differences in cue-evoked expectations. A broader network, including areas of the default mode network and striatum, also contributed to conceptual generalization of pain modulation, while threat-related regions such as the amygdala responded to generalization stimuli but did not mediate effects on pain ratings. These findings extend our understanding of expectancy-driven pain modulation by showing how conceptual processes can influence pain and its neurobiological substrates, offering new insight into placebo effects and maladaptive learning in chronic pain. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2407.19892 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2407.19892v2 Announce Type: replace-cross Abstract: Motivation: Networks underlie the generation and interpretation of many biological datasets: gene networks shed light on the regulatory structure of the genome, and cell networks can capture structure of the tumor micro-environment. However, most methods that learn such networks make the faulty 'independence assumption'; to learn the gene network, they assume that no cell network exists. 'Multi-axis' methods, which do not make this assumption, fail to scale beyond a few thousand cells or genes. This limits their applicability to only the smallest datasets. Results: We develop a multi-axis method capable of processing million-cell datasets within minutes. This was previously impossible, and unlocks the use of such methods on modern scRNA-seq datasets, as well as more complex datasets. We show that our method yields novel biological insights from real single-cell data, and compares favorably to the existing hdWGCNA methodology. In particular, it identifies long non-coding RNA genes that potentially have a regulatory or functional role in neuronal development. Availability and implementation: Our methodology is available as a Python package GmGM on PyPI (https://pypi.org/project/GmGM/0.5.3/). The code for all experiments performed in this paper is available on GitHub (https://github.com/BaileyAndrew/GmGM-Bioinformatics). Contact: sceba@leeds.ac.uk Supplementary information: Our proofs, and some additional experiments, are available in the supplementary material. Keywords: gaussian graphical models, multi-axis models, transcriptomics, multi-omics, scalability Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.11872 Wed, 18 Mar 2026 00:00:00 -0400 arXiv:2603.11872v2 Announce Type: replace Abstract: Translating single-cell RNA sequencing (scRNA-seq) data into mechanistic biological hypotheses remains a critical bottleneck, as agentic AI systems lack direct access to transcriptomic representations while expression foundation models remain opaque to natural language. Here we introduce ELISA (Embedding-Linked Interactive Single-cell Agent), an interpretable framework that unifies scGPT expression embeddings with BioBERT-based semantic retrieval and LLM-mediated interpretation for interactive single-cell discovery. An automatic query classifier routes inputs to gene marker scoring, semantic matching, or reciprocal rank fusion pipelines depending on whether the query is a gene signature, natural language concept, or mixture of both. Integrated analytical modules perform pathway activity scoringacross 60+ gene sets, ligand--receptor interaction prediction using 280+ curated pairs, condition-aware comparative analysis, and cell-type proportion estimation all operating directly on embedded data without access to the original count matrix. Benchmarked across six diverse scRNA-seq datasets spanning inflammatory lung disease, pediatric and adult cancers, organoid models, healthy tissue, and neurodevelopment, ELISA significantly outperforms CellWhisperer in cell type retrieval (combined permutation test, $p < 0.001$), with particularly large gains on gene-signature queries (Cohen's $d = 5.98$ for MRR). ELISA replicates published biological findings (mean composite score 0.90) with near-perfect pathway alignment and theme coverage (0.98 each), and generates candidate hypotheses through grounded LLM reasoning, bridging the gap between transcriptomic data exploration and biological discovery. Code available at: https://github.com/omaruno/ELISA-An-AI-Agent-for-Expression-Grounded-Discovery-in-Single-Cell-Genomics.git (If you use ELISA in your research, please cite this work). Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.14806 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.14806v1 Announce Type: cross Abstract: Understanding cellular machinery requires atomic-scale reconstruction of large biomolecular assemblies. However, predicting the structures of these systems has been constrained by hardware memory requirements of models like AlphaFold 3, imposing a practical ceiling of a few thousand residues that can be processed on a single GPU. Here we present NVIDIA BioNeMo Fold-CP, a context parallelism framework that overcomes this barrier by distributing the inference and training pipelines of co-folding models across multiple GPUs. We use the Boltz models as open source reference architectures and implement custom multidimensional primitives that efficiently parallelize both the dense triangular updates and the irregular, data-dependent pattern of window-batched local attention. Our approach achieves efficient memory scaling; for an N-token input distributed across P GPUs, per-device memory scales as $O(N^2/P)$, enabling the structure prediction of assemblies exceeding 30,000 residues on 64 NVIDIA B300 GPUs. We demonstrate the scientific utility of this approach through successful developer use cases: Fold-CP enabled the scoring of over 90% of Comprehensive Resource of Mammalian protein complexes (CORUM) database, as well as folding of disease-relevant PI4KA lipid kinase complex bound to an intrinsically disordered region without cropping. By providing a scalable pathway for modeling massive systems with full global context, Fold-CP represents a significant step toward the realization of a virtual cell. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2602.23179 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2602.23179v2 Announce Type: replace-cross Abstract: Protein sequences are abundant in repeating segments, both as exact copies and as approximate segments with mutations. These repeats are important for protein structure and function, motivating decades of algorithmic work on repeat identification. Recent work has shown that protein language models (PLMs) identify repeats, by examining their behavior in masked-token prediction. To elucidate their internal mechanisms, we investigate how PLMs detect both exact and approximate repeats. We find that the mechanism for approximate repeats functionally subsumes that of exact repeats. We then characterize this mechanism, revealing two main stages: PLMs first build feature representations using both general positional attention heads and biologically specialized components, such as neurons that encode amino-acid similarity. Then, induction heads attend to aligned tokens across repeated segments, promoting the correct answer. Our results reveal how PLMs solve this biological task by combining language-based pattern matching with specialized biological knowledge, thereby establishing a basis for studying more complex evolutionary processes in PLMs. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2508.13201 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2508.13201v3 Announce Type: replace Abstract: Background: The surge in single-cell omics data exposes limitations in traditional, manually defined analysis workflows. AI agents offer a paradigm shift, enabling adaptive planning, executable code generation, traceable decisions, and real-time knowledge fusion. However, the lack of a comprehensive benchmark critically hinders progress. Results: We introduce a novel benchmarking evaluation system to rigorously assess agent capabilities in single-cell omics analysis. This system comprises: a unified platform compatible with diverse agent frameworks and LLMs; multidimensional metrics assessing cognitive program synthesis, collaboration, execution efficiency, bioinformatics knowledge integration, and task completion quality; and 50 diverse real-world single-cell omics analysis tasks spanning multi-omics, species, and sequencing technologies. Our evaluation reveals that Grok3-beta achieves state-of-the-art performance among tested agent frameworks. Multi-agent frameworks significantly enhance collaboration and execution efficiency over single-agent approaches through specialized role division. Attribution analyses of agent capabilities identify that high-quality code generation is crucial for task success, and self-reflection has the most significant overall impact, followed by retrieval-augmented generation (RAG) and planning. Conclusions: This work highlights persistent challenges in code generation, long-context handling, and context-aware knowledge retrieval, providing a critical empirical foundation and best practices for developing robust AI agents in computational biology. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.04748 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.04748v2 Announce Type: replace Abstract: Motivation: Receptor-binding proteins (RBPs) initiate viral infection and determine host specificity, serving as key targets for phage engineering and therapy. However, the identification of RBPs is complicated by their extreme sequence divergence, which often renders traditional homology-based alignment methods ineffective. While machine learning offers a promising alternative, such approaches struggle with severe class imbalance and the difficulty of selecting informative negative samples from heterogeneous tail proteins. Existing methods often fail to balance learning from these ``hard negatives'' while maintaining generalization. Results: We present SeekRBP, a sequence--structure framework that models negative sampling as a sequential decision-making problem. By employing a multi-armed bandit strategy, SeekRBP dynamically prioritizes informative non-RBP sequences based on real-time training feedback, complemented by a multimodal fusion of protein language and structural embeddings. Benchmarking demonstrates that SeekRBP consistently outperforms static sampling strategies. Furthermore, a case study on Vibrio phages validates that SeekRBP effectively identifies RBPs to improve host prediction, highlighting its potential for large-scale annotation and synthetic biology applications. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.15208 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.15208v1 Announce Type: new Abstract: This study investigates the cognitive motor control detection and the underlying neuroregulatory mechanisms during music-assisted simulated driving. Using a dynamic higher-order network model constructed with EEG-based cross-information entropy, we quantify the dynamic coordination within brain networks activated during both music listening and driving. This approach, which contrasts with previous static network analyses, provides novel insights into how musical stimuli modulate the complex interplay of brain regions during demanding tasks. Results demonstrated enhanced third-order connectivity and elevated higher-order information entropy in music-stimulated driving compared to baseline driving, as evidenced by increasing Phi values of higher-order network indices. Supervised machine learning, including support vector machines, revealed a strong correlation between model accuracy and ROC-AUC values and the hierarchy of brain network features. This underscores the importance of higher-order features in decoding brain motor-control states during music-simulated driving. These findings deepen our understanding of the interplay between music cognition and motor control, offering valuable insights for the development of novel brain-computer-music interfaces (BCMI) and adaptive human-machine systems to enhance performance in demanding tasks like driving. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.15339 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.15339v1 Announce Type: new Abstract: Neuroscience has long informed the development of artificial neural networks, but the success of modern architectures invites, in turn, the converse: can modern networks teach us lessons about brain function? Here, we examine the structure of the cortical column and propose that the transformer provides a natural computational analogy for multiple elements of cortical microcircuit organization. Rather than claiming a literal implementation of transformer equations in cortex, we develop a hypothetical mapping between transformer operations and laminar cortical features, using the analogy as an orienting framework for analysis and discussion. This mapping allows us to examine in greater depth how contextual selection, content routing, recurrent integration, and interlaminar transformations may be distributed across cortical circuitry. In doing so, we generate a broad set of predictions and experimentally testable hypotheses concerning laminar specialization, contextual modulation, dendritic integration, oscillatory coordination, and the effective connectivity of cortical columns. This proposal is intended as a structured hypothesis rather than a definitive account of cortical computation. Placing transformer operations and cortical architectonics into a common descriptive framework sharpens questions, reveals new functional correspondences, and opens a productive route for reciprocal exchange between systems neuroscience and modern AI. More broadly, this perspective suggests that comparing brains and architectures at the level of computational organization can yield genuine insight into both. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.13478 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.13478v1 Announce Type: cross Abstract: In a spiking neural network, is it enough for each neuron to spike at most once? In recent work, approximation bounds for spiking neural networks have been derived, quantifying how well they can fit target functions. However, these results are only valid for neurons that spike at most once, which is commonly thought to be a strong limitation. Here, we show that the opposite is true for a large class of spiking neuron models, including the commonly used leaky integrate-and-fire model with subtractive reset: for every approximation bound that is valid for a set of multi-spike neural networks, there is an equivalent set of single-spike neural networks with only linearly more neurons (in the maximum number of spikes) for which the bound holds. The same is true for the reverse direction too, showing that regarding their approximation capabilities in general machine learning tasks, single-spike and multi-spike neural networks are equivalent. Consequently, many approximation results in the literature for single-spike neural networks also hold for the multi-spike case. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.13994 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.13994v1 Announce Type: cross Abstract: Vision foundation models trained with self-supervised objectives achieve strong performance across diverse tasks and exhibit emergent object segmentation properties. However, their alignment with human object perception remains poorly understood. Here, we introduce a behavioral benchmark in which participants make same/different object judgments for dot pairs on naturalistic scenes, scaling up a classical psychophysics paradigm to over 1000 trials. We test a diverse set of vision models using a simple readout from their representations to predict subjects' reaction times. We observe a steady improvement across model generations, with both architecture and training objective contributing to alignment, and transformer-based models trained with the DINO self-supervised objective showing the strongest performance. To investigate the source of this improvement, we propose a novel metric to quantify the object-centric component of representations by measuring patch similarity within and between objects. Across models, stronger object-centric structure predicts human segmentation behavior more accurately. We further show that matching the Gram matrix of supervised transformer models, capturing similarity structure across image patches, with that of a self-supervised model through distillation improves their alignment with human behavior, converging with the prior finding that Gram anchoring improves DINOv3's feature quality. Together, these results demonstrate that self-supervised vision models capture object structure in a behaviorally human-like manner, and that Gram matrix structure plays a role in driving perceptual alignment. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.14161 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.14161v1 Announce Type: cross Abstract: Many disciplines need quantitative models that synthesize experimental data across multiple instances of the same general system. For example, neuroscientists must combine data from the brains of many individual animals to understand the species' brain in general. However, typical machine learning models treat one system instance at a time. Here we introduce a machine learning framework, deep probabilistic model synthesis (DPMS), that leverages system properties auxiliary to the model to combine data across system instances. DPMS specifically uses variational inference to learn a conditional prior distribution and instance-specific posterior distributions over model parameters that respectively tie together the system instances and capture their unique structure. DPMS can synthesize a wide variety of model classes, such as those for regression, classification, and dimensionality reduction, and we demonstrate its ability to improve upon single-instance models on synthetic data and whole-brain neural activity data from larval zebrafish. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2506.17083 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2506.17083v2 Announce Type: replace Abstract: Traditional artificial neural networks consist of nodes with non-oscillatory dynamics. Biological neural networks, on the other hand, consist of oscillatory components embedded in an oscillatory environment. Motivated by this feature of biological neurons, we describe a neural network framework with explicit damped, oscillatory node dynamics. We express the oscillatory dynamics using two history dependent terms to connect these dynamics with standard recurrent neural network formulations, apply physical constraints from observed brain dynamics to choose the oscillatory frequencies, and stationary constraints to reduce the number of free parameters. We then optimize and illustrate network performance by classifying hand-written digits and simulated neuronal spike train activity and show that these oscillatory network elements support accurate classification with few trainable parameters. Choosing oscillator frequencies according to a proposed theory for brain rhythms improves classification accuracy compared to alternative frequency configurations and compared to standard recurrent neural network frameworks with comparable numbers of parameters. Compared to existing approaches, the proposed resonant recurrent network (RRN) utilizes oscillatory dynamics expressed as a straightforward extension of standard recurrent neural networks, produces interpretable features for classification, and performs well with few parameters when oscillator frequencies follow a configuration observed in vivo. We propose that RRNs may serve as efficient, biologically inspired building blocks to achieve complex goals in biological and artificial neural networks. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2507.16495 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2507.16495v2 Announce Type: replace Abstract: Neurons communicate with downstream systems via sparse and incredibly brief electrical pulses, or spikes. Using these events, they control various targets such as neuromuscular units, neurosecretory systems, and other neurons in connected circuits. This gave rise to the idea of spiking neurons as controllers, in which spikes are the control signal. Using instantaneous events directly as the control inputs, also called `impulse control', is challenging as it does not scale well to larger networks and has low analytical tractability. Therefore, current spiking control usually relies on filtering the spike signal to approximate analog control. This ultimately means spiking neural networks (SNNs) have to output a continuous control signal, necessitating continuous energy input into downstream systems. Here, we circumvent the need for rate-based representations, providing a scalable method for task-specific spiking control with sparse neural activity. In doing so, we take inspiration from both optimal control and neuroscience theory, and define a spiking rule where spikes are only emitted if they bring a dynamical system closer to a target. From this principle, we derive the required connectivity for an SNN, and show that it can successfully control linear systems. We show that for physically constrained systems, predictive control is required, and the control signal ends up exploiting the passive dynamics of the downstream system to reach a target. Finally, we show that the control method scales to both high-dimensional networks and systems. Importantly, in all cases, we maintain a closed-form mathematical derivation of the network connectivity, the network dynamics and the control objective. This work advances the understanding of SNNs as biologically-inspired controllers, providing insight into how real neurons could exert control, and enabling applications in neuromorphic hardware design. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2512.15891 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2512.15891v5 Announce Type: replace Abstract: In the last century, most sensorimotor studies of cortical neurons relied on average firing rates. Rate coding is efficient for fast sensorimotor processing that occurs within a few seconds. Much less is known about the neural mechanisms underlying long-term working memory with a time scale of hours (Ericsson and Kintsch, 1995). Cognitive states may not have sensory or motor correlates. For example, you can sit in a quiet room making plans without moving or sensory processing. You can also make plans while out walking. This suggests that the neural substrate for cognitive states neither depends on nor interferes with ongoing sensorimotor brain activity. In this perspective, I make the case for a possible second tier of neural activity that coexists with the well-established sensorimotor tier, based on coordinated spike-timing activity. The discovery of millisecond-precision spike initiation in cortical neurons was unexpected (Mainen and Sejnowski, 1995). Even more striking was the precision of spiking in vivo, in response to rapidly fluctuating sensory inputs, suggesting that neural circuits could preserve and manipulate sensory information through spike timing. High temporal resolution can also mediate spike-timing-dependent plasticity (STDP) by controlling the relative timing of presynaptic and postsynaptic spikes at the millisecond scale. Cortical traveling waves with high temporal precision are observed across many frequency bands. They can plausibly trigger STDP that lasts for hours in cortical neurons. This temporary cortical network, riding astride the long-term sensorimotor network, could support cognitive processing and long-term working memory. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.18946 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2601.18946v2 Announce Type: replace Abstract: Schemas -- abstract relational structures that capture the commonalities across experiences -- are thought to underlie humans' and animals' ability to rapidly generalize knowledge, rebind new experiences to existing structures, and flexibly adapt behavior across contexts. Despite their central role in cognition, the computational principles and neural mechanisms supporting schema formation and use remain elusive. Here, we introduce schema-based hierarchical active inference (S-HAI), a novel computational framework that combines predictive processing and active inference with schema-based mechanisms. In S-HAI, a higher-level generative model encodes abstract task structure, while a lower-level model encodes spatial navigation, with the two levels linked by a grounding likelihood that maps abstract goals to physical locations. Through a series of simulations, we show that S-HAI reproduces key behavioral signatures of rapid schema-based generalization in spatial navigation tasks, including the ability to flexibly remap abstract schemas onto novel contexts, resolve goal ambiguity, and balance reuse versus accommodation of novel mappings. Crucially, S-HAI also reproduces prominent neural codes reported in rodent medial prefrontal cortex during a schema-dependent navigation and decision task, including task-invariant goal-progress cells, goal-and-spatially conjunctive cells, and place-like codes at the lower level. Taken together, these results provide a mechanistic account of schema-based learning and inference that bridges behavior, neural data, and theory. More broadly, our findings suggest that schema formation and generalization may arise from predictive processing principles implemented hierarchically across cortical and hippocampal circuits, enabling the generalization of experience. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2602.17820 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2602.17820v2 Announce Type: replace Abstract: From 1/f noise to neuronal avalanches, evidence of scaling in brain activity has been increasingly linked to tuning to or near criticality. The concept of scaling is intimately related to the renormalization group (RG), in essence providing coarse-grained, simplified descriptions that generalize to classes of diverse physical systems. Following the RG idea, scaling laws have been reported in populations of spiking neurons at microscopic scales. Whether similar scaling principles govern large-scale neural activity in the human brain and how they relate to underlying neural physiology remains unresolved. Here, we analyze large-scale electrophysiological recordings (MEG) of human resting-state brain activity and apply a RG-inspired coarse-graining approach to track collective neural dynamics across spatial scales. We find that multiple observables exhibit robust scale-invariant behavior under coarse-graining: activity variance and correlations grow according to power laws, covariance eigenspectra follow a characteristic scaling relation, and neuronal avalanche statistics remain invariant. Using an analytically tractable neural network model, we show that the observed scaling signatures arise when the system operates slightly below criticality, and that the scaling exponents depend on the excitation-inhibition balance. These findings demonstrate that RG-inspired scaling analysis can uncover signatures of critical dynamics in non-invasive human electrophysiology and suggest a principled route toward estimating excitation-inhibition balance from large-scale brain recordings. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.12279 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.12279v2 Announce Type: replace Abstract: Intracranial language brain-computer interfaces (BCIs) are a promising route for restoring communication in people with severe motor and speech impairments, but clinical translation remains limited by fragmented evidence and unresolved design trade-offs across neuroscience, hardware, algorithm, evaluation, and clinical deployment. This review synthesizes progress in neural mechanisms of overt, mimed, and imagined speech; decision-oriented hardware comparisons of microelectrode array (MEA), electrocorticography (ECoG), and stereotactic electroencephalography (SEEG) recording modalities; experiment design for cross-subject and multilingual generalization; and neural decoding advances spanning sequence models, transformers, articulatory intermediates, and language-prior-assisted frameworks. We highlight persistent bottlenecks, including weak cross-subject transfer, long-term non-stationarity and recalibration burden, heterogeneous and non-comparable evaluation practices, limited naturalistic expressivity (especially for tonal/logosyllabic languages), and low signal-to-noise ratio (SNR) of neural activity in covert speech decoding. Our contributions are threefold: (1) an end-to-end, decision-oriented synthesis linking neural representations to recording choices, experimental design, decoding model architectures, and translational constraints; (2) a structured framework organized around five coupled design questions, together with a unified evaluation framework and a cross-language/cross-task benchmark template integrating objective, perceptual, expressive, conversational, and longitudinal metrics; and (3) user-centered translational guidance covering agency-preserving shared control, verifiable performance priorities, and scenario-specific minimum viable system (MVP) profiles for reliability-first home communication versus fidelity-first conversational speech restoration. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.12286 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.12286v2 Announce Type: replace Abstract: Modern neuroscience has accumulated extensive evidence on perception, memory, prediction, valuation, and consciousness, yet still lacks an explicit operational architecture capable of integrating these phenomena within a unified computational framework. Existing theories address specific aspects of neural function: predictive coding and active inference emphasize hierarchical inference and prediction error minimization; engram theories explain memory through distributed cell assemblies; neuromodulatory accounts focus on value-dependent regulation of plasticity and behaviour; and global workspace or large-scale network models investigate mechanisms underlying conscious access. Despite their explanatory power, these approaches remain only partially integrated at the architectural level. This work introduces DIME (Detect-Integrate-Mark-Execute), a neural architecture organizing perception, memory, valuation, and conscious access within a common operational cycle. The framework includes four interacting components: engrams, distributed recurrent neural structures supporting multiple activation trajectories; execution threads, spatiotemporal trajectories implementing neural processes; marker systems, neuromodulatory and limbic mechanisms regulating gain, plasticity, and trajectory selection; and hyperengrams, large-scale integrative states associated with operational conscious access. The framework is consistent with empirical evidence from hippocampal indexing, recurrent cortical processing, replay phenomena, large-scale network integration, and neuromodulatory regulation. Formulated at an abstract computational level, DIME may also inform artificial intelligence and robotics by providing an architectural template in which representation, valuation, and temporal sequencing emerge from a unified mechanism. An extended theoretical exposition is available in a companion monograph on Zenodo. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2506.02164 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2506.02164v4 Announce Type: replace-cross Abstract: Previous studies have compared neural activities in the visual cortex to representations in deep neural networks trained on image classification. Interestingly, while some suggest that their representations are highly similar, others argued the opposite. Here, we propose a new approach to characterize the similarity of the decision strategies of two observers (models or brains) using decision variable correlation (DVC). DVC quantifies the image-by-image correlation between the decoded decisions based on the internal neural representations in a classification task. Thus, it can capture task-relevant information rather than general representational alignment. We evaluate DVC using monkey V4/IT recordings and network models trained on image classification tasks. We find that model-model similarity is comparable to monkey-monkey similarity, whereas model-monkey similarity is consistently lower. Strikingly, DVC decreases with increasing network performance on ImageNet-1k. Adversarial training does not improve model-monkey similarity in task-relevant dimensions assessed using DVC, although it markedly increases the model-model similarity. Similarly, pre-training on larger datasets does not improve model-monkey similarity. These results suggest a divergence between the task-relevant representations in monkey V4/IT and those learned by models trained on image classification tasks. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.15198 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.15198v1 Announce Type: new Abstract: We develop a generally covariant description of evolutionary dynamics that operates consistently in both genotype and phenotype spaces. We show that the maximum entropy principle yields a fundamental identification between the inverse metric tensor and the covariance matrix, revealing the Lande equation as a covariant gradient ascent equation. This demonstrates that evolution can be modeled as a learning process on the fitness landscape, with the specific learning algorithm determined by the functional relation between the metric tensor and the noise covariance arising from microscopic dynamics. While the metric (or the inverse genotypic covariance matrix) has been extensively characterized empirically, the noise covariance and its associated observable (the covariance of evolutionary changes) have never been directly measured. This poses the experimental challenge of determining the functional form relating metric to noise covariance. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.14711 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2603.14711v1 Announce Type: cross Abstract: During the COVID-19 crisis, policymakers have implemented "social bubble" merging strategies, which allowed people from different households to meet and interact. Although these measures can mitigate the negative effects of extreme isolation, they also introduce additional contacts that may facilitate disease spread. As a result, several modeling studies have explored the epidemiological impact of different household-merging strategies, in which the selection of households to be merged is guided by specific demographic criteria, such as household size or the age composition of their members. Here we investigate an alternative pairing strategy in which households are merged according to the number of economically active (working) members. We develop a mathematical model of household networks using real demographic data from multiple regions around the world, and simulate a lockdown scenario in which only economically active individuals can leave their households, while the remaining non-working members stay indoors. By using numerical simulations and the generating function technique, we then estimate the epidemic risk for different household merging strategies. We found that merging strategies based on the number of working members can keep epidemic risk at similar levels as those based on household size. Moreover, the worker-based approach allows significantly more people to form larger social bubbles, exceeding 40\% of the population in some countries. We found that merging households with at most one worker provides the best balance between controlling epidemic risk and addressing people's need for social contact. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2504.14728 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2504.14728v3 Announce Type: replace-cross Abstract: We present a unified geometric framework for modeling learning dynamics in physical, biological, and machine learning systems. The theory reveals three fundamental regimes, each emerging from the power-law relationship $g \propto \kappa^\alpha$ between the metric tensor $g$ in the space of trainable variables and the noise covariance matrix $\kappa$. The quantum regime corresponds to $\alpha = 1$ and describes Schr\"odinger-like dynamics that emerges from a discrete shift symmetry. The efficient learning regime corresponds to $\alpha = \tfrac{1}{2}$ and describes very fast machine learning algorithms. The equilibration regime corresponds to $\alpha = 0$ and describes classical models of biological evolution. We argue that the emergence of the intermediate regime $\alpha = \tfrac{1}{2}$ is a key mechanism underlying the emergence of biological complexity. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2601.04434 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2601.04434v2 Announce Type: replace-cross Abstract: Men who have sex with men (MSM) remain disproportionately affected by HIV, yet optimizing Pre-exposure Prophylaxis (PrEP) distribution remains a public health challenge. Current guidelines and most modelling studies do not incorporate sociodemographic or network-level factors that shape transmission. While network reconstruction from egocentric data has been studied, the relative importance of demographic mixing dimensions remains uncertain. Using data from 4,667 MSM participants, we show that uncertainty in network reconstruction from egocentric survey data - specifically whether assortativity by age or race is incorporated - affects simulated HIV prevalence under the same observed PrEP uptake. We simulate HIV transmission over 50 years across this structural space and evaluate whether empirically observed uptake reaches transmission-critical network positions. Network structure strongly influences outcomes: assortative by degree networks show 17% lower equilibrium prevalence due to hub isolation within communities. Targeted PrEP strategies based on degree or k-shell centrality achieved the highest prevalence reductions, particularly in assortative by age and race networks where hubs bridge demographic groups. PrEP uptake from data is suboptimal in assortative by age and race networks, underperforming compared with network-based strategies. Results demonstrate that uncertainty in network reconstruction affects intervention design and highlight the need for robust prevention strategies under structural ambiguity. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2602.18982 Tue, 17 Mar 2026 00:00:00 -0400 arXiv:2602.18982v3 Announce Type: replace-cross Abstract: Common deep learning approaches for antibody engineering focus on modeling the marginal distribution of sequences. By treating sequences as independent samples, however, these methods overlook affinity maturation as a rich and largely untapped source of information about the evolutionary process by which antibodies explore the underlying fitness landscape. In contrast, classical phylogenetic models explicitly represent evolutionary dynamics but lack the expressivity to capture complex epistatic interactions. We bridge this gap with CoSiNE, a continuous-time Markov chain parameterized by a deep neural network. Mathematically, we prove that CoSiNE provides a first-order approximation to the intractable sequential point mutation process, capturing epistatic effects with an error bound that is quadratic in branch length. Empirically, CoSiNE outperforms state-of-the-art language models in zero-shot variant effect prediction by explicitly disentangling selection from context-dependent somatic hypermutation. Finally, we introduce Guided Gillespie, a classifier-guided sampling scheme that steers CoSiNE at inference time, enabling efficient optimization of antibody binding affinity toward specific antigens. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.13126 Mon, 16 Mar 2026 00:00:00 -0400 arXiv:2603.13126v1 Announce Type: new Abstract: This study presents the development of the PsyCogMetrics AI Lab (psycogmetrics.ai), an integrated, cloud-based platform that operationalizes psychometric and cognitive-science methodologies for Large Language Model (LLM) evaluation. Framed as a three-cycle Action Design Science study, the Relevance Cycle identifies key limitations in current evaluation methods and unfulfilled stakeholder needs. The Rigor Cycle draws on kernel theories such as Popperian falsifiability, Classical Test Theory, and Cognitive Load Theory to derive deductive design objectives. The Design Cycle operationalizes these objectives through nested Build-Intervene-Evaluate loops. The study contributes a novel IT artifact, a validated design for LLM evaluation, benefiting research at the intersection of AI, psychology, cognitive science, and the social and behavioral sciences. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.10161 Mon, 16 Mar 2026 00:00:00 -0400 arXiv:2603.10161v2 Announce Type: replace Abstract: The biomedical literature contains a vast collection of omics studies, yet most published data remain functionally inaccessible for computational reuse. When raw data are deposited in public repositories, essential information for reproducing reported results is dispersed across main text, supplementary files, and code repositories. In rarer instances where intermediate data is made available (e.g. protein abundance files), its location is irregular. In this article, we present an agentic framework that fetches omics-related articles and transforms the unstructured information into searchable research objects. Our system employs large language model (LLM) agents with access to tools for fetching omics studies, extracting article metadata, identifying and downloading published data, executing containerized quantification pipelines, and running analyses to address novel question. We demonstrate automated metadata extraction from PubMed Central articles, achieving 80% precision for dataset identification from standard data repositories. Using model context protocol (MCP) servers to expose containerized analysis tools, our set of agents were able to identify a set of relevant articles, download the associated datasets, and re-quantify the proteomics data. The results had a 63% overlap in differentially expressed proteins when matching reported preprocessing methods. Furthermore, we show that agents can identify semantically similar studies, determine data compatibility, and perform cross-study comparisons, revealing consistent protein regulation patterns in liver fibrosis. This work establishes a foundation for converting the static biomedical literature into an executable, queryable resource that enables automated data reuse at scale. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2507.20205 Mon, 16 Mar 2026 00:00:00 -0400 arXiv:2507.20205v5 Announce Type: replace Abstract: Accurately characterizing higher-order interactions of brain regions and extracting interpretable organizational patterns from Functional Magnetic Resonance Imaging data is crucial for brain disease diagnosis. Current graph-based deep learning models primarily focus on pairwise or triadic patterns while neglecting signed higher-order interactions, limiting comprehensive understanding of brain-wide communication. We propose HOI-Brain, a novel computational framework leveraging signed higher-order interactions and organizational patterns in fMRI data for brain disease diagnosis. First, we introduce a co-fluctuation measure based on Multiplication of Temporal Derivatives to detect higher-order interactions with temporal resolution. We then distinguish positive and negative synergistic interactions, encoding them in signed weighted simplicial complexes to reveal brain communication insights. Using Persistent Homology theory, we apply two filtration processes to these complexes to extract signed higher-dimensional neural organizations spatiotemporally. Finally, we propose a multi-channel brain Transformer to integrate heterogeneous topological features. Experiments on Alzheimer' s disease, Parkinson' s syndrome, and autism spectrum disorder datasets demonstrate our framework' s superiority, effectiveness, and interpretability. The identified key brain regions and higher-order patterns align with neuroscience literature, providing meaningful biological insights. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2511.07024 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2511.07024v2 Announce Type: replace Abstract: For several decades, experimental and computational studies have been used to investigate the potential functional role of knots in protein structures. A property that has attracted considerable attention is thermal stability, i.e., the extent to which a protein retains its native conformation and biological activity at high temperatures, without undergoing denaturation or aggregation. Thermal stability is quantified by the melting temperature Tm, an equilibrium property that corresponds to the peak of heat capacity in differential scanning calorimetry (DSC) experiments. Experimental and computational studies report conflicting effects of knotting on protein thermal stability. Here, we use extensive Monte Carlo simulations of a simple C-alpha model of protein YibK, with energetics modeled by the Go potential, to show that Tm does not depend on the topological state of the protein. Our simulations further support the view that the discrepancy between the experimental and computational results stems from a pronounced separation of timescales for unknotting and unfolding that is inherent to deeply knotted proteins like YibK. In particular, the timescale separation implies that the complete unfolding-untying transition may not be accessible within the duration of a DSC experiment, whose apparent Tm measurements likely reflect a non-equilibrium distribution lacking unfolded states that are also unknotted. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.11244 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2603.11244v1 Announce Type: new Abstract: The rapid development of generative models for single-cell gene expression data has created an urgent need for standardised evaluation frameworks. Current evaluation practices suffer from inconsistent metric implementations, incomparable hyperparameter choices, and a lack of biologically-grounded metrics. We present Generated Genetic Expression Evaluator (GGE), an open-source Python framework that addresses these challenges by providing a comprehensive suite of distributional metrics with explicit computation space options and biologically-motivated evaluation through differentially expressed gene (DEG)-focused analysis and perturbation-effect correlation, enabling standardized reporting and reproducible benchmarking. Through extensive analysis of the single-cell generative modeling literature, we identify that no standardized evaluation protocol exists. Methods report incomparable metrics computed in different spaces with different hyperparameters. We demonstrate that metric values vary substantially depending on implementation choices, highlighting the critical need for standardization. GGE enables fair comparison across generative approaches and accelerates progress in perturbation response prediction, cellular identity modeling, and counterfactual inference. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.12073 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2603.12073v1 Announce Type: cross Abstract: Transcription factors (TFs) regulate gene expression through complex and co-operative mechanisms. While many TFs act together, the logic underlying TFs binding and their interactions is not fully understood yet. Most current approaches for TF binding site prediction focus on individual TFs and binary classification tasks, without a full analysis of the possible interactions among various TFs. In this paper we investigate DNA TF binding site recognition as a multi-label classification problem, achieving reliable predictions for multiple TFs on DNA sequences retrieved in public repositories. Our deep learning models are based on Temporal Convolutional Networks (TCNs), which are able to predict multiple TF binding profiles, capturing correlations among TFs andtheir cooperative regulatory mechanisms. Our results suggest that multi-label learning leading to reliable predictive performances can reveal biologically meaningful motifs and co-binding patterns consistent with known TF interactions, while also suggesting novel relationships and cooperation among TFs. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2602.21550 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2602.21550v2 Announce Type: replace-cross Abstract: Gene expression prediction, which predicts mRNA expression levels from DNA sequences, presents significant challenges. Previous works often focus on extending input sequence length to locate distal enhancers, which may influence target genes from hundreds of kilobases away. Our work first reveals that for current models, long sequence modeling can decrease performance. Even carefully designed algorithms only mitigate the performance degradation caused by long sequences. Instead, we find that proximal multimodal epigenomic signals near target genes prove more essential. Hence we focus on how to better integrate these signals, which has been overlooked. We find that different signal types serve distinct biological roles, with some directly marking active regulatory elements while others reflect background chromatin patterns that may introduce confounding effects. Simple concatenation may lead models to develop spurious associations with these background patterns. To address this challenge, we propose Prism, a framework that learns multiple combinations of high-dimensional epigenomic features to represent distinct background chromatin states and uses backdoor adjustment to mitigate confounding effects. Our experimental results demonstrate that proper modeling of multimodal epigenomic signals achieves state-of-the-art performance using only short sequences for gene expression prediction. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2405.08979 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2405.08979v3 Announce Type: replace-cross Abstract: A challenge in drug response prediction is result interpretation compared to established knowledge. drGT is a graph deep learning model that predicts sensitivity and aids in biomarker identification using attention coefficients (ACs). drGT leverages a heterogeneous graph composed of relationships drawn from drugs, genes, and cell line responses. The model is trained and evaluated using major benchmark datasets: Sanger GDSC, NCI60, and Broad CTRP, which cover a wide range of drugs and cancer cell lines. drGT demonstrates AUROC of up to 94.5% under random splitting, 84.4% for unseen drugs, and 70.6% for unseen cell lines, comparable to existing benchmark methods while also providing interpretability. Regarding interpretability, we review drug-gene co-occurrences by text-mining PubMed abstracts for high-coefficient genes mentioning particular drugs. Across 976 drugs from NCI60 with known drug-target interactions (DTIs), model predictions utilized both known DTIs (36.9%) as well as additional predictive associations, many supported by literature. In addition, we compare the drug-gene associations identified by drGT with those from an established DTI prediction model and find that 63.67% are supported by either PubMed literature or predictions from the DTI model. Further, we describe the utilization of ACs to identify affected biological processes by each drug via enrichment analyses, thereby enhancing biological interpretability. Code is available at https://github.com/sciluna/drGT. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2603.11347 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2603.11347v1 Announce Type: new Abstract: The study of navigation behaviour and the associated brain dynamics have been a focus increasing research over the last decades. Coinciding with this has been an increased focus on a more ecological understanding of cognition. Here we review recent research seeking to provide a more naturalistic, ecological understanding of human navigation behaviour and brain dynamics. Research in this area falls into four categories: testing navigation in real-world environments, analysis of data collected from tracking individuals during daily life, navigation in simulated or virtual environments mimicking the real-world, and mobile brain recording methods. Combining these different approaches to understand the neural basis of navigation shows excellent promise. We conclude with future directions for this research area. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.11663 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2603.11663v1 Announce Type: new Abstract: Representations learned by convolutional neural networks (CNNs) exhibit a remarkable resemblance to information processing patterns observed in the primate visual system on large neuroimaging datasets collected under diverse, naturalistic visual stimulation, but with instruction for participants to maintain central fixation. This viewing condition, however, diverges significantly from ecologically valid visual behaviour, suppresses activity in visually active regions, and imposes substantial cognitive load on the viewing task. We present a modification of the encoding model framework, adapting it for use with naturalistic vision datasets acquired under fully natural viewing conditions, without fixation, by incorporating eye-tracking data. Our gaze-aware encoding models were trained on the StudyForrest dataset, which features task-free naturalistic movie viewing. By combining eye-tracking data with the visual content of movie frames, we generate combined subject-wise gaze-stimulus specific feature time series. These time series are constructed by sampling only the locally and temporally relevant elements of the CNN feature map for each fixation. Our results demonstrate that gaze-aware encoding models match the performance of conventional encoding models with 112x fewer model parameters. Gaze-aware encoding models were especially beneficial for participants with more dynamic eye-movement patterns. Therefore, this approach opens the door to more ecologically valid models that can be built in more naturalistic settings, such as playing games or navigating virtual environments. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.09600 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2603.09600v2 Announce Type: replace Abstract: Brains remain unrivaled in their ability to recognize and generate complex spatiotemporal patterns. While AI is able to reproduce some of these capabilities, deep learning algorithms remain largely at odds with our current understanding of brain circuitry and dynamics. This is prominently the case for backpropagation through time (BPTT), the go-to algorithm for learning complex temporal dependencies. In this work we propose a general formalism to approximate BPTT in a controlled, biologically plausible manner. Our approach builds on, unifies and extends several previous approaches to local, time-continuous, phase-free spatiotemporal credit assignment based on principles of energy conservation and extremal action. Our starting point is a prospective energy function of neuronal states, from which we calculate real-time error dynamics for time-continuous neuronal networks. In the general case, this provides a simple and straightforward derivation of the adjoint method result for neuronal networks, the time-continuous equivalent to BPTT. With a few modifications, we can turn this into a fully local (in space and time) set of equations for neuron and synapse dynamics. Our theory provides a rigorous framework for spatiotemporal deep learning in the brain, while simultaneously suggesting a blueprint for physical circuits capable of carrying out these computations. These results reframe and extend the recently proposed Generalized Latent Equilibrium (GLE) model. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03190 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2603.03190v2 Announce Type: replace-cross Abstract: During music listening, cortical activity encodes both acoustic and expectation-related information. Prior work has shown that ANN representations resemble cortical representations and can serve as supervisory signals for EEG recognition. Here we show that distinguishing acoustic and expectation-related ANN representations as teacher targets improves EEG-based music identification. Models pretrained to predict either representation outperform non-pretrained baselines, and combining them yields complementary gains that exceed strong seed ensembles formed by varying random initializations. These findings show that teacher representation type shapes downstream performance and that representation learning can be guided by neural encoding. This work points toward advances in predictive music cognition and neural decoding. Our expectation representation, computed directly from raw signals without manual labels, reflects predictive structure beyond onset or pitch, enabling investigation of multilayer predictive encoding across diverse stimuli. Its scalability to large, diverse datasets further suggests potential for developing general-purpose EEG models grounded in cortical encoding principles. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.13010 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2601.13010v2 Announce Type: replace Abstract: Evolutionary accumulation models (EvAMs) are an emerging class of machine learning methods designed to infer the evolutionary pathways by which features are acquired. Applications include cancer evolution (accumulation of mutations), anti-microbial resistance (accumulation of drug resistances), genome evolution (organelle gene transfers), and more diverse themes in biology and beyond. Following these themes, many EvAMs assume that features are gained irreversibly -- no loss of features can occur. Reversible approaches do exist but are often computationally (much) more demanding and statistically less stable. Our goal here is to explore whether useful information about evolutionary dynamics which are in reality reversible can be obtained from modelling approaches with an assumption of irreversibility. We identify, and use simulation studies to quantify, errors involved in neglecting reversible dynamics, and show the situations in which approximate results from tractable models can be informative and reliable. In particular, EvAM inferences about the relative orderings of acquisitions and the core dynamic structure of evolutionary pathways -- which features are likely present when another is acquired -- are robust to reversibility in many cases, while estimations of uncertainty and feature interactions are more error-prone. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.11435 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2603.11435v1 Announce Type: new Abstract: Head-mounted miniaturized microscopes, commonly known as miniscopes, have undergone rapid development and seen widespread adoption over the past two decades, enabling the imaging of neural activity in freely-behaving animals such as rodents, songbirds, and non-human primates. These miniscopes facilitate numerous studies that are not feasible with head-fixed preparations. Recent advancements have enhanced their capabilities, allowing for faster imaging, larger fields of view, and deeper brain penetration. In this review, we examine the latest progress in one-photon and multi-photon miniscopes. We highlight the unique opportunities these devices present for neuroscience research, discuss the current technical challenges, and explore emerging technologies that promise to advance the development of miniscopes. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.12107 Fri, 13 Mar 2026 00:00:00 -0400 arXiv:2603.12107v1 Announce Type: cross Abstract: The mathematical characterization of social-distancing games in classical epidemic theory remains an important question, for their applications to both infectious-disease theory and memetic theory. We consider a special case of the dynamic finite-duration SI social-distancing game where payoffs are accounted using Markov decision theory with zero-discounting, while distancing is constrained by threshold-linear running-costs, and the running-cost of perfect-distancing is finite. In this special case, we are able construct strategic equilibria satisfying the Nash best-response condition explicitly by integration. Our constructions are obtained using a new change of variables which simplifies the geometry and analysis.As it turns out, there are no singular solutions, and a time-dependent bang-bang strategy consisting of a wait-and-see phase followed by a lock-down phase is always the unique strategic equilibrium. We also show that in a restricted strategy space the bang-bang Nash equilibrium is an ESS, and that the optimal public policy exactly corresponds with the equilibrium strategy. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.10261 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2603.10261v1 Announce Type: cross Abstract: We report the discovery and extraction of a compact hematopoietic algorithm from the single-cell foundation model scGPT, to our knowledge the first biologically useful, competitive algorithm extracted from a foundation model via mechanistic interpretability. We show that scGPT internally encodes a compact hematopoietic manifold with significant developmental branch structure, validated on a strict non-overlap Tabula Sapiens external panel and confirmed via frozen-head zero-shot transfer to an independent multi-donor immune panel. To isolate this geometry, we introduce a general three-stage extraction method consisting of direct operator export from frozen attention weights, a lightweight learned adaptor, and a task-specific readout, producing a standalone algorithm without target-dataset retraining. In 88-split donor-holdout benchmarks against scVI, Palantir, DPT, CellTypist, PCA, and raw-expression baselines, the extracted algorithm achieves the strongest pseudotime-depth ordering and leads on key subtype endpoints (CD4/CD8 AUROC 0.867, mono/macro AUROC 0.951). Compared to standard probing of frozen scGPT embeddings with a 3-layer MLP, the extracted head is BH-significantly better on 6/8 classification endpoints while completing a full 12-split evaluation campaign 34.5x faster with approximately 1000x fewer trainable parameters. The exported operator compresses from three pooled attention heads to a single head without statistically significant loss, and further to a rank-64 surrogate. Mechanistic interpretability of the compact operator reveals a concentrated four-factor core explaining 66.2% of ablation impact, with factors resolving into explicit T/lymphoid, B/plasma, granulocytic, and monocyte/macrophage gene programs. A supplementary second-manifold validation (intercellular communication geometry) confirms that the extraction method generalizes beyond hematopoiesis. Quantitative_Biology/q-bio.CB_(Cell_Behavior) https://arxiv.org/abs/2507.09038 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2507.09038v3 Announce Type: replace Abstract: The process of programmed cell death, namely apoptosis, is a natural mechanism that regulates healthy tissue, multicellular structures, and homeostasis. An improved understanding of apoptosis can significantly enhance our knowledge of biological processes and systems. For instance, pathogens can manipulate the apoptotic process to either evade immune detection or to facilitate their spread. Furthermore, of particular clinical interest is the ability of cancer cells to evade apoptosis, hence allowing them to survive and proliferate uncontrollably. Thus, in this work, we propose a phase-field framework for simulating intrinsic or extrinsic apoptosis induced by an activation field, including deriving the configurational mechanics underlying such phenomena. Along with exploring varying conditions needed to initiate or reduce apoptosis, this can serve as a starting point for computational therapeutic testing. To showcase model capabilities, we present simulations exhibiting different types of cellular dynamics produced when varying the mechanisms underlying apoptosis. The model is subsequently applied to probe different morphological transitions, such as cell shrinkage, membrane blebbing, cavity formation and fragmentation. Lastly, we compare the characteristics observed in our simulations to electron microscopy images, providing additional support for the model. Quantitative_Biology/q-bio.CB_(Cell_Behavior) https://arxiv.org/abs/2603.10873 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2603.10873v1 Announce Type: cross Abstract: Polygenic risk scores and other genomic analyses require large individual-level genotype datasets, yet strict data access restrictions impede sharing. Synthetic genotype generation offers a privacy-preserving alternative, but most existing methods operate unconditionally, producing samples without phenotype alignment, or rely on unsupervised compression, creating a gap between statistical fidelity and downstream task utility. We present SNPgen, a two-stage conditional latent diffusion framework for generating phenotype-supervised synthetic genotypes. SNPgen combines GWAS-guided variant selection (1,024-2,048 trait-associated SNPs) with a variational autoencoder for genotype compression and a latent diffusion model conditioned on binary disease labels via classifier-free guidance. Evaluated on 458,724 UK Biobank individuals across four complex diseases (coronary artery disease, breast cancer, type 1 and type 2 diabetes), models trained on synthetic data matched real-data predictive performance in a train-on-synthetic, test-on-real protocol, approaching genome-wide PRS methods that use $2$-$6\times$ more variants. Privacy analysis confirmed zero identical matches, near-random membership inference (AUC $\approx 0.50$), preserved linkage disequilibrium structure, and high allele frequency correlation ($r \geq 0.95$) with source data. A controlled simulation with known causal effects verified faithful recovery of the imposed genetic association structure. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.10885 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2603.10885v1 Announce Type: cross Abstract: We present a parameter-efficient Diffusion Transformer (DiT) for generating 200bp cell-type-specific regulatory DNA sequences. By replacing the U-Net backbone of DNA-Diffusion with a transformer denoiser equipped with a 2D CNN input encoder, our model matches the U-Net's best validation loss in 13 epochs (60$\times$ fewer) and converges 39% lower, while reducing memorization from 5.3% to 1.7% of generated sequences aligning to training data via BLAT. Ablations show the CNN encoder is essential: without it, validation loss increases 70% regardless of positional embedding choice. We further apply DDPO finetuning using Enformer as a reward model, achieving a 38$\times$ improvement in predicted regulatory activity. Cross-validation against DRAKES on an independent prediction task confirms that improvements reflect genuine regulatory signal rather than reward model overfitting. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2512.04393 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2512.04393v2 Announce Type: replace Abstract: Computing haplotypes from sequencing data, i.e. haplotype assembly, is an important component of molecular and population genetics problems, including interpreting the effects of genetic variation on complex traits and reconstructing genealogical relationships. Assembling the haplotypes of polyploid genomes remains a significant challenge due to the exponential search space of haplotype phasings and read assignment ambiguity; the latter challenge is particularly difficult for haplotype assemblers since the information contained within the observed sequence reads is often insufficient for unambiguous haplotype assignment in polyploid genomes. We present pHapCompass, probabilistic haplotype assembly algorithms for diploid and polyploid genomes that explicitly model and propagate read assignment ambiguity to compute a distribution over polyploid haplotype phasings. We develop graph theoretic algorithms to enable statistical inference and uncertainty quantification despite an exponential space of possible phasings. Since prior work evaluates polyploid haplotype assembly on synthetic genomes that do not reflect the realistic genomic complexity of polyploidy organisms, we develop a computational workflow for simulating genomes and DNA-seq for auto- and allopolyploids. Additionally, we generalize the vector error rate and minimum error correction evaluation criteria for partially phased haplotypes. Benchmarking of pHapCompass and several existing polyploid haplotype assemblers shows that pHapCompass yields competitive performance across varying genomic complexities and polyploid structures while retaining an accurate quantification of phase uncertainty. The source code for pHapCompass, simulation scripts, and datasets are freely available at https://github.com/bayesomicslab/pHapCompass. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.11000 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2603.11000v1 Announce Type: cross Abstract: Single-cell electrophysiological recordings provide a powerful window into neuronal functional diversity and offer an interpretable route for linking intrinsic physiology to transcriptomic identity. Here, we replicate and extend the electrophysiology-to-transcriptomics framework introduced by Gouwens et al. (2020) using publicly available Allen Institute Patch-seq datasets from both mouse and human cortex. We focus on GABAergic inhibitory interneurons to target a subclass structure (Lamp5, Pvalb, Sst, Vip) that is comparable and conserved across species. After quality control, we analyzed 3,699 mouse visual cortex neurons and 506 human neocortical neurons from neurosurgical resections. Using standardized electrophysiological features and sparse PCA, we reproduced the major class-level separations reported in the original mouse study. For supervised prediction, a class-balanced random forest provided a strong feature-engineered baseline in mouse data and a reduced but still informative baseline in human data. We then developed an attention-based BiLSTM that operates directly on the structured IPFX feature-family representation, avoiding sPCA and providing feature-family-level interpretability via learned attention weights. Finally, we evaluated a cross-species transfer setting in which the sequence model is pretrained on mouse data and fine-tuned on human data for an aligned 4-class task, improving human macro-F1 relative to a human-only training baseline. Together, these results confirm reproducibility of the Gouwens pipeline in mouse data, demonstrate that sequence models can match feature-engineered baselines, and show that mouse-to-human transfer learning can provide measurable gains for human subclass prediction. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.02182 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2510.02182v2 Announce Type: replace Abstract: Understanding how neural populations in higher visual areas encode object-centered visual information remains a central challenge in computational neuroscience. Prior works have investigated representational alignment between artificial neural networks and the visual cortex. Nevertheless, these findings are indirect and offer limited insights to the structure of neural populations themselves. Similarly, decoding-based methods have quantified semantic features from neural populations but have not uncovered their underlying organizations. This leaves open a scientific question: "how feature-specific visual information is distributed across neural populations in higher visual areas, and whether it is organized into structured, semantically meaningful subspaces." To tackle this problem, we present MIG-Vis, a method that leverages the generative power of diffusion models to visualize and validate the visual-semantic attributes encoded in neural latent subspaces. Our method first uses a variational autoencoder to infer a group-wise disentangled neural latent subspace from neural populations. Subsequently, we propose a mutual information (MI)-guided diffusion synthesis procedure to visualize the specific visual-semantic features encoded by each latent group. We validate MIG-Vis on multi-session neural spiking datasets from the inferior temporal (IT) cortex of two macaques. The synthesized results demonstrate that our method identifies neural latent groups with clear semantic selectivity to diverse visual features, including object pose, inter-category transformations, and intra-class content. These findings provide direct, interpretable evidence of structured semantic representation in the higher visual cortex and advance our understanding of its encoding principles. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2507.19218 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2507.19218v3 Announce Type: replace-cross Abstract: Artificial intelligence chatbots have achieved unprecedented adoption, with millions now using these systems for emotional support and companionship in contexts of widespread social isolation and capacity-constrained mental health services. While some users report psychological benefits, concerning edge cases are emerging, including reports of suicide, violence, and delusional thinking linked to perceived emotional relationships with chatbots. To understand this new risk profile we need to consider the interaction between human cognitive and emotional biases, and chatbot behavioural tendencies such as agreeableness (sycophancy) and adaptability (in-context learning). We argue that individuals with mental health conditions face increased risks of chatbot-induced belief destabilization and dependence, owing to altered belief-updating, impaired reality-testing, and social isolation. Current AI safety measures are inadequate to address these interaction-based risks. To address this emerging public health concern, we need coordinated action across clinical practice, AI development, and regulatory frameworks. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.10911 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2603.10911v1 Announce Type: new Abstract: How do competing populations convert a spatial advantage into macroscopic dominance? We introduce a stochastic model for resource competition that decouples the transient discovery phase from monopolization. Initial symmetry breaking is governed by extreme value statistics of first-passage times: a linear spatial disadvantage requires an exponentially larger population to overcome. However, transient superiority cannot stabilize dominance. A non-reciprocal interaction bias is strictly necessary to arrest local fluctuations and drive the system into a robust absorbing state. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2504.12432 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2504.12432v3 Announce Type: replace Abstract: Since early 2024, highly pathogenic avian influenza virus (HPAIV) H5N1 of clade 2.3.4.4b has spilled over from wild birds to dairy cattle in the United States (U.S.), spreading to more than 1000 herds and threatening both animal and public health. Denmark's location along major migratory flyways and the lack of active HPAIV surveillance in cattle underscore the need to assess potential spillover risk from wild birds to cattle to strengthen preparedness. A quantitative spillover risk assessment model was developed to integrate data from Bird Flu Radar, eBird, and cattle density to estimate the weekly probability of HPAIV introduction from wild birds to cattle. The model was calibrated using observed U.S. spillover data and extrapolated to Denmark under the assumption of a comparable transmission rate parameter. Under the frequency-dependent model, the expected HPAIV introductions to Danish cattle via wild birds remain below 0.35 cases per week, with the highest temporal risk from December to March. High-risk areas were concentrated along the Danish coastline and near the German border. In contrast, applying a density-dependent model shifted the spatial risk toward regions with higher cattle densities, while the high-risk temporal periods remained unchanged. Overall, the results indicate a spatially and temporally variable risk of HPAIV spillover from wild birds to cattle in Denmark. The model establishes a data-driven framework to strengthen early warning and guide targeted surveillance efforts in high-risk regions. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.10093 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2603.10093v1 Announce Type: cross Abstract: Recent 3D molecular generation methods primarily use asynchronous auto-regressive or synchronous diffusion models. While auto-regressive models build molecules sequentially, they're limited by a short horizon and a discrepancy between training and inference. Conversely, synchronous diffusion models denoise all atoms at once, offering a molecule-level horizon but failing to capture the causal relationships inherent in hierarchical molecular structures. We introduce Equivariant Asynchronous Diffusion (EAD) to overcome these limitations. EAD is a novel diffusion model that combines the strengths of both approaches: it uses an asynchronous denoising schedule to better capture molecular hierarchy while maintaining a molecule-level horizon. Since these relationships are often complex, we propose a dynamic scheduling mechanism to adaptively determine the denoising timestep. Experimental results show that EAD achieves state-of-the-art performance in 3D molecular generation. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.10302 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2603.10302v1 Announce Type: cross Abstract: A plethora of protein language models have been released in recent years. Yet comparatively little work has addressed how to best sample from them to optimize desired biological properties. We fill this gap by proposing a flexible, effective sampling method for masked language models (MLMs), and by systematically evaluating models and methods both in silico and in vitro on actual antibody therapeutics campaigns. Firstly, we propose sampling with stochastic beam search, exploiting the fact that MLMs are remarkably efficient at evaluating the pseudo-perplexity of the entire 1-edit neighborhood of a sequence. Reframing generation in terms of entire-sequence evaluation enables flexible guidance with multiple optimization objectives. Secondly, we report results from our extensive in vitro head-to-head evaluation for the antibody engineering setting. This reveals that choice of sampling method is at least as impactful as the model used, motivating future research into this under-explored area. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2507.19553 Thu, 12 Mar 2026 00:00:00 -0400 arXiv:2507.19553v3 Announce Type: replace Abstract: Eutrophication and harmful algal blooms, driven by complex interactions among nutrients and climate, threaten freshwater ecosystems globally, particularly in densely populated Asian regions where rapid urbanization and agricultural intensification exacerbate nutrient pollution. Understanding the non-linear interactions among water temperature, nutrient levels, and chlorophyll-a (Chl-a) dynamics is crucial for addressing eutrophication in freshwater ecosystems. Many existing studies, however, tend to oversimplify these relationships and lack validation with long-term field data. Here, we conducted multi-year field monitoring (2020-2024) of key environmental factors, including total nitrogen (TN), total phosphorus (TP), water temperature, and Chl-a, across three reservoirs in Guangdong Province, China: Tiantangshan (S1), Baisha River (S2), and Meizhou (S3). Strong positive correlations were found between Chl-a and TN, TP, and temperature. Numerical analysis of the long-term data revealed TN as a more influential driver than TP for Chl-a proliferation in these systems, with Chl-a increasing by an average of 4.2 ug/L per unit increase in TN, compared to 2.8 ug/L per unit increase in TP. Based on the collected data, we developed and calibrated a dynamic multi-factor hydro-ecological model. The model accurately reproduced the observed Chl-a patterns, identifying synergistic effects between temperature and nutrients, particularly a 15% enhancement in Chl-a growth rate when temperature exceeded 25 concurrent with high TN. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2501.17901 Wed, 11 Mar 2026 00:00:00 -0400 arXiv:2501.17901v3 Announce Type: replace Abstract: Understanding peptide properties is often assumed to require modeling long-range molecular interactions, motivating the use of complex graph neural networks and pretrained transformers. Yet, whether such long-range dependencies are essential remains unclear. We investigate if simple, domain-specific molecular fingerprints can capture peptide function without these assumptions. Atomic-level representation aims to provide richer information than purely sequence-based models and better efficiency than structural ones. Across 132 datasets, including LRGB and five other peptide benchmarks, models using count-based ECFP, Topological Torsion, and RDKit fingerprints with LightGBM achieve state-of-the-art accuracy. Despite encoding only short-range molecular features, these models outperform GNNs and transformer-based approaches. Control experiments with sequence shuffling and amino acid counts confirm that fingerprints, though inherently local, suffice for robust peptide property prediction. Our results challenge the presumed necessity of long-range interaction modeling and highlight molecular fingerprints as efficient, interpretable, and computationally lightweight alternatives for peptide prediction. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.09451 Wed, 11 Mar 2026 00:00:00 -0400 arXiv:2603.09451v1 Announce Type: new Abstract: Due to its ability to summarise 'real-time' epidemic behaviour, the time-dependent reproduction number, Rt, is a useful metric for tracking pathogen transmission and quantifying the effects of interventions during infectious disease outbreaks. The predominant models underlying inferred Rt trajectories are renewal equations, their success owing in part to the relatively few assumptions they require. One necessary assumption is the generation time distribution, which summarises the time periods between infections in infector-infectee transmission pairs. This distribution is typically assumed to be the same across all members of a population. In reality, however, it may vary systematically between population groups. In this study, we consider two Rt inference frameworks based on renewal equation models: one for a single, homogeneous group and another accounting for a structured population. We compare the estimates of Rt generated by the two models and investigate, both analytically and through simulations, under which conditions the conclusions drawn from these modelling paradigms differ. We also demonstrate a methodology for selecting the generation time for the one-group model that correctly encapsulates variations between different population groups; this allows us to use a renewal framework for a one-group model to infer Rt when, in fact, the population is structured. Finally, we use real epidemic data to demonstrate that practical Rt estimates can differ depending on whether the underlying model is the one-group model or the multi-group model. Our results motivate the need for rigorous collection of detailed epidemic data and consideration of differences between population groups to improve the accuracy of Rt estimates that are used to guide public health policy responses. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2602.10152 Mon, 09 Mar 2026 00:00:00 -0400 arXiv:2602.10152v2 Announce Type: replace Abstract: Saliency maps are increasingly used as design guidance in siRNA efficacy prediction, yet attribution methods are rarely validated before motivating sequence edits. We introduce a pre-synthesis gate: a protocol for counterfactual sensitivity faithfulness that tests whether mutating high-saliency positions changes model output more than composition-matched controls. Cross-dataset transfer reveals two failure modes that would otherwise go undetected: faithful-but-wrong (saliency valid, predictions fail) and inverted saliency (top-saliency edits less impactful than random). Strikingly, models trained on mRNA-level assays collapse on a luciferase reporter dataset, demonstrating that protocol shifts can silently invalidate deployment. Across four benchmarks, 19/20 fold instances pass; the single failure shows inverted saliency. A biology-informed regularizer (BioPrior) strengthens saliency faithfulness with modest, dataset-dependent predictive trade-offs. Our results establish saliency validation as essential pre-deployment practice for explanation-guided therapeutic design. Code is available at https://github.com/shadi97kh/BioPrior. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2511.02263 Mon, 09 Mar 2026 00:00:00 -0400 arXiv:2511.02263v4 Announce Type: replace Abstract: Rare disease diagnosis requires matching variant-bearing genes to complex patient phenotypes across large and heterogeneous evidence sources. This process remains time-intensive in current clinical interpretation pipelines. To overcome these limitations, We present LA-MARRVEL, a knowledge-grounded, language-aware LLM framework and designed for clinical robustness and practical deployment. LA-MARRVEL delivers a 12-15 percentage-point absolute improvement in Recall@1 over established gene prioritization approaches, showing that architectural design can drive substantial accuracy gains. We found that the central contributor is structured, phenotype-rich prompt construction that explicitly encodes patient and disease phenotypes, preserving clinically meaningful context more effectively than disease labels alone. Across three real-world cohorts, LA-MARRVEL consistently improves gene-ranking performance, including in challenging cases where the causal gene was initially ranked lower by first-stage prioritization. For each candidate gene, the system delivers clinically relevant, ACMG-aligned reasoning that integrates phenotype concordance, inheritance patterns, and variant-level evidence into auditable explanations, enabling streamlined clinical review. These findings suggest that knowledge-grounded LLM layer can enhance existing rare-disease gene prioritization workflows without altering established diagnostic pipelines. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.04622 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2603.04622v1 Announce Type: new Abstract: 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. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.04688 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2603.04688v1 Announce Type: new Abstract: 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. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.04747 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2603.04747v1 Announce Type: new Abstract: 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. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.05418 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2603.05418v1 Announce Type: new Abstract: 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. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2511.01870 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2511.01870v2 Announce Type: replace Abstract: 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. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.10482 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2601.10482v3 Announce Type: replace Abstract: 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. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.12424 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2601.12424v2 Announce Type: replace Abstract: 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. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03347 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2603.03347v2 Announce Type: replace Abstract: Synapses are information efficient in the sense that their natural conductance values convey as many bits per Joule as possible, but efficiency falls rapidly if the conductance is forced to deviate from its natural value (Harris et al, 2015. However, the exact manner in which efficiency falls as conductance deviates from its natural value remains unexplained. Recently, Malkin et al (2026) showed that synaptic noise is minimised given the available energy, consistent with a minimal energy boundary. This minimal energy boundary is a necessary, but not sufficient, condition for maximising information efficiency. By expressing the minimal energy boundary in terms of Shannon's information theory (Shannon, 1949), we show that synapses operate at signal-to-noise ratios which maximise information efficiency, and that this accurately predicts the decrease in efficiency values observed in Harris et al (2015) across a wide range of synaptic conductances. Crucially, the proposed model contains no free parameters because it is derived from the biophysics of the synapse. The results reported here are consistent with the general principle that neuronal systems in the brain have evolved to be as efficient as possible in terms of the number of bits per Joule. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2602.23344 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2602.23344v2 Announce Type: replace Abstract: 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. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.04638 Fri, 06 Mar 2026 00:00:00 -0500 arXiv:2603.04638v1 Announce Type: cross Abstract: 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. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.04251 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.04251v1 Announce Type: cross Abstract: 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. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.03591 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03591v1 Announce Type: new Abstract: In population genetics, mutation rate is often treated as a homogeneous parameter across the genome. Empirical evidence, however, shows systematic variation across genomic contexts associated with chromatin organization and epigenomic features. Using gene-level de novo mutation data from Arabidopsis thaliana, we test whether chromatin features predict not only the mean per-base mutation rate but also its variability across genes. To reduce heterogeneity in selective regime, we restrict analysis to essential and lethal loci subject to strong purifying selection. Across complementary multivariable models including heteroskedasticity-robust linear regression, length-weighted regression, and Poisson generalized linear models with exposure offsets, histone marks associated with active transcription (H3K4me1, H3K4me3, H3K36ac) are consistently associated with lower mean mutation rates and substantially reduced between-gene variance. GC content shows little association with the mean once chromatin predictors are controlled but is positively associated with mutation-rate variability. Estimates of skewness and kurtosis reveal no significant higher-order structure attributable to epigenomic predictors. A standardized Tajima's $D$ statistic yields directionally consistent but statistically underpowered associations with both the mean and variance of gene-level mutation rates. These results indicate that mutation rate is systematically structured by chromatin state within functionally constrained genes and suggest that evolutionary processes may act not only on expected mutation rate but also on its variability across loci. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2603.01387 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.01387v2 Announce Type: replace Abstract: The Bayesian brain hypothesis has been a leading theory in understanding perceptual decision-making under uncertainty. While extensive psychophysical evidence supports the notion of the brain performing Bayesian computations, how uncertainty information is encoded in sensory neural populations remains elusive. Specifically, two competing hypotheses propose that early sensory populations encode either the likelihood function (exemplified by probabilistic population codes) or the posterior distribution (exemplified by neural sampling codes) over the stimulus, with the key distinction lying in whether stimulus priors would modulate the neural responses. However, experimentally differentiating these two hypotheses has remained challenging, as it is unclear what task design would effectively distinguish the two. In this work, we present an information-theoretic framework for optimizing the task stimulus distribution that would maximally differentiate competing probabilistic neural codes. To quantify how distinguishable the two probabilistic coding hypotheses are under a given task design, we derive the information gap--the expected performance difference when likelihood versus posterior decoders are applied to neural populations--by evaluating the Kullback-Leibler divergence between the true posterior and a task-marginalized surrogate posterior. Through extensive simulations, we demonstrate that the information gap accurately predicts decoder performance differences across diverse task settings. Critically, maximizing the information gap yields stimulus distributions that optimally differentiate likelihood and posterior coding hypotheses. Our framework enables principled, theory-driven experimental designs with maximal discriminative power to differentiate probabilistic neural codes, advancing our understanding of how neural populations represent and process sensory uncertainty. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2511.14555 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2511.14555v3 Announce Type: replace Abstract: Decoded Neurofeedback (DecNef) is a flourishing non-invasive approach to brain modulation with wide-ranging applications in neuromedicine and cognitive neuroscience. However, progress in DecNef research remains constrained by subject-dependent learning variability, reliance on indirect measures to quantify progress, and the high cost and time demands of experimentation. We present DecNefSimulator, a modular and interpretable simulation framework that formalizes DecNef as a machine learning problem. Beyond providing a virtual laboratory, DecNefSimulator enables researchers to model, analyze and understand neurofeedback dynamics. Using latent variable generative models as simulated participants, DecNefSimulator allows direct observation of internal cognitive states and systematic evaluation of how different protocol designs and subject characteristics influence learning. We demonstrate how this approach can (i) reproduce empirical phenomena of DecNef learning, (ii) identify conditions under which DecNef feedback fails to induce learning, and (iii) guide the design of more robust and reliable DecNef protocols in silico before human implementation. In summary, DecNefSimulator bridges computational modeling and cognitive neuroscience, offering a principled foundation for methodological innovation, robust protocol design, and ultimately, a deeper understanding of DecNef-based brain modulation. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03507 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03507v1 Announce Type: cross Abstract: Adversarial attacks - input perturbations imperceptible to humans that fool neural networks - remain both a persistent failure mode in machine learning, and a phenomenon with mysterious origins. To shed light, we define and analyze a network's perceptual manifold (PM) for a class concept as the space of all inputs confidently assigned to that class by the network. We find, strikingly, that the dimensionalities of neural network PMs are orders of magnitude higher than those of natural human concepts. Since volume typically grows exponentially with dimension, this suggests exponential misalignment between machines and humans, with exponentially many inputs confidently assigned to concepts by machines but not humans. Furthermore, this provides a natural geometric hypothesis for the origin of adversarial examples: because a network's PM fills such a large region of input space, any input will be very close to any class concept's PM. Our hypothesis thus suggests that adversarial robustness cannot be attained without dimensional alignment of machine and human PMs, and therefore makes strong predictions: both robust accuracy and distance to any PM should be negatively correlated with the PM dimension. We confirmed these predictions across 18 different networks of varying robust accuracy. Crucially, we find even the most robust networks are still exponentially misaligned, and only the few PMs whose dimensionality approaches that of human concepts exhibit alignment to human perception. Our results connect the fields of alignment and adversarial examples, and suggest the curse of high dimensionality of machine PMs is a major impediment to adversarial robustness. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.04149 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.04149v1 Announce Type: new Abstract: Structural and functional heterogeneity are hallmarks of cortical circuits, from broad degree distributions in the mouse connectome to diverse intrinsic neuronal timescales. Yet a mechanistic link between connectivity heterogeneity and functional diversity is lacking. To bridge this gap, we introduce a random recurrent network in which connectivity is generated by a configuration model with tunable degree heterogeneity and synaptic weights exhibiting varying levels of correlation. Using generating-functional methods, we derive a heterogeneous dynamical mean-field theory (hDMFT) with degree-conditioned stochastic dynamics. The theory shows that the interaction of partial symmetry in the weights and degree heterogeneity induces a non-Markovian memory term in the form of an emergent self-coupling whose strength scales with degree and produces a broad distribution of activity timescales. We obtain analytic stability criteria demonstrating that degree heterogeneity lowers the critical gain and localizes unstable modes onto hubs. The resulting rich dynamical landscape includes silent, chaotic, and multistable regimes, which we uncover via spectral, replica, and Lyapunov exponent analyses. We highlight the computational benefits of the observed timescale heterogeneity by revealing that, under an external input drive featuring a broadband spectrum, slow hub neurons act as integrators, demixing slow input components. Finally, instantiating the model with the empirically measured topology from the MICrONS cubic-millimeter mouse connectome explains the broad range of single-neuron timescales and their positive correlation with in-degree observed in resting-state recordings. Our results provide a mechanistic link between connectome topology, neural dynamics, and computation, identifying hubs in partially symmetric networks as a natural substrate for multiplexed processing across timescales. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03864 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03864v1 Announce Type: new Abstract: While EEG features differentiate Major Depressive Disorder (MDD) from healthy controls (HC), their clinical utility as biomarkers depends on a monotonic trajectory across the disease spectrum, from the acute (AC) phase to the maintenance (MA) phase and finally to the healthy baseline. However, the progression of the MA phase remains poorly understood in traditional marker analysis. Analyzing EEG data from 74 individuals (24 AC, 23 MA, and 27 HC), this study provides a comprehensive evaluation of classic ERP and resting-state indices across AC, MA, and HC groups. Our results demonstrate that almost no conventional metrics strictly satisfy the criterion of monotonic progression, likely due to profound inter-individual heterogeneity. These findings highlight the inherent limitations of group-level feature extraction and provide critical insights for developing future paradigms and algorithms to identify neurobiological markers with genuine clinical utility. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03476 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03476v1 Announce Type: new Abstract: We propose a novel computational framework for analyzing electroencephalography (EEG) time series using methods from stringology, the study of efficient algorithms for string processing, to systematically identify and characterize recurrent temporal patterns in neural signals. The primary aim is to introduce quantitative measures to understand neural signal dynamics, with the present findings serving as a proof-of-concept. The framework adapts order-preserving matching (OPM) and Cartesian tree matching (CTM) to detect temporal motifs that preserve relative ordering and hierarchical structure while remaining invariant to amplitude scaling. This approach provides a temporally precise representation of EEG dynamics that complements traditional spectral and global complexity analyses. To evaluate its utility, we applied the framework to multichannel EEG recordings from individuals with attention-deficit/hyperactivity disorder (ADHD) and matched controls using a publicly available dataset. Highly recurrent, group-specific motifs were extracted and quantified using both OPM and CTM. The ADHD group exhibited significantly higher motif frequencies, suggesting increased repetitiveness in neural activity. OPM analysis revealed shorter motif lengths and greater gradient instability in ADHD, reflected in larger mean and maximal inter-sample amplitude changes. CTM analysis further demonstrated reduced hierarchical complexity in ADHD, characterized by shallower tree structures and fewer hierarchical levels despite comparable motif lengths. These findings suggest that ADHD-related EEG alterations involve systematic differences in the structure, stability, and hierarchical organization of recurrent temporal patterns. The proposed stringology-based motif framework provides a complementary computational tool with potential applications for objective biomarker development in neurodevelopmental disorders. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03414 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03414v1 Announce Type: new Abstract: We propose that the jagged intelligence landscape of modern AI systems arises from a missing training signal that we call "cognitive dark matter" (CDM): brain functions that meaningfully shape behavior yet are hard to infer from behavior alone. We identify key CDM domains-metacognition, cognitive flexibility, episodic memory, lifelong learning, abductive reasoning, social and common-sense reasoning, and emotional intelligence-and present evidence that current AI benchmarks and large-scale neuroscience datasets are both heavily skewed toward already-mastered capabilities, with CDM-loaded functions largely unmeasured. We then outline a research program centered on three complementary data types designed to surface CDM for model training: (i) latent variables from large-scale cognitive models, (ii) process-tracing data such as eye-tracking and think-aloud protocols, and (iii) paired neural-behavioral data. These data will enable AI training on cognitive process rather than behavioral outcome alone, producing models with more general, less jagged intelligence. As a dual benefit, the same data will advance our understanding of human intelligence itself. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03362 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03362v1 Announce Type: new Abstract: The brain achieves stability and plasticity in a topologically complex, shifting world through Metric-Topology Factorization (MTF), separating discrete topological indexing for context selection from continuous metric condensation for local inference. Semantically rich environments defy single globally contractive geometries, causing obstructions under shifts, so intelligence factorizes these: the hippocampus provides sparse signatures indexing manifold identity, while the neocortex untangles geometry hierarchically. In the ventral stream, a dynamic-programming-like process quotients symmetries (e.g., translation, scale), transforming non-convex sensory mazes into separable bowls. Offline replay and consolidation amortize transformations for rapid task switching. Dreaming in REM involves stochastic hippocampal traversal to expose and regularize latent structures. Consciousness arises from resolving topological uncertainty into stable embeddings, with awareness for unamortized states. Evolutionarily, transitions like sensorimotor control to language expand topological complexity, demanding advanced indexing-metric separation. Intelligence emerges via recalibrating context-specific geometries, converting global navigation into local dynamics, not deeper search. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03358 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03358v1 Announce Type: new Abstract: Over the past two decades, quantum-like modeling (QLM) has emerged as a powerful framework for describing non-classical features of cognition and decision-making. Rather than assuming physical quantum processes in the brain, QLM employs the Hilbert space formalism to model contextuality, incompatibility of mental observables, and entanglement-like correlations. In this paper, we develop a quantum-informational model of mental markers within the broader I-field (information field) approach. We propose that, under conditions of information overload and limited cognitive resources, individuals primarily respond not to detailed semantic content but to compact content labels - mental markers - carrying cognitive and affective components. We formalize mental markers as structured quantum-like states and analyze the nonclassical correlations between their cognitive and affective components using the Contextuality-Incompatibility-Entanglement triad. Special attention is given to intra-system entanglement between rational (cognitive) evaluation and emotional (affective) coloring, accounting for context-dependent judgments, order effects, and affect-driven decision shifts. Illustrative examples with psychological interpretation and experimental perspectives are provided. An Appendix briefly discusses neurobiological analogues of information overload in neural networks, highlighting structural parallels with the proposed marker-based framework; coupling to the origin and diagnostics of neurological diseases is analyzed. The paper contributes to QLM by distinguishing inter-system and intra-system entanglement and by demonstrating that cognitive - affective entanglement constitutes a fundamental structural feature of mental markers in socially mediated information environments. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03355 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03355v1 Announce Type: new Abstract: We present a memory-augmented transformer in which attention serves simultaneously as a retrieval, consolidation, and write-back operator. The core update, $A^\top A V W$, re-grounds retrieved values into persistent memory slots via the Gram matrix $A^\top A$, providing a principled tripartite projection: observation space $\to$ latent memory $\to$ supervised transformation. We partition the memory into lateralized left and right banks coupled through a sign-controlled cross-talk matrix $W_s$, and show that the sign of this coupling is decisive for specialization. Excitatory cross-talk ($s=+1$) causes bank-dominance collapse: one bank monopolises all inputs and $\mathcal{P}_{ct} \to 0.5$, despite lowering task loss. Inhibitory cross-talk ($s=-1$), motivated by the net inhibitory effect of callosal projections in human cortex, actively suppresses contralateral bank activation and achieves saturated specialization ($\mathcal{D}_{sep} = \pm 1.00$, $\mathcal{P}_{ct} \approx 0$). On a controlled symbolic benchmark combining an episodic bijection cipher (requiring associative recall) with a strict arithmetic progression (requiring rule extraction), the inhibitory model reduces cipher-domain loss by $124{\times}$ over the baseline while matching it on the arithmetic domain, confirming that persistent lateralized memory is necessary for episodic recall but not for rule-based prediction. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03354 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03354v1 Announce Type: new Abstract: 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 Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.03343 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03343v1 Announce Type: new Abstract: We propose NEURONA, a neuro-symbolic framework for fMRI decoding and concept grounding in neural activity. Leveraging image- and video-based fMRI question-answering datasets, NEURONA learns to decode interacting concepts from visual stimuli based on patterns of fMRI responses, integrating symbolic reasoning and compositional execution with fMRI grounding across brain regions. We demonstrate that incorporating structural priors (e.g., compositional predicate-argument dependencies between concepts) into the decoding process significantly improves both decoding accuracy over precise queries, and notably, generalization to unseen queries at test time. With NEURONA, we highlight neuro-symbolic frameworks as promising tools for understanding neural activity. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2506.15581 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2506.15581v3 Announce Type: replace Abstract: Biological systems operate under persistent noise, which can alter system states and induce transitions between attractors. Here, we study the attractor dynamics of Boolean networks focusing on the transitions between attractors induced by noise. By computing transition probabilities between attractors, we present methods at the attractor level to determine dominance, stability, and diversity of attractors, and systematically compare local and global noise. Whereas global noise leads to attractor behavior dictated primarily by basin sizes, local noise produces structured transition patterns characterized by enhanced stability, non-trivial dominance patterns, and broader exploration of the attractor space. Our work offers insight into the dynamics of attractors, showing the importance of transition patterns under noise. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2505.07053 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2505.07053v2 Announce Type: replace Abstract: Genes are connected in complex networks of interactions where often the product of one gene is a transcription factor that alters the expression of another. Many of these networks are based on a few fundamental motifs leading to switches and oscillators of various kinds. And yet, there is more to the story than which transcription factors control these various circuits. These transcription factors are often themselves under the control of effector molecules that bind them and alter their level of activity. Traditionally, much beautiful work has shown how to think about the stability of the different states achieved by these fundamental regulatory architectures by examining how parameters such as transcription rates, degradation rates and dissociation constants tune the circuit, giving rise to behavior such as bistability. However, such studies explore dynamics without asking how these quantities are altered in real time in living cells as opposed to at the fingertips of the synthetic biologist's pipette or on the computational biologist's computer screen. In this paper, we make a departure from the conventional dynamical systems view of these regulatory motifs by using statistical mechanical models to focus on endogenous signaling knobs such as effector concentrations rather than on the convenient but more experimentally remote knobs such as dissociation constants, transcription rates and degradation rates that are often considered. We also contrast the traditional use of Hill functions to describe transcription factor binding with more detailed thermodynamic models. This approach provides insights into how biological parameters are tuned to control the stability of regulatory motifs in living cells, sometimes revealing quite a different picture than is found by using Hill functions and tuning circuit parameters by hand. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2603.03866 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.03866v1 Announce Type: cross Abstract: Regulation of contraction in striated muscle is controlled by a dual mechanism involving both thin filaments containing actin and thick filaments containing myosin. The thin filament is activated by calcium ions binding to troponin, leading to tropomyosin azimuthal displacement which allows the activation of a regulatory unit (composed of one troponin, one tropomyosin and seven actin monomers) that exposes the actin sites for interaction with the myosin motors. Motor attachment to actin contributes to spreading activation within and beyond a regulatory unit along the thin filament through a cooperative mechanism. We introduce a one-dimensional Ising model to elucidate the mechanism of cooperativity in thin filament activation in relation to the force generated by the attached myosin motor. The model characterizes thin filament activation and cooperativity using only two parameters: one related to calcium concentration and the other to the force exerted by the attached myosin motor, which is modulated by temperature. At any force, the model is able to determine the extent of actin-myosin interactions on a correlation length ranging from two to seven actin monomers in addition to the seven actin monomers of the regulatory unit. Our theoretical predictions are successfully tested on experimental data, and our tests also include the condition of hindered filament activation by the use of the specific drug Omecamtiv Mecarbil (OM). According to our model, the effect of OM results in an anti-cooperativity mechanism accounting for the experimental data. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2601.16151 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2601.16151v2 Announce Type: replace-cross Abstract: Transcription factors (TFs) regulate gene expression by binding to specific genomic loci determined by DNA sequence. Their sequence specificity is commonly summarized by a consensus binding motif. However, eukaryotic genomes contain billions of low-affinity DNA sequences to which TFs associate with a sequence-dependent binding energy. We currently lack insight into how the genomic sequence defines this spectrum of binding energies and the resulting pattern of TF localization. Here, we set out to obtain a quantitative understanding of sequence-dependent TF binding to both motif and non-motif sequences. We achieve this by first pursuing accurate measurements of physical binding energies of the human TF Klf4 to a library of short DNA sequences in a fluorescence-anisotropy-based bulk competitive binding assay. Second, we show that the highly non-linear sequence dependence of Klf4 binding energies can be captured by combining a linear model of binding energies with an Ising model of the coupled recognition of nucleotides by a TF. We find that this statistical mechanics model parametrized by our in vitro measurements captures Klf4 binding patterns on individual long DNA molecules stretched in the optical tweezer, and is predictive for Klf4 occupancy across the entire human genome without additional fit parameters. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.01752 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2603.01752v2 Announce Type: replace-cross Abstract: Motivation: Sparse autoencoders (SAEs) decompose foundation model activations into interpretable features, but causal feature-to-feature interactions across network depth remain unknown for biological foundation models. Results: We introduce causal circuit tracing by ablating SAE features and measuring downstream responses, and apply it to Geneformer V2-316M and scGPT whole-human across four conditions (96,892 edges, 80,191 forward passes). Both models show approximately 53 percent biological coherence and 65 to 89 percent inhibitory dominance, invariant to architecture and cell type. scGPT produces stronger effects (mean absolute d = 1.40 vs. 1.05) with more balanced dynamics. Cross-model consensus yields 1,142 conserved domain pairs (10.6x enrichment, p < 0.001). Disease-associated domains are 3.59x more likely to be consensus. Gene-level CRISPRi validation shows 56.4 percent directional accuracy, confirming co-expression rather than causal encoding. Quantitative_Biology/q-bio.CB_(Cell_Behavior) https://arxiv.org/abs/2510.02903 Thu, 05 Mar 2026 00:00:00 -0500 arXiv:2510.02903v2 Announce Type: replace-cross Abstract: Modeling the dynamics of cellular differentiation is fundamental to advancing the understanding and treatment of diseases associated with this process, such as cancer. With the rapid growth of single-cell datasets, this has also become a particularly promising and active domain for machine learning. Current state-of-the-art models, however, rely on computationally expensive optimal transport preprocessing and multi-stage training, while also not discovering explicit gene interactions. To address these challenges we propose Cell-Mechanistic Neural Networks (Cell-MNN), an encoder-decoder architecture whose latent representation is a locally linearized ODE governing the dynamics of cellular evolution from stem to tissue cells. Cell-MNN is fully end-to-end (besides a standard PCA pre-processing) and its ODE representation explicitly learns biologically consistent and interpretable gene interactions. Empirically, we show that Cell-MNN achieves competitive performance on single-cell benchmarks, surpasses state-of-the-art baselines in scaling to larger datasets and joint training across multiple datasets, while also learning interpretable gene interactions that we validate against the TRRUST database of gene interactions. Quantitative_Biology/q-bio.CB_(Cell_Behavior) https://arxiv.org/abs/2603.02572 Wed, 04 Mar 2026 00:00:00 -0500 arXiv:2603.02572v1 Announce Type: cross Abstract: Huntington's disease (HD) is caused by CAG-repeat expansion in HTT, which lengthens the polyglutamine (polyQ) tract in huntingtin (HTT) and promotes misfolding and aggregation. While polyQ-length-dependent aggregation is well established, the atomistic conformational dynamics preceding aggregation remain less defined. Here we perform all-atom molecular dynamics simulations of HTT exon-1 constructs containing the N17 domain, polyQ tracts of clinically relevant lengths (Q21, wildtype; Q40, adult onset threshold; Q70, juvenile onset), and the polyproline (polyP) region. Multi-copy simulations (four chains) were run for 100 ns in explicit SPC/E water using the OPLS-AA force field. We quantified radius of gyration (Rg), solvent-accessible surface area (SASA), root-mean-square deviation (RMSD), and intra-protein hydrogen bonds as proxies for conformational expansion and aggregation propensity. PolyQ expansion drove progressive increases in Rg and SASA, consistent with more extended, solvent-exposed ensembles. We further tested organic co-solvents (methanol, hexane, trichloroethylene; 0.5 to 1.0 M), which modulated these landscapes in a solvent-dependent manner. Trichloroethylene induced marked expansion in Q21 and Q40, whereas methanol produced mild compaction in Q21. To our knowledge, this is the first MD study to systematically examine co-solvent effects on HTT exon-1 conformational dynamics. Although limited sampling precludes definitive mechanistic conclusions, the observed trends suggest that hydrophobic co-solvents can bias HTT exon-1 toward more expanded ensembles, motivating computational studies of gene-environment modulation in HD. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2503.20513 Wed, 04 Mar 2026 00:00:00 -0500 arXiv:2503.20513v2 Announce Type: replace Abstract: RNA structure determination is essential for understanding its biological functions. However, the reconstruction process often faces challenges, such as atomic clashes, which can lead to inaccurate models. To address these challenges, we introduce the principal submanifold (PSM) approach for analyzing RNA data on a torus. This method provides an accurate, low-dimensional feature representation, overcoming the limitations of previous torus-based methods. By combining PSM with DBSCAN, we propose a novel clustering technique, the principal submanifold-based DBSCAN (PSM-DBSCAN). Our approach achieves superior clustering accuracy and increased robustness to noise. Additionally, we apply this new method for multiscale corrections, effectively resolving RNA backbone clashes at both microscopic and mesoscopic scales. Extensive simulations and comparative studies highlight the enhanced precision and scalability of our method, demonstrating significant improvements over existing approaches. The proposed methodology offers a robust foundation for correcting complex RNA structures and has broad implications for applications in structural biology and bioinformatics. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2510.08946 Wed, 04 Mar 2026 00:00:00 -0500 arXiv:2510.08946v2 Announce Type: replace Abstract: Biomolecular interaction modeling has been substantially advanced by foundation models, yet they often produce all-atom structures that violate basic steric feasibility. We address this limitation by enforcing physical validity as a strict constraint during both training and inference with a uniffed module. At its core is a differentiable projection that maps the provisional atom coordinates from the diffusion model to the nearest physically valid conffguration. This projection is achieved using a Gauss-Seidel scheme, which exploits the locality and sparsity of the constraints to ensure stable and fast convergence at scale. By implicit differentiation to obtain gradients, our module integrates seamlessly into existing frameworks for end-to-end ffnetuning. With our Gauss-Seidel projection module in place, two denoising steps are sufffcient to produce biomolecular complexes that are both physically valid and structurally accurate. Across six benchmarks, our 2-step model achieves the same structural accuracy as state-of-the-art 200-step diffusion baselines, delivering approximately 10 times faster wall-clock speed while guaranteeing physical validity. The code is available at https://github.com/chensiyuan030105/ProteinGS.git. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.02461 Wed, 04 Mar 2026 00:00:00 -0500 arXiv:2603.02461v1 Announce Type: new Abstract: Understanding how decision making changes across the lifespan is a central challenge for neuroscience, yet research on cognitive aging has remained largely disconnected from the theoretical and computational advances that now shape modern systems neuroscience. Over the past two decades, theoretical frameworks have transformed how we study cognition in young, healthy brains, providing principled tools to model latent decision states, neural dynamics, population codes, and interareal communication. In contrast, aging research has often relied on single metric behavioral readouts, cross sectional comparisons, and descriptive neural analyses, limiting our ability to explain fundamental differences in individual aging trajectories. This gap represents a missed opportunity because aging offers a powerful platform for testing theories of neural computation, stability, and flexibility under changing biological constraints. Here, we argue that closer integration between aging research and contemporary theoretical neuroscience can move the field beyond descriptive accounts toward more mechanistic explanations of decision making across the lifespan. To this end, we outline how recent advances in behavioral quantification, latent state modeling, dynamical systems, encoding models, representational geometry, and recurrent neural networks offer a rich theoretical toolkit for neuroscientists studying decision making across the lifespan. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2509.00555 Wed, 04 Mar 2026 00:00:00 -0500 arXiv:2509.00555v2 Announce Type: replace Abstract: As neuroscientific theories of consciousness continue to proliferate, the need to assess their similarities and differences - as well as their predictive and explanatory power - becomes ever more pressing. Recently, a number of structured adversarial collaborations have been devised to test the competing predictions of several candidate theories of consciousness. In this review, we compare and contrast three theories being investigated in one such adversarial collaboration: Integrated Information Theory, Neurorepresentationalism, and Active Inference. We begin by presenting the core claims of each theory, before comparing them in terms of the phenomena they seek to explain, the sorts of explanations they avail, and the methodological strategies they endorse. We then consider some of the inherent challenges of theory-testing, and how adversarial collaboration addresses some of these difficulties. The stage is then set for the empirical work to come: first, we outline the key hypotheses to be tested across a series of multi-site experiments; second, we discuss the kinds of observations that would support or challenge each theory; third, we consider how these theories might assimilate or accommodate such observations. Finally, we show how data harvested across disparate experiments (and their replicates) may be formally integrated to provide a quantitative measure of the evidential support accrued under each theory. Besides orienting the reader to the theoretical foundations of our collaboration, this review aims to provide valuable meta-scientific insights into the mechanics of adversarial collaboration and theory-testing in general - including the way theories may be evaluated in terms of the scientific progress they deliver. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2506.01303 Wed, 04 Mar 2026 00:00:00 -0500 arXiv:2506.01303v3 Announce Type: replace-cross Abstract: Neural population activity in cortical and hippocampal circuits can be flexibly reorganized by context, suggesting that cognition relies on dynamic manifolds rather than static representations. However, how such dynamic organization can be realized mechanistically within a unified dynamical system remains unclear. Continuous Hopfield networks provide a classical attractor framework in which neural dynamics follow gradient descent on a fixed energy landscape, constraining retrieval within a static attractor manifold geometry. Extending this approach, we introduce Dynamic Manifold Hopfield Networks (DMHN), continuous dynamical models in which contextual modulation dynamically reshapes attractor geometry, transforming a static attractor manifold into a context-dependent family of neural manifolds. In DMHN, network interactions are learned in a data-driven manner, to intrinsically deform the geometry of its attractor manifold across cues without explicit context-specific parameterization. As a result, in associative retrieval, DMHN achieve substantially higher capacity and robustness than classical and modern Hopfield networks: when storing $2N$ patterns in a network of $N$ neurons, DMHN attain reliable retrieval with an average accuracy of 64%, compared with 1% and 13% for classical and modern variants, respectively. Together, these results establish dynamic reorganization of attractor manifold geometry as a principled mechanism for context-dependent remapping in neural associative memory. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.02753 Wed, 04 Mar 2026 00:00:00 -0500 arXiv:2603.02753v1 Announce Type: cross Abstract: Designing novel proteins with desired characteristics remains a significant challenge due to the large sequence space and the complexity of sequence-function relationships. Efficient exploration of this space to identify sequences that meet specific design criteria is crucial for advancing therapeutics and biotechnology. Here, we present BoGA (Bayesian Optimization Genetic Algorithm), a framework that combines evolutionary search with Bayesian optimization to efficiently navigate the sequence space. By integrating a genetic algorithm as a stochastic proposal generator within a surrogate modeling loop, BoGA prioritizes candidates based on prior evaluations and surrogate model predictions, enabling data-efficient optimization. We demonstrate the utility of BoGA through benchmarking on sequence and structure design tasks, followed by its application in designing peptide binders against pneumolysin, a key virulence factor of \textit{Streptococcus pneumoniae}. BoGA accelerates the discovery of high-confidence binders, demonstrating the potential for efficient protein design across diverse objectives. The algorithm is implemented within the BoPep suite and is available under an MIT license at \href{https://github.com/ErikHartman/bopep}{GitHub}. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2504.10525 Wed, 04 Mar 2026 00:00:00 -0500 arXiv:2504.10525v2 Announce Type: replace Abstract: The automated extraction of chemical structures and their corresponding bioactivity data is essential for accelerating drug discovery and enabling data-driven research. Current optical chemical structure recognition tools lack the capability to autonomously link molecular structures with their bioactivity profiles, posing a significant bottleneck in structure-activity relationship analysis. To address this, we present BioChemInsight, an open-source pipeline that integrates DECIMER Segmentation with MolNexTR for chemical structure recognition, GLM-4.5V for compound identifier association, and PaddleOCR combined with GLM-4.6 for bioactivity extraction and unit normalization. We evaluated BioChemInsight on 181 patents covering 15 therapeutic targets. The system achieved an average extraction accuracy of above 90% across three key tasks: chemical structure recognition, bioactivity data extraction, and compound identifier association. Our analysis indicates that the chemical space covered by patents is largely complementary to that contained in established public database ChEMBL. Consequently, by enabling systematic patent mining, BioChemInsight provides access to chemical information underrepresented in ChEMBL. This capability expands the landscape of explorable compound-target interactions, enriches the data foundation for quantitative structure-activity relationship modeling and targeted screening, and reduces data preprocessing time from weeks to hours. BioChemInsight is available at https://github.com/dahuilangda/BioChemInsight. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.03237 Wed, 04 Mar 2026 00:00:00 -0500 arXiv:2603.03237v1 Announce Type: cross Abstract: Spatial relationships in multi-species data can indicate and affect system outcomes and behaviors, ranging from disease progression in cancer to coral reef resilience in ecology; therefore, quantifying these relationships is an important problem across scientific disciplines. Persistent homology (PH), a key mathematical and computational tool in topological data analysis (TDA), provides a multiscale description of the shape of data. While it effectively describes spatial organization of species, such as cellular patterns in pathology, it cannot detect the shape relations between different types of species. Traditionally, PH analyzes single-species data, which limits the spatial analysis of interactions between different species. Leveraging recent developments in TDA and computational geometry, we introduce a scalable approach to quantify higher-order interactions in multi-species data. The framework can distinguish the presence of shape features or patterns in the data that are (i) common to multiple species of points, (ii) present in some species but disappear in the presence of other species, (iii) only visible when multiple species are considered together, and (iv) formed by some species and remain visible in the presence of others. We demonstrate our approach on two example applications. We identify (1) different behavioral regimes in a synthetic tumor micro-environment model, and (2) interspecies spatial interactions that are most significantly altered in colorectal cancer tissue samples during disease progression. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2512.06116 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2512.06116v2 Announce Type: replace-cross Abstract: Quantitative characterization of cellular spatial organization is critical for understanding tumor progression and immune response. Recent advances in artificial intelligence (AI) enable large-scale segmentation and classification of nuclei from digitized histopathology slides, producing massive point pattern and marked point pattern data. However, accessible and standardized tools for downstream spatial statistical analysis remain limited. We present SASHIMI (Spatial Analysis for Segmented Histopathology Images using Machine Intelligence), a browser-based platform for real-time spatial analysis of AI-segmented histopathology images. Rather than proposing new spatial methods, SASHIMI systematically organizes and operationalizes 27 widely used spatial summary statistics, areal indices, and topological features within a unified computational framework. The platform computes mathematically grounded descriptors including K-, L-, G-, F-, and J-functions, pair correlation and mark connection functions, spatial autocorrelation measures, similarity indices, and persistent homology-based topological summaries. Outputs include both functional curves and scalar feature tables suitable for downstream statistical modeling. We illustrate the framework using two cancer cohorts: oral potentially malignant disorders and non-small-cell lung cancer. Across datasets, cross-type spatial interactions and topological descriptors show associations with patient survival, demonstrating that complementary spatial features capture distinct aspects of tumor microenvironment architecture. SASHIMI provides an accessible, reproducible platform for single-cell-level spatial profiling of tumor tissue, enabling interactive visualization and standardized feature extraction without requiring programming expertise. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2509.20719 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2509.20719v2 Announce Type: replace-cross Abstract: Inspired by the effectiveness of genetic algorithms and the importance of synthesizability in molecular design, we present SynGA, a simple genetic algorithm that operates directly over synthesis routes. Our method features custom crossover and mutation operators that explicitly constrain it to synthesizable molecular space. By modifying the fitness function, we demonstrate the effectiveness of SynGA on a variety of design tasks, including synthesizable analog search and sample-efficient property optimization, for both 2D and 3D objectives. Furthermore, by coupling SynGA with a machine learning-based filter that focuses the building block set, we boost SynGA to state-of-the-art performance. For property optimization, this manifests as a model-based variant SynGBO, which employs SynGA and block filtering in the inner loop of Bayesian optimization. Since SynGA is lightweight and enforces synthesizability by construction, our hope is that SynGA can not only serve as a strong standalone baseline but also as a versatile module that can be incorporated into larger synthesis-aware workflows in the future. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2509.04778 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2509.04778v2 Announce Type: replace-cross Abstract: It is difficult or infeasible to directly measure how much of a drug actually enters the human brain and a brain tumor, how long it remains there, and to estimate drug-specific or patient-specific parameters, as well as how changes in these parameters influence model outputs and pharmacokinetic characteristics. Compartmental modeling offers a powerful mathematical approach to describe drug distribution and elimination in the body using systems of differential equations. This study introduces TumorPred, an R/Shiny-based web application designed for model simulation, sensitivity analysis, and pharmacokinetic parameter calculation in a permeability-limited four-compartment brain model. The model closely mimics human brain functionality for drug delivery and aims to predict the pharmacokinetics of drugs in the brain blood, brain mass, and cranial and spinal cerebrospinal fluid (CSF) of the human brain. The app provides real-time output updates in response to input modifications and allows users to visualize and download simulated plots and data tables. The computational accuracy of TumorPred is validated against results from the Simcyp Simulator (Certara Inc.). TumorPred is freely accessible and serves as an invaluable computational tool and data-driven resource for advancing drug development and optimizing treatment strategies for more effective brain cancer therapy. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2509.04718 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2509.04718v2 Announce Type: replace-cross Abstract: The ubiquitous regression to the mean (RTM) effect complicates statistical inference regarding the relationship between baseline levels of a biological variable and its subsequent change. We demonstrate that common RTM correction methods are problematic: the Berry et al. method, popularized by Kelly & Price in The American Naturalist, is unreliable for hypothesis testing or effect-size estimation, leading to systematic bias and inflated error rates. Conversely, while the Blomqvist method is theoretically unbiased, its high sampling variance limits its practical utility in small-to-moderate datasets. Using a structural linear model, we show that the most robust approach to navigating RTM is not to correct the data, but to evaluate the uncorrected crude slope against a structural null expectation derived from measurement repeatability-the proportion of total variance attributable to true individual differences. We illustrate this approach using empirical data from studies on lizard thermal physiology and bird telomere dynamics. Ultimately, we argue that any conclusion regarding a differential treatment effect is statistically unfounded without a clear understanding of the experiment's repeatability. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2507.00445 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2507.00445v3 Announce Type: replace-cross Abstract: We address the problem of fine-tuning diffusion models for reward-guided generation in biomolecular design. While diffusion models have proven highly effective in modeling complex, high-dimensional data distributions, real-world applications often demand more than high-fidelity generation, requiring optimization with respect to potentially non-differentiable reward functions such as physics-based simulation or rewards based on scientific knowledge. Although RL methods have been explored to fine-tune diffusion models for such objectives, they often suffer from instability, low sample efficiency, and mode collapse due to their on-policy nature. In this work, we propose an iterative distillation-based fine-tuning framework that enables diffusion models to optimize for arbitrary reward functions. Our method casts the problem as policy distillation: it collects off-policy data during the roll-in phase, simulates reward-based soft-optimal policies during roll-out, and updates the model by minimizing the KL divergence between the simulated soft-optimal policy and the current model policy. Our off-policy formulation, combined with KL divergence minimization, enhances training stability and sample efficiency compared to existing RL-based methods. Empirical results demonstrate the effectiveness and superior reward optimization of our approach across diverse tasks in protein, small molecule, and regulatory DNA design. The source code is released at (https://divelab.github.io/VIDD/). Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2506.09007 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2506.09007v2 Announce Type: replace-cross Abstract: Predicting the intermediate trajectories between an initial and target distribution is a central problem in generative modeling. Existing approaches, such as flow matching and Schr\"odinger bridge matching, effectively learn mappings between two distributions by modeling a single stochastic path. However, these methods are inherently limited to unimodal transitions and cannot capture branched or divergent evolution from a common origin to multiple distinct modes. To address this, we introduce Branched Schr\"odinger Bridge Matching (BranchSBM), a novel framework that learns branched Schr\"odinger bridges. BranchSBM parameterizes multiple time-dependent velocity fields and growth processes, enabling the representation of population-level divergence into multiple terminal distributions. We show that BranchSBM is not only more expressive but also essential for tasks involving multi-path surface navigation, modeling cell fate bifurcations from homogeneous progenitor states, and simulating diverging cellular responses to perturbations. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2506.07459 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2506.07459v3 Announce Type: replace-cross Abstract: Protein generative models have shown remarkable promise in protein design, yet their success rates remain constrained by reliance on curated sequence-structure datasets and by misalignment between supervised objectives and real design goals. We present ProteinZero, an online reinforcement learning framework for inverse folding models that enables scalable, automated, and continuous self-improvement with computationally efficient feedback. ProteinZero employs a reward pipeline that combines structural guidance from ESMFold with a novel self-derived ddG predictor, providing stable multi-objective signals while avoiding the prohibitive cost of physics-based methods. To ensure robustness in online RL, we further introduce a novel embedding-level diversity regularizer that mitigates mode collapse and promotes functionally meaningful sequence variation. Within a general RL formulation balancing multi-reward optimization, KL-divergence from a reference model, and diversity regularization, ProteinZero achieves robust improvements across designability, stability, recovery, and diversity. On the CATH-4.3 benchmark, it consistently outperforms state-of-the-art baselines including ProteinMPNN, ESM-IF, and InstructPLM, reducing design failure rates by 36-48% and achieving success rates above 90% across diverse folds. Importantly, a complete RL run can be executed on a single 8 X GPU node within three days, including reward computation and data generation. These results indicate that efficient online RL fine-tuning can complement supervised pretraining by allowing protein generative models to evolve continuously from their own outputs and optimize multiple design objectives without labeled data, opening new possibilities for exploring the vast protein design space. Full source code and model checkpoints will be released upon publication. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2505.12565 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2505.12565v3 Announce Type: replace-cross Abstract: Despite their ability to understand chemical knowledge, large language models (LLMs) remain limited in their capacity to propose novel molecules with desired functions (e.g., drug-like properties). In addition, the molecules that LLMs propose can often be challenging to make, and are almost never compatible with automated synthesis approaches. To better enable the discovery of functional small molecules, LLMs need to learn a new molecular language that is more effective in predicting properties and inherently synced with automated synthesis technology. Current molecule LLMs are limited by representing molecules based on atoms. In this paper, we argue that just like tokenizing texts into meaning-bearing (sub-)word tokens instead of characters, molecules should be tokenized at the level of functional building blocks, i.e., parts of molecules that bring unique functions and serve as effective building blocks for real-world automated laboratory synthesis. This motivates us to propose mCLM, a modular Chemical-Language Model that comprises a bilingual language model that understands both natural language descriptions of functions and molecular blocks. mCLM front-loads synthesizability considerations while improving the predicted functions of molecules in a principled manner. Experiments on FDA-approved drugs showed that mCLM is capable of significantly improving chemical functions. mCLM, with only 3B parameters, also achieves improvements in synthetic accessibility relative to 7 other leading generative AI methods including GPT-5. When tested on 122 out-of-distribution medicines using only building blocks/tokens that are compatible with automated modular synthesis, mCLM outperforms all baselines in property scores and synthetic accessibility. mCLM can also reason on multiple functions and iteratively self-improve to rescue drug candidates that failed late in clinical trials ("fallen angels"). Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2402.10018 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2402.10018v5 Announce Type: replace-cross Abstract: In this paper, we propose an efficient two-stage decoding algorithm for non-adaptive Group Testing (GT) with general correlated prior statistics. The proposed solution can be applied to any correlated statistical prior represented in trellis, e.g., finite state machines and Markov processes. We introduce a variation of List Viterbi Algorithm (LVA) to enable accurate recovery using much fewer tests than objectives, which efficiently gains from the correlated prior statistics structure. We also provide a sufficiency bound to the number of pooled tests required by any Maximum A Posteriori (MAP) decoder with an arbitrary correlation, i.e., dependence between infected items. Our numerical results demonstrate that the proposed two-stage decoding GT (2SDGT) algorithm can obtain the optimal MAP performance with feasible complexity in practical regimes, such as with COVID-19 and sparse signal recovery applications, and reduce in the scenarios tested the number of pooled tests by at least $25\%$ compared to existing classical low complexity GT algorithms. Moreover, we analytically characterize the complexity of the proposed 2SDGT algorithm that guarantees its efficiency. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2307.14025 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2307.14025v3 Announce Type: replace-cross Abstract: Multiple instance learning (MIL) is a framework for weakly supervised classification, where labels are assigned to sets of instances, i.e., bags, rather than to individual data points. This paradigm has proven effective in tasks where fine-grained annotations are unavailable or costly to obtain. However, the effectiveness of MIL drops sharply when training data are scarce, such as for rare disease classification. To address this challenge, we propose incorporating topological inductive biases into the data representation space within the MIL framework. This bias introduces a topology-preserving constraint that encourages the instance encoder to maintain the topological structure of the instance distribution within each bag when mapping them to MIL latent space. As a result, our Topology Guided MIL (TG-MIL) method enhances the performance and generalizability of MIL classifiers across different aggregation functions, especially under scarce-data regimes. Our evaluations show average performance improvements of 15.3% for synthetic MIL datasets, 2.8% for MIL benchmarks, and 5.5% for rare anemia classification compared to current state-of-the-art MIL models, where only 17-120 samples per class are available. We make our code publicly available. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2512.18114 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2512.18114v2 Announce Type: replace Abstract: Protein representation learning has advanced rapidly with the scale-up of sequence and structure supervision, but most models still encode proteins either as per-residue token sequences or as single global embeddings. This overlooks a defining property of protein organization: proteins are built from recurrent, evolutionarily conserved substructures that concentrate biochemical activity and mediate core molecular functions. Although substructures such as domains and functional sites are systematically cataloged, they are rarely used as training signals or representation units in protein models. We introduce Magneton, an environment for developing substructure-aware protein models. Magneton provides (1) a dataset of 530,601 proteins annotated with over 1.7 million substructures spanning 13,075 types, (2) a training framework for incorporating substructures into existing protein models, and (3) a benchmark suite of 13 tasks probing representations at the residue, substructural, and protein levels. Using Magneton, we develop substructure-tuning, a supervised fine-tuning method that distills substructural knowledge into pretrained protein models. Across state-of-the-art sequence- and structure-based models, substructure-tuning improves function prediction, yields more consistent representations of substructure types never observed during tuning, and shows that substructural supervision provides information that is complementary to global structure inputs. The Magneton environment, datasets, and substructure-tuned models are all openly available (https://github.com/rcalef/magneton/). Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2511.11758 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2511.11758v2 Announce Type: replace Abstract: Protein structure is central to biological function, and enabling multimodal protein models requires joint reasoning over sequence, structure, and function. A key barrier is the lack of principled protein structure tokenizers (PSTs): existing approaches fix token size or rely on continuous vector codebooks, limiting interpretability, multi-scale control, and transfer across architectures. We introduce GeoBPE, a geometry-grounded PST that transforms continuous, noisy, multi-scale backbone conformations into discrete ``sentences'' of geometry while enforcing global constraints. Analogous to byte-pair encoding, GeoBPE generates a hierarchical vocabulary of geometric primitives by iteratively (i) clustering Geo-Pair occurrences with k-medoids to yield a resolution-controllable vocabulary; (ii) quantizing each Geo-Pair to its closest medoid prototype; and (iii) reducing drift through differentiable inverse kinematics that optimizes boundary glue angles under an $\mathrm{SE}(3)$ end-frame loss. GeoBPE offers compression ($>$10x reduction in bits-per-residue at similar distortion rate), data efficiency ($>$10x less training data), and generalization (maintains test/train distortion ratio of $1.0-1.1$). It is architecture-agnostic: (a) its hierarchical vocabulary provides a strong inductive bias for coarsening residue-level embeddings from large PLMs into motif- and protein-level representations, consistently outperforming leading PSTs across $12$ tasks and $24$ test splits; (b) paired with a transformer, GeoBPE supports unconditional backbone generation via language modeling; and (c) tokens align with CATH functional families and support expert-interpretable case studies, offering functional meaning absent in prior PSTs. Code is available at https://github.com/shiningsunnyday/PT-BPE/. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.01965 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.01965v1 Announce Type: cross Abstract: Multimodal Variational Autoencoders have emerged as a popular tool to extract effective representations from rich multimodal data. However, such models rely on fusion strategies in latent space that destroy the joint statistical structure of the multimodal data, with profound implications for generation and uncertainty quantification. In this work, we introduce Correlated Variational Autoencoders (CoVAE), a new generative architecture that captures the correlations between modalities. We test CoVAE on a number of real and synthetic data sets demonstrating both accurate cross-modal reconstruction and effective quantification of the associated uncertainties. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.01396 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.01396v1 Announce Type: cross Abstract: Single-cell perturbation studies face dual heterogeneity bottlenecks: (i) semantic heterogeneity--identical biological concepts encoded under incompatible metadata schemas across datasets; and (ii) statistical heterogeneity--distribution shifts from biological variation demanding dataset-specific inductive biases. We propose HarmonyCell, an end-to-end agent framework resolving each challenge through a dedicated mechanism: an LLM-driven Semantic Unifier autonomously maps disparate metadata into a canonical interface without manual intervention; and an adaptive Monte Carlo Tree Search engine operates over a hierarchical action space to synthesize architectures with optimal statistical inductive biases for distribution shifts. Evaluated across diverse perturbation tasks under both semantic and distribution shifts, HarmonyCell achieves a 95% valid execution rate on heterogeneous input datasets (versus 0% for general agents) while matching or even exceeding expert-designed baselines in rigorous out-of-distribution evaluations. This dual-track orchestration enables scalable automatic virtual cell modeling without dataset-specific engineering. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.01849 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.01849v1 Announce Type: new Abstract: Background: Klebsiella pneumoniae is a major opportunistic pathogen responsible for various invasive infections. The rise of carbapenem-resistant K. pneumoniae, primarily due to acquisition of bla NDM genes, presents a serious global health threat. In French Polynesia, where international travel is frequent, sporadic cases of NDM-producing Enterobacteriales have emerged. This study aims to characterize the genomic features of NDM-producing K. pneumoniae isolates collected in French Polynesia and evaluate the roles of clonal expansion and horizontal gene transfer mediated by mobile genetic elements in bla NDM spread. Materials and Methods: Between July 2006 and September 2021, 17 carbapenemase-producing K. pneumoniae isolates were identified from 715 clinical samples in Tahiti. Whole-genome sequencing using Illumina MiSeq and Oxford Nanopore technologies was performed. Results: Seven NDM-producing K. pneumoniae strains were identified, five bla NDM-1 and two bla NDM-9 variants. All isolates were resistant to ertapenem (MICs 1 to >32 mg/L), with three resistants to imipenem (MICs 8 to >32 mg/L) and six to meropenem (MICs 2 to >8 mg/L). A novel IS26mediated composite transposon, Tn7722 (16,246 bp), was detected in four isolates on IncF and IncR plasmids. This transposon also carried qnrS1 and aph(3')-VI genes, conferring resistance to fluoroquinolones and aminoglycosides. Tn7722-like elements were found in diverse bacterial genomes worldwide, suggesting it facilitates bla NDM transmission across multiple species and regions. Conclusion: NDM-producing K. pneumoniae in French Polynesia remain sporadic but genetically diverse, without evidence of local outbreak. It underscores the role of plasmid and Tn7722-driven evolution and adaptation. Ongoing genomic surveillance is vital to track the evolution of highrisk clones and MGEs guiding effective containment. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2603.00208 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.00208v1 Announce Type: new Abstract: Objective: ML-based clinical risk prediction models are increasingly used to support decision-making in healthcare. While class-imbalance correction techniques are commonly applied to improve model performance in settings with rare outcomes, their impact on probabilistic calibration remains insufficiently understood. This study evaluated the effect of widely used resampling strategies on both discrimination and calibration across real-world clinical prediction tasks. Methods: Ten clinical datasets spanning diverse medical domains and including 605,842 patients were analyzed. Multiple machine-learning model families, including linear models and several non-linear approaches, were evaluated. Models were trained on the original data and under three commonly used 1:1 class-imbalance correction strategies (SMOTE, RUS, ROS). Performance was assessed on held-out data using discrimination and calibration metrics. Results: Across all datasets and model families, resampling had no positive impact on predictive performance. Changes in the Receiver Operating Characteristic Area Under Curve (ROC-AUC) relative to models trained on the original data were small and inconsistent (ROS: -0.002, p 0.05; SMOTE: -0.01, p<0.05), with no resampling strategy demonstrating a systematic improvement. In contrast, resampling in general degraded the calibration performance. Models trained using imbalance correction exhibited higher Brier scores (0.029 to 0.080, p<0.05), reflecting poorer probabilistic accuracy, and marked deviations in calibration intercept and slope, indicating systematic distortions of predicted risk despite preserved rank-based performance. Conclusion: In a diverse set of real-world clinical prediction tasks, commonly used class-imbalance correction techniques did not provide generalizable improvements in discrimination and were associated with degraded calibration. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2602.23410 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2602.23410v2 Announce Type: replace-cross Abstract: Brain foundation models have achieved remarkable advances across a wide range of neuroscience tasks. However, most existing models are limited to a single functional modality, restricting their ability to exploit complementary spatiotemporal dynamics and the collective data scale across imaging techniques. To address this limitation, we propose Brain-OF, the first omnifunctional brain foundation model jointly pretrained on fMRI, EEG and MEG, capable of handling both unimodal and multimodal inputs within a unified framework. To reconcile heterogeneous spatiotemporal resolutions, we introduce the Any-Resolution Neural Signal Sampler, which projects diverse brain signals into a shared semantic space. To further manage semantic shifts, the Brain-OF backbone integrates DINT attention with a Sparse Mixture of Experts, where shared experts capture modality-invariant representations and routed experts specialize in modality-specific semantics. Furthermore, we propose Masked Temporal-Frequency Modeling, a dual-domain pretraining objective that jointly reconstructs brain signals in both the time and frequency domains. Brain-OF is pretrained on a large-scale corpus comprising around 40 datasets and demonstrates superior performance across diverse downstream tasks, highlighting the benefits of joint multimodal integration and dual-domain pretraining. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2512.11582 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2512.11582v2 Announce Type: replace-cross Abstract: The development of foundation models for functional magnetic resonance imaging (fMRI) time series holds significant promise for predicting phenotypes related to disease and cognition. Current models, however, are often trained using a mask-and-reconstruct objective on small brain regions. This focus on low-level information leads to representations that are sensitive to noise and temporal fluctuations, necessitating extensive fine-tuning for downstream tasks. We introduce Brain-Semantoks, a self-supervised framework designed specifically to learn abstract representations of brain dynamics. Its architecture is built on two core innovations: a semantic tokenizer that aggregates noisy regional signals into robust tokens representing functional networks, and a self-distillation objective that enforces representational stability across time. We show that this objective is stabilized through a novel training curriculum, ensuring the model robustly learns meaningful features from low signal-to-noise time series. We demonstrate that learned representations enable strong performance on a variety of downstream tasks even when only using a linear probe. Furthermore, we provide comprehensive scaling analyses indicating more unlabeled data reliably results in out-of-distribution performance gains without domain adaptation. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.25976 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2510.25976v2 Announce Type: replace-cross Abstract: Reconstructing images seen by people from their fMRI brain recordings provides a non-invasive window into the human brain. Despite recent progress enabled by diffusion models, current methods often lack faithfulness to the actual seen images. We present "Brain-IT", a brain-inspired approach that addresses this challenge through a Brain Interaction Transformer (BIT), allowing effective interactions between clusters of functionally-similar brain-voxels. These functional-clusters are shared by all subjects, serving as building blocks for integrating information both within and across brains. All model components are shared by all clusters & subjects, allowing efficient training with a limited amount of data. To guide the image reconstruction, BIT predicts two complementary localized patch-level image features: (i)high-level semantic features which steer the diffusion model toward the correct semantic content of the image; and (ii)low-level structural features which help to initialize the diffusion process with the correct coarse layout of the image. BIT's design enables direct flow of information from brain-voxel clusters to localized image features. Through these principles, our method achieves image reconstructions from fMRI that faithfully reconstruct the seen images, and surpass current SotA approaches both visually and by standard objective metrics. Moreover, with only 1-hour of fMRI data from a new subject, we achieve results comparable to current methods trained on full 40-hour recordings. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.18808 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2510.18808v2 Announce Type: replace-cross Abstract: Feedback alignment and related weight-transport-free algorithms are often proposed as biologically plausible alternatives to backpropagation, yet they are typically formulated in discrete phases with implicitly synchronized forward and error signals. We develop a continuous-time model of feedback-alignment-type learning in which neural activities and synaptic weights evolve together under coupled first-order dynamics with distinct propagation, plasticity, and decay time constants. We show that learning is governed by the temporal overlap between presynaptic drive and a locally projected error signal, providing an analytic explanation for robustness to moderate timing mismatch and for failure when mismatch eliminates overlap. Our results show that in order for feedback-alignment-type algorithms to work at biological timescales, they must obey the same temporal overlap principle that applies to other biological processes like eligibility traces. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2509.26560 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2509.26560v2 Announce Type: replace-cross Abstract: The global dimensionality of a neural representation manifold provides rich insight into the computational process underlying both artificial and biological neural networks. However, all existing measures of global dimensionality are sensitive to the number of samples, i.e., the number of rows and columns of the sample matrix. We show that, in particular, the participation ratio of eigenvalues, a popular measure of global dimensionality, is highly biased with small sample sizes, and propose a bias-corrected estimator that is more accurate with finite samples and with noise. On synthetic data examples, we demonstrate that our estimator can recover the true known dimensionality. We apply our estimator to neural brain recordings, including calcium imaging, electrophysiological recordings, and fMRI data, and to the neural activations in a large language model and show our estimator is invariant to the sample size. Finally, our estimators can additionally be used to measure the local dimensionalities of curved neural manifolds by weighting the finite samples appropriately. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2508.11674 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2508.11674v2 Announce Type: replace-cross Abstract: This study proposes a novel learning paradigm for spiking neural networks (SNNs) that replaces the perceptron-inspired abstraction with biologically grounded neuron models, jointly optimizing synaptic weights and intrinsic neuronal parameters. We evaluate two architectures, leaky integrate-and-fire (LIF) and a meta-neuron model, under fixed and learnable intrinsic dynamics. Additionally, we introduce a biologically inspired classification framework that combines SNN dynamics with Lempel-Ziv complexity (LZC), enabling efficient and interpretable classification of spatiotemporal spike data. Training is conducted using surrogate-gradient backpropagation, spike-timing-dependent plasticity (STDP), and the Tempotron rule on spike trains generated from Poisson processes, widely adopted in computational neuroscience as a standard stochastic model of neuronal spike generation due to their analytical tractability and empirical relevance. Learning intrinsic parameters improves classification accuracy by up to 13.50 percentage points for LIF networks and 8.50 for meta-neuron models compared to baselines tuning only network size and learning rate. The proposed SNN-LZC classifier achieves up to 99.50% accuracy with sub-millisecond inference latency and competitive energy consumption. We further provide theoretical justification by formalizing how optimizing intrinsic dynamics enlarges the hypothesis class and proving descent guarantees for intrinsic-parameter updates under standard smoothness assumptions, linking intrinsic optimization to provable improvements in the surrogate objective. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2506.06750 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2506.06750v2 Announce Type: replace-cross Abstract: Training spiking neural networks (SNNs) remains challenging due to temporal dynamics, non-differentiability of spike events, and sparse event-driven activations. This paper studies how the choice of learning paradigm (unsupervised, supervised, and hybrid) affects classification performance and computational cost in temporal pattern recognition. Building on our earlier study [Rudnicka et al., 2026], we use Lempel-Ziv complexity (LZC) as a compact, decision-relevant descriptor of spike-train temporal organization to quantify how different learning rules reshape class-conditional temporal structure. The pipeline combines a leaky integrate-and-fire (LIF) SNN with an LZC-based decision rule. We evaluate learning rules on synthetic sources with controlled temporal statistics (Bernoulli, two-state Markov, and Poisson spike processes) and on two-class subsets of MNIST and N-MNIST. Across datasets, gradient-based learning achieves the highest accuracy but at high computational cost, whereas bio-inspired rules (e.g., Tempotron and SpikeProp) offer favorable accuracy--efficiency trade-offs. These results highlight that selecting a learning rule should be guided by application constraints and the desired balance between separability and computational overhead. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2502.01334 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2502.01334v2 Announce Type: replace-cross Abstract: Focal deficits in ischaemic stroke result from impaired perfusion downstream of a critical vascular occlusion. While parenchymal lesions are traditionally used to predict clinical deficits, the underlying pattern of disrupted perfusion provides information upstream of the lesion, potentially yielding earlier predictive and localizing signals. Such perfusion maps can be derived from routine CT angiography (CTA) widely deployed in clinical practice. Analysing computed perfusion maps from 1,393 CTA-imaged-patients with acute ischaemic stroke, we use deep generative inference to localise neural substrates of NIHSS sub-scores. We show that our approach replicates known lesion-deficit relations without knowledge of the lesion itself and reveals novel neural dependents. The high achieved anatomical fidelity suggests acute CTA-derived computed perfusion maps may be of substantial clinical-and-scientific value in rich phenotyping of acute stroke. Using only hyperacute imaging, deep generative inference could power highly expressive models of functional anatomical relations in ischaemic stroke within the pre-interventional window. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.09951 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2510.09951v3 Announce Type: replace Abstract: Sequential firing of hippocampal place cells is often attributed to sequential sensory drive along a trajectory, and has also been attributed to planning and other cognitive functions. Here, we propose a mechanistic and parsimonious interpretation to complement these ideas: hippocampal sequences arise from intrinsic recurrent circuitry that propagates transient input over long horizons, acting as a temporal memory buffer that is especially useful when reliable sensory evidence is sparse. We implement this idea with a minimal sequence generator inspired by neurobiology and pair it with an actor-critic learner for egocentric visual navigation. Our agent reliably solves a continuous maze without explicit geometric cues, with performance depending on the length of the recurrent sequence. Crucially, the model outperforms LSTM cores under sparse input conditions (16 channels, $\sim2.5\%$ activity), but not under dense input, revealing a strong interaction between representational sparsity and memory architecture. Through learning, units develop localized place fields, distance-dependent spatial kernels, and task-dependent remapping, while inputs to the sequence generator orthogonalize and spatial information increases across layers. These phenomena align with neurobiological data and are causal to performance. Together, our results show that sparse input synergizes with sequence-generating dynamics, providing both a mechanistic account of place cell sequences in the mammalian hippocampus and a simple inductive bias for reinforcement learning based on sparse egocentric inputs in navigation tasks. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2501.06762 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2501.06762v3 Announce Type: replace Abstract: Continuous, adaptive learning, the ability to adapt to the environment and keep improving performance, is a hallmark of natural intelligence. Biological organisms excel in acquiring, transferring, and retaining knowledge while adapting to volatile environments, making them a source of inspiration for artificial neural networks (ANNs). This study explores how neuromodulation, a building block of learning in biological systems, can help address catastrophic forgetting and enhance the robustness of ANNs in continual learning. Driven by neuromodulators including dopamine (DA), acetylcholine (ACh), serotonin (5-HT) and noradrenaline (NA), neuromodulatory processes in the brain operate at multiple scales, facilitating dynamic responses to environmental changes through mechanisms ranging from local synaptic plasticity to global network-wide adaptability. Importantly, the relationship between neuromodulators and their interplay in modulating sensory and cognitive processes is more complex than previously expected, demonstrating a "many-to-one" neuromodulator-to-task mapping. To inspire neuromodulation-aware learning rules, we highlight (i) how multi-neuromodulatory interactions enrich single-neuromodulator-driven learning, (ii) the impact of neuromodulators across multiple spatio-temporal scales, and correspondingly, (iii) strategies for approximating and integrating neuromodulated learning processes in ANNs. To illustrate these principles, we present a conceptual study to showcase how neuromodulation-inspired mechanisms, such as DA-driven reward processing and NA-based cognitive flexibility, can enhance ANN performance in a Go/No-Go task. Though multi-scale neuromodulation, we aim to bridge the gap between biological and artificial learning, paving the way for ANNs with greater flexibility, robustness, and adaptability. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.01568 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.01568v1 Announce Type: cross Abstract: Generalization to novel visual conditions remains a central challenge for both human and machine vision, yet standard robustness metrics offer limited insight into how systems trade accuracy for robustness. We introduce a rate-distortion-theoretic framework that treats stimulus-response behavior as an effective communication channel, derives rate-distortion (RD) frontiers from confusion matrices, and summarizes each system with two interpretable geometric signatures - slope ($\beta$) and curvature ($\kappa$) - which capture the marginal cost and abruptness of accuracy-robustness trade-offs. Applying this framework to human psychophysics and 18 deep vision models under controlled image perturbations, we compare generalization geometry across model architectures and training regimes. We find that both biological and artificial systems follow a common lossy-compression principle but occupy systematically different regions of RD space. In particular, humans exhibit smoother, more flexible trade-offs, whereas modern deep networks operate in steeper and more brittle regimes even at matched accuracy. Across training regimes, robustness training induces systematic but dissociable shifts in beta/kappa, revealing cases where improved robustness or accuracy does not translate into more human-like generalization geometry. These results demonstrate that RD geometry provides a compact, model-agnostic lens for comparing generalization behavior across systems beyond standard accuracy-based metrics. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2603.01184 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.01184v1 Announce Type: cross Abstract: Representation learning from complex data typically involves models with a large number of parameters, which in turn require large amounts of data samples. In neural network models, model complexity grows with the number of inputs to each neuron, with a trade-off between model expressivity and learning time. A precise characterization of this trade-off would help explain the connectivity and learning times observed in artificial and biological networks. We present a theoretical analysis of how learning time depends on input dimensionality for a Hebbian learning model performing independent component analysis. Based on the geometry of high-dimensional spaces, we show that the learning dynamics reduce to a unidimensional problem, with learning times dependent only on initial conditions. For higher input dimensions, initial parameters have smaller learning gradients and larger learning times. We find that learning times have supralinear scaling, becoming quickly prohibitive for high input dimensions. These results reveal a fundamental limitation for learning in high dimensions and help elucidate how the optimal design of neural networks depends on data complexity. Our approach outlines a new framework for analyzing learning dynamics and model complexity in neural network models. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2503.04490 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2503.04490v3 Announce Type: replace-cross Abstract: Large Language Models (LLMs) are revolutionizing bioinformatics, enabling advanced analysis of DNA, RNA, proteins, and single-cell data. This survey provides a systematic review of recent advancements, focusing on genomic sequence modeling, RNA structure prediction, protein function inference, and single-cell transcriptomics. Meanwhile, we also discuss several key challenges, including data scarcity, computational complexity, and cross-omics integration, and explore future directions such as multimodal learning, hybrid AI models, and clinical applications. By offering a comprehensive perspective, this paper underscores the transformative potential of LLMs in driving innovations in bioinformatics and precision medicine. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2602.17739 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2602.17739v2 Announce Type: replace Abstract: Genomic sequences span billions of base pairs (bp), posing a fundamental challenge for genome-scale foundation models. Existing approaches largely sidestep this barrier by either scaling relatively small models to long contexts or relying on heavy multi-GPU parallelism. Here we introduce GeneZip, a DNA compression model that leverages a key biological prior: genomic information is highly imbalanced. Coding regions comprise only a small fraction (about 2 percent) yet are information-dense, whereas most non-coding sequence is comparatively information-sparse. GeneZip couples HNet-style dynamic routing with a region-aware compression-ratio objective, enabling adaptive allocation of representation budget across genomic regions. As a result, GeneZip learns region-aware compression and achieves 137.6x compression with only 0.31 perplexity increase. On downstream long-context benchmarks, GeneZip achieves comparable or better performance on contact map prediction, expression quantitative trait loci prediction, and enhancer-target gene prediction. By reducing effective sequence length, GeneZip unlocks simultaneous scaling of context and capacity: compared to the prior state-of-the-art model JanusDNA, it enables training models 82.6x larger at 1M-bp context, supporting a 636M-parameter GeneZip model at 1M-bp context. All experiments in this paper can be trained on a single A100 80GB GPU. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.01780 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.01780v1 Announce Type: cross Abstract: Early DNA foundation models adopted BERT-style training, achieving good performance on DNA understanding tasks but lacking generative capabilities. Recent autoregressive models enable DNA generation, but employ left-to-right causal modeling that is suboptimal for DNA where regulatory relationships are inherently bidirectional. We present D3LM (\textbf{D}iscrete \textbf{D}NA \textbf{D}iffusion \textbf{L}anguage \textbf{M}odel), which unifies bidirectional representation learning and DNA generation through masked diffusion. D3LM directly adopts the Nucleotide Transformer (NT) v2 architecture but reformulates the training objective as masked diffusion in discrete DNA space, enabling both bidirectional understanding and generation capabilities within a single model. Compared to NT v2 of the same size, D3LM achieves improved performance on understanding tasks. Notably, on regulatory element generation, D3LM achieves an SFID of 10.92, closely approaching real DNA sequences (7.85) and substantially outperforming the previous best result of 29.16 from autoregressive models. Our work suggests diffusion language models as a promising paradigm for unified DNA foundation models. We further present the first systematic study of masked diffusion models in the DNA domain, investigating practical design choices such as tokenization schemes and sampling strategies, thereby providing empirical insights and a solid foundation for future research. D3LM has been released at https://huggingface.co/collections/Hengchang-Liu/d3lm. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2603.00678 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.00678v1 Announce Type: cross Abstract: The capacity to precisely edit genomes has outpaced our ability to predict the consequences. A cell can be genetically perfect and therapeutically useless: edited exactly as intended, yet unstable, drifting toward unintended fates, or selected for properties that compromise safety. This paradox reflects a deeper gap in how we evaluate biological intervention. Current frameworks excel at measuring what was done to a cell but remain blind to what the cell has become. We argue that this blindness stems from treating cells as collections of independent variables rather than as dynamical systems occupying positions on high-dimensional state manifolds. Drawing on Waddington's epigenetic landscape, we propose geometric stability as a missing axis of evaluation: the directional coherence of cellular responses to perturbation. This metric distinguishes interventions that guide cells coherently toward stable states from those that scatter them across the state manifold. Validation across diverse perturbation datasets reveals that geometric stability captures regulatory architecture invisible to conventional metrics, discriminating pleiotropic master regulators from lineage-specific factors without prior biological annotation. As precision medicine increasingly relies on cellular reprogramming, the question shifts from ``did the intervention occur?'' to ``is the resulting state stable?'' Geometric stability provides a framework for answering. Quantitative_Biology/q-bio.CB_(Cell_Behavior) https://arxiv.org/abs/2411.02109 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2411.02109v3 Announce Type: replace-cross Abstract: Generalization beyond training data remains a central challenge in machine learning for biology. A common way to enhance generalization is self-supervised pre-training on large datasets. However, aiming to perform well on all possible proteins can limit a model's capacity to excel on any specific one, whereas experimentalists typically need accurate predictions for individual proteins they study, often not covered in training data. To address this limitation, we propose a method that enables self-supervised customization of protein language models to one target protein at a time, on the fly, and without assuming any additional data. We show that our Protein Test-Time Training (ProteinTTT) method consistently enhances generalization across different models, their sizes, and datasets. ProteinTTT improves structure prediction for challenging targets, achieves new state-of-the-art results on protein fitness prediction, and enhances function prediction on two tasks. Through two challenging case studies, we also show that customization via ProteinTTT achieves more accurate antibody-antigen loop modeling and enhances 19% of structures in the Big Fantastic Virus Database, delivering improved predictions where general-purpose AlphaFold2 and ESMFold struggle. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2506.02052 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2506.02052v3 Announce Type: replace Abstract: Recently, extensive deep learning architectures and pretraining strategies have been explored to support downstream protein applications. Additionally, domain-specific models incorporating biological knowledge have been developed to enhance performance in specialized tasks. In this work, we introduce $\textbf{Protap}$, a comprehensive benchmark that systematically compares backbone architectures, pretraining strategies, and domain-specific models across diverse and realistic downstream protein applications. Specifically, Protap covers five applications: three general tasks and two novel specialized tasks, i.e., enzyme-catalyzed protein cleavage site prediction and targeted protein degradation, which are industrially relevant yet missing from existing benchmarks. For each application, Protap compares various domain-specific models and general architectures under multiple pretraining settings. Our empirical studies imply that: (i) Though large-scale pretraining encoders achieve great results, they often underperform supervised encoders trained on small downstream training sets. (ii) Incorporating structural information during downstream fine-tuning can match or even outperform protein language models pretrained on large-scale sequence corpora. (iii) Domain-specific biological priors can enhance performance on specialized downstream tasks. Code and datasets are publicly available at https://github.com/Trust-App-AI-Lab/protap. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2505.23354 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2505.23354v4 Announce Type: replace Abstract: The local structure of a protein strongly impacts its function and interactions with other molecules. Therefore, a concise, informative representation of a local protein environment is essential for modeling and designing proteins and biomolecular interactions. However, these environments' extensive structural and chemical variability makes them challenging to model, and such representations remain under-explored. In this work, we propose a novel representation for a local protein environment derived from the intermediate features of atomistic foundation models (AFMs). We demonstrate that this embedding effectively captures both local structure (e.g., secondary motifs), and chemical features (e.g., amino-acid identity and protonation state). We further show that the AFM-derived representation space exhibits meaningful structure, enabling the construction of data-driven priors over the distribution of biomolecular environments. Finally, in the context of biomolecular NMR spectroscopy, we demonstrate that the proposed representations enable a first-of-its-kind physics-informed chemical shift predictor that achieves state-of-the-art accuracy. Our results demonstrate the surprising effectiveness of atomistic foundation models and their emergent representations for protein modeling beyond traditional molecular simulations. We believe this will open new lines of work in constructing effective functional representations for protein environments. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.01537 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.01537v1 Announce Type: cross Abstract: The contributions of model complexity, data volume, and feature modalities to knowledge graph-based drug repurposing remain poorly quantified under rigorous temporal validation. We constructed a pharmacology knowledge graph from ChEMBL 36 comprising 5,348 entities including 3,127 drugs, 1,156 proteins, and 1,065 indications. A strict temporal split was enforced with training data up to 2022 and testing data from 2023 to 2025, together with biologically verified hard negatives mined from failed assays and clinical trials. We benchmarked five knowledge graph embedding models and a standard graph neural network with 3.44 million parameters that incorporates drug chemical structure using a graph attention encoder and ESM-2 protein embeddings. Scaling experiments ranging from 0.78 to 9.75 million parameters and from 25 to 100 percent of the data, together with feature ablation studies, were used to isolate the contributions of model capacity, graph density, and node feature modalities. Removing the graph attention based drug structure encoder and retaining only topological embeddings combined with ESM-2 protein features improved drug protein PR-AUC from 0.5631 to 0.5785 while reducing VRAM usage from 5.30 GB to 353 MB. Replacing the drug encoder with Morgan fingerprints further degraded performance, indicating that explicit chemical structure representations can be detrimental for predicting pharmacological network interactions. Increasing model size beyond 2.44 million parameters yielded diminishing returns, whereas increasing training data consistently improved performance. External validation confirmed 6 of the top 14 novel predictions as established therapeutic indications. These results show that drug pharmacological behavior can be accurately predicted using target-centric information and drug network topology alone, without requiring explicit chemical structure representations. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2603.01873 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2603.01873v1 Announce Type: new Abstract: Representation learning for protein biochemical space faces a difficult trade-off: protein language models excel at capturing long-range biological semantics but often miss fine-grained chemical details. Conversely, chemical language models encode atomic information but lack broader sequence context. To address this, we introduce Bi-TEAM (Bi-gated Residual Space Modification), a general framework that injects localized chemical variation into global protein contexts. By ensuring robustness against perturbations such as non-canonical amino acids, post-translational modifications (PTMs), and topological constraints, Bi-TEAM uncovers functional chemical dependencies often missed by evolutionary baselines. Mechanistically, Bi-TEAM maps non-canonical residues to their natural counterparts and injects atomic-level data via a bi-gated residual fusion mechanism. Crucially, this process uses modification-aware prompts to ensure that local structural changes influence global functional representations without requiring alphabet expansion. We evaluated Bi-TEAM on ten datasets spanning chemically modified peptides, PTMs, and natural proteins. The model consistently outperformed state-of-the-art baselines, achieving up to a 66 percent improvement in Matthews correlation coefficient (MCC) on scaffold-similarity splits and a 350 percent increase in hemolysis prediction accuracy. Furthermore, when deployed as an oracle for generative modeling, Bi-TEAM nearly quadrupled the success rate for designing cell-penetrating cyclic peptides. By unifying biological semantics with chemical precision, Bi-TEAM provides a versatile foundation for machine learning driven exploration of peptide and protein biochemical space. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2510.18516 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2510.18516v2 Announce Type: replace Abstract: Neural recordings exhibit a distinctive form of heterogeneity rooted in differences in cell types, intrinsic circuit dynamics, and stochastic stimulus-response variability that goes beyond ordinary dataset variability, mixing statistically regular neurons with highly stochastic, stimulus-contingent ones within the same dataset. This heterogeneity poses a challenge for self-supervised learning (SSL) -- learnable statistical regularity -- thereby destabilizing representation learning and limiting reliable scaling. We introduce POYO-CAP (Cell-pattern Aware Pretraining), a biologically grounded hybrid pretraining strategy that first trains with masked reconstruction plus lightweight auxiliary supervision on statistically regular neurons -- identified via skewness and kurtosis -- and then fine-tunes on more stochastic populations. On the Allen Brain Observatory dataset, this curriculum yields 12--13\% relative improvements over from-scratch training and enables smooth, monotonic scaling with model size, whereas baselines trained on mixed populations plateau or destabilize. By making statistical predictability an explicit data-selection criterion, POYO-CAP turns neural heterogeneity into a scalable learning advantage for robust neural decoding. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2508.10760 Tue, 03 Mar 2026 00:00:00 -0500 arXiv:2508.10760v2 Announce Type: replace Abstract: Drug discovery is a complex, multi-step pipeline that remains heavily dependent on manual, experience-driven operations; meanwhile, existing customized artificial intelligence tools are fragmented across web applications, desktop software, and code libraries, resulting in incompatible interfaces and inefficient, burdensome workflows. To overcome these challenges, we propose FROGENT, a full-process drug design multi-agent system that leverages the planning, reasoning, and tool-use capabilities of large language models (LLMs) to unify drug discovery within a closed-loop and autonomous framework. FROGENT is a collaborative multi-agent system comprising a central Orchestrate Agent for strategic workflow coordination and three distributed agents, Retrieve, Forge, and Gauge, that employ dynamic biochemical databases, extensible tool libraries, and task-specific computational models via the Model Context Protocol. This architecture enables end-to-end execution of complex drug discovery pipelines, covering target identification, small-molecule generation, peptide optimization, and retrosynthetic planning. Across eight benchmarks spanning core drug discovery tasks, FROGENT consistently outperforms six increasingly advanced ReAct-style agents. Case studies further demonstrate its practicality and generalization across real-world small-molecule and peptide design scenarios. Overall, FROGENT not only achieves substantial gains in efficiency and accuracy, but also demonstrates the potential of LLM-based agentic systems to autonomously orchestrate drug development pipelines, reducing, or even replacing, reliance on manual, experience-driven human intervention. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2511.13550 Mon, 02 Mar 2026 00:00:00 -0500 arXiv:2511.13550v2 Announce Type: replace Abstract: Molecular dynamics (MD) simulations provide atomistic insights into the structure, dynamics, and function of biomolecules by generating time-resolved, high-dimensional trajectories. Analyzing such data benefits from estimating the minimal number of variables required to describe the explored conformational manifold, known as the intrinsic dimension (ID). We present MDIntrinsicDimension, an open-source Python package that estimates ID directly from MD trajectories by combining rotation- and translation-invariant molecular projections (e.g., backbone dihedrals and inter-residue distances) with state-of-the-art estimators. The package provides three complementary analysis modes: whole-molecule ID; sliding windows along the sequence; and per-secondary-structure elements. It computes both overall ID (a single summary value) and instantaneous, time-resolved ID that can reveal transitions and heterogeneity over time. We illustrate the approach on fast folding-unfolding trajectories from the DESRES dataset, demonstrating that ID complements conventional geometric descriptors by highlighting spatially localized flexibility and differences across structural segments. Quantitative_Biology/q-bio.BM_(Biomolecules) https://arxiv.org/abs/2601.17582 Mon, 02 Mar 2026 00:00:00 -0500 arXiv:2601.17582v2 Announce Type: replace-cross Abstract: Biomolecular networks underpin emerging technologies in synthetic biology-from robust biomanufacturing and metabolic engineering to smart therapeutics and cell-based diagnostics-and also provide a mechanistic language for understanding complex dynamics in natural and ecological systems. Yet designing chemical reaction networks (CRNs) that implement a desired dynamical function remains largely manual: while a proposed network can be checked by simulation, the reverse problem of discovering a network from a behavioral specification is difficult, requiring substantial human insight to navigate a vast space of topologies and kinetic parameters with nonlinear and possibly stochastic dynamics. Here we introduce GenAI-Net, a generative AI framework that automates CRN design by coupling an agent that proposes reactions to simulation-based evaluation defined by a user-specified objective. GenAI-Net efficiently produces novel, topologically diverse solutions across multiple design tasks, including dose responses, complex logic gates, classifiers, oscillators, and robust perfect adaptation in deterministic and stochastic settings (including noise reduction). By turning specifications into families of circuit candidates and reusable motifs, GenAI-Net provides a general route to programmable biomolecular circuit design and accelerates the translation from desired function to implementable mechanisms. Quantitative_Biology/q-bio.MN_(Molecular_Networks) https://arxiv.org/abs/2507.09513 Mon, 02 Mar 2026 00:00:00 -0500 arXiv:2507.09513v2 Announce Type: replace Abstract: The brain can only be fully understood through the lens of the behavior it generates -- a guiding principle in modern neuroscience research that nevertheless presents significant technical challenges. Many studies capture behavior with cameras, but video analysis approaches typically rely on specialized models requiring extensive labeled data. We address this limitation with BEAST(BEhavioral Analysis via Self-supervised pretraining of Transformers), a novel and scalable framework that pretrains experiment-specific vision transformers for diverse neuro-behavior analyses. BEAST combines masked autoencoding with temporal contrastive learning to effectively leverage unlabeled video data. Through comprehensive evaluation across multiple species, we demonstrate improved performance in three critical neuro-behavioral tasks: extracting behavioral features that correlate with neural activity, and pose estimation and action segmentation in both the single- and multi-animal settings. Our method establishes a powerful and versatile backbone model that accelerates behavioral analysis in scenarios where labeled data remains scarce. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2602.13368 Mon, 02 Mar 2026 00:00:00 -0500 arXiv:2602.13368v2 Announce Type: replace Abstract: This study investigates the relationship between interocular distance relative to overall facial width (width ratio) and perceived subjective beauty in male faces. Building on the methodology of Pallett et al. (2010), who found that average proportions in female faces were rated as most attractive, the current study aimed to test this hypothesis in male faces. Faces from the Chicago Face Database (Ma et al., 2015) were morphed into average faces within three groups (with low, medium, and high width ratios), each composed of 96 or 97 individual images. These three average faces were then systematically manipulated in their width ratios across three levels in both directions, respectively, resulting in a total of 21 comparable faces. The use of multiple base faces served as a control for potential artifacts of image processing. Consequently, comparisons were restricted to within-group pairs to avoid confounding by co-varying facial features (e.g., skin tone), which precluded direct cross-condition comparisons but ensured internal validity. In a two-alternative forced-choice task, participants selected the more beautiful face from each pair. The data were analyzed using a Bayesian model which enables inference of the width ratio perceived as most beautiful. Results support the hypothesis that averageness in facial proportions correlates with higher perceived attractiveness. The study highlights the importance of controlling for image manipulation, including attempts at methodological implementation, and of considering ethnicity as a potential moderating variable. These findings offer a data-driven foundation for understanding facial aesthetics and cognitive processes of human perception, with applications in advertising, artificial face generation, and plastic surgery. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.06091 Mon, 02 Mar 2026 00:00:00 -0500 arXiv:2510.06091v2 Announce Type: replace-cross Abstract: Mixtures of linear dynamical systems (MoLDS) provide a path to model time-series data that exhibit diverse temporal dynamics across trajectories. However, its application remains challenging in complex and noisy settings, limiting its effectiveness for neural data analysis. Tensor-based moment methods can provide global identifiability guarantees for MoLDS, but their performance degrades under noise and complexity. Commonly used expectation-maximization (EM) methods offer flexibility in fitting latent models but are highly sensitive to initialization and prone to poor local minima. Here, we propose a tensor-based method that provides identifiability guarantees for learning MoLDS, which is followed by EM updates to combine the strengths of both approaches. The novelty in our approach lies in the construction of moment tensors using the input-output data to recover globally consistent estimates of mixture weights and system parameters. These estimates can then be refined through a Kalman EM algorithm, with closed-form updates for all LDS parameters. We validate our framework on synthetic benchmarks and real-world datasets. On synthetic data, the proposed Tensor-EM method achieves more reliable recovery and improved robustness compared to either pure tensor or randomly initialized EM methods. We then analyze neural recordings from the primate somatosensory cortex while a non-human primate performs reaches in different directions. Our method successfully models and clusters different conditions as separate subsystems, consistent with supervised single-LDS fits for each condition. Finally, we apply this approach to another neural dataset where monkeys perform a sequential reaching task. These results demonstrate that MoLDS provides an effective framework for modeling complex neural data, and that Tensor-EM is a reliable approach to MoLDS learning for these applications. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2508.11724 Mon, 02 Mar 2026 00:00:00 -0500 arXiv:2508.11724v2 Announce Type: replace Abstract: Pollinating insects can obtain information from electric fields arising from flowers. The density and usefulness of electric information remain unknown. Here, we show that electric information can be used to reconstruct geometrical features of the field source. We develop an algorithm that infers the shapes of polarisable flowers from the electric field generated in response to a nearby charged arthropod. We computed the electric fields arising from arthropod flower interactions for varying petal geometries, and used these data to train a deep learning U Net model to recreate the floral shapes. The model accurately reconstructed diverse shapes, including more complex flower morphologies not included in training. Reconstruction performance peaked at an optimal arthropod flower distance, indicating distance dependent encoding of shape information. These findings indicate that electroreception can impart rich spatial detail, offering insights into the electric ecology of arthropods. Together, this work introduces a deep learning framework for solving the inverse electrostatic imaging problem, enabling object shape reconstruction directly from measured electric fields. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2602.23459 Mon, 02 Mar 2026 00:00:00 -0500 arXiv:2602.23459v1 Announce Type: cross Abstract: Psychiatric questionnaires are highly context sensitive and often only weakly predict subsequent symptom severity, which makes the prognostic relationship difficult to learn. Although flexible nonlinear models can improve predictive accuracy, their limited interpretability can erode clinical trust. In fields such as imaging and omics, investigators commonly address visit- and instrument-specific artifacts by extracting stable signal through preprocessing and then fitting an interpretable linear model. We adopt the same strategy for questionnaire data by decoupling preprocessing from prediction: we restrict nonlinear capacity to a baseline preprocessing module that estimates stable item values, and then learn a linear mapping from these stabilized baseline items to future severity. We refer to this two-stage method as REFINE (Redundancy-Exploiting Follow-up-Informed Nonlinear Enhancement), which concentrates nonlinearity in preprocessing while keeping the prognostic relationship transparently linear and therefore globally interpretable through a coefficient matrix, rather than through post hoc local attributions. In experiments, REFINE outperforms other interpretable approaches while preserving clear global attribution of prognostic factors across psychiatric and non-psychiatric longitudinal prediction tasks. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2602.22247 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.22247v1 Announce Type: new Abstract: Single-cell foundation models such as scGPT learn high-dimensional gene representations, but what biological knowledge these representations encode remains unclear. We systematically decode the geometric structure of scGPT internal representations through 63 iterations of automated hypothesis screening (183 hypotheses tested), revealing that the model organizes genes into a structured biological coordinate system rather than an opaque feature space. The dominant spectral axis separates genes by subcellular localization, with secreted proteins at one pole and cytosolic proteins at the other. Intermediate transformer layers transiently encode mitochondrial and ER compartments in a sequence that mirrors the cellular secretory pathway. Orthogonal axes encode protein-protein interaction networks with graded fidelity to experimentally measured interaction strength (Spearman rho = 1.000 across n = 5 STRING confidence quintiles, p = 0.017). In a compact six-dimensional spectral subspace, the model distinguishes transcription factors from their target genes (AUROC = 0.744, all 12 layers significant). Early layers preserve which specific genes regulate which targets, while deeper layers compress this into a coarser regulator versus regulated distinction. Repression edges are geometrically more prominent than activation edges, and B-cell master regulators BATF and BACH2 show convergence toward the B-cell identity anchor PAX5 across transformer depth. Cell-type marker genes cluster with high fidelity (AUROC = 0.851). Residual-stream geometry encodes biological structure complementary to attention patterns. These results indicate that biological transformers learn an interpretable internal model of cellular organization, with implications for regulatory network inference, drug target prioritization, and model auditing. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2602.22239 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.22239v1 Announce Type: cross Abstract: Mutational signature analysis has emerged as a powerful method for uncovering the underlying biological processes driving cancer development. However, the signature extraction process, typically performed using non-negative matrix factorization (NMF), often lacks reliability and clinical applicability. To address these limitations, several solutions have been introduced, including the use of neural networks to achieve more accurate estimates and probabilistic methods to better capture natural variation in the data. In this work, we introduce a Variational Autoencoder for Mutational Signatures (VAE-MS), a novel model that leverages both an asymmetric architecture and probabilistic methods for the extraction of mutational signatures. VAE-MS is compared to with three state-of-the-art models for mutational signature extraction: SigProfilerExtractor, the NMF-based gold standard; MUSE-XAE, an autoencoder that employs an asymmetric design without probabilistic components; and SigneR, a Bayesian NMF model, to illustrate the strength in combining a nonlinear extraction with a probabilistic model. In the ability to reconstruct input data and generalize to unseen data, models with probabilistic components (VAE-MS, SigneR) dramatically outperformed models without (SigProfilerExtractor, MUSE-XAE). The NMF-baed models (SigneR, SigProfilerExtractor) had the most accurate reconstructions in simulated data, while VAE-MS reconstructed more accurately on real cancer data. Upon evaluating the ability to extract signatures consistently, no model exhibited a clear advantage over the others. Software for VAE-MS is available at https://github.com/CLINDA-AAU/VAE-MS. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2602.22289 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.22289v1 Announce Type: cross Abstract: When biological foundation models such as scGPT and Geneformer process single-cell gene expression, what geometric and topological structure forms in their internal representations? Is that structure biologically meaningful or a training artifact, and how confident should we be in such claims? We address these questions through autonomous large-scale hypothesis screening: an AI-driven executor-brainstormer loop that proposed, tested, and refined 141 geometric and topological hypotheses across 52 iterations, covering persistent homology, manifold distances, cross-model alignment, community structure, and directed topology, all with explicit null controls and disjoint gene-pool splits. Three principal findings emerge. First, the models learn genuine geometric structure. Gene embedding neighborhoods exhibit non-trivial topology, with persistent homology significant in 11 of 12 transformer layers at p < 0.05 in the weakest domain and 12 of 12 in the other two. A multi-level distance hierarchy shows that manifold-aware metrics outperform Euclidean distance for identifying regulatory gene pairs, and graph community partitions track known transcription factor target relationships. Second, this structure is shared across independently trained models. CCA alignment between scGPT and Geneformer yields canonical correlation of 0.80 and gene retrieval accuracy of 72 percent, yet none of 19 tested methods reliably recover gene-level correspondences. The models agree on the global shape of gene space but not on precise gene placement. Third, the structure is more localized than it first appears. Under stringent null controls applied across all null families, robust signal concentrates in immune tissue, while lung and external lung signals weaken substantially. Quantitative_Biology/q-bio.GN_(Genomics) https://arxiv.org/abs/2602.22895 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.22895v1 Announce Type: new Abstract: Implementations of symmetric positive definite (SPD) matrix-based neural networks for neural decoding remain fragmented across research codebases and Python packages. Existing implementations often employ ad hoc handling of manifold constraints and non-unified training setups, which hinders reproducibility and integration into modern deep-learning workflows. To address this gap, we introduce SPD Learn, a unified and modular Python package for geometric deep learning with SPD matrices. SPD Learn provides core SPD operators and neural-network layers, including numerically stable spectral operators, and enforces Stiefel/SPD constraints via trivialization-based parameterizations. This design enables standard backpropagation and optimization in unconstrained Euclidean spaces while producing manifold-constrained parameters by construction. The package also offers reference implementations of representative SPDNet-based models and interfaces with widely used brain computer interface/neuroimaging toolkits and modern machine-learning libraries (e.g., MOABB, Braindecode, Nilearn, and SKADA), facilitating reproducible benchmarking and practical deployment. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2602.22408 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.22408v1 Announce Type: cross Abstract: Humans exhibit remarkable flexibility in abstract reasoning, and can rapidly learn and apply rules from sparse examples. To investigate the cognitive strategies underlying this ability, we introduce the Cognitive Abstraction and Reasoning Corpus (CogARC), a diverse human-adapted subset of the Abstraction and Reasoning Corpus (ARC) which was originally developed to benchmark abstract reasoning in artificial intelligence. Across two experiments, CogARC was administered to a total of 260 human participants who freely generated solutions to 75 abstract visual reasoning problems. Success required inferring input-output rules from a small number of examples to transform the test input into one correct test output. Participants' behavior was recorded at high temporal resolution, including example viewing, edit sequences, and multi-attempt submissions. Participants were generally successful (mean accuracy ~90% for experiment 1 (n=40), ~80% for experiment 2 (n=220) across problems), but performance varied widely across problems and participants. Harder problems elicited longer deliberation times and greater divergence in solution strategies. Over the course of the task, participants initiated responses more quickly but showed a slight decline in accuracy, suggesting increased familiarity with the task structure rather than improved rule-learning ability. Importantly, even incorrect solutions were often highly convergent, even when the problem-solving trajectories differed in length and smoothness. Some trajectories progressed directly and efficiently toward a stable outcome, whereas others involved extended exploration or partial restarts before converging. Together, these findings highlight CogARC as a rich behavioral environment for studying human abstract reasoning, providing insight into how people generalize, misgeneralize, and adapt their strategies under uncertainty. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2602.22523 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.22523v1 Announce Type: cross Abstract: While contemporary large language models (LLMs) are increasingly capable in isolation, there are still many difficult problems that lie beyond the abilities of a single LLM. For such tasks, there is still uncertainty about how best to take many LLMs as parts and combine them into a greater whole. This position paper argues that potential blueprints for designing such modular language agents can be found in the existing literature on cognitive models and artificial intelligence (AI) algorithms. To make this point clear, we formalize the idea of an agent template that specifies roles for individual LLMs and how their functionalities should be composed. We then survey a variety of existing language agents in the literature and highlight their underlying templates derived directly from cognitive models or AI algorithms. By highlighting these designs, we aim to call attention to agent templates inspired by cognitive science and AI as a powerful tool for developing effective, interpretable language agents. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2602.23274 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.23274v1 Announce Type: cross Abstract: Simulation code for conventional supercomputers serves as a reference for neuromorphic computing systems. The present bottleneck of distributed large-scale spiking neuronal network simulations is the communication between compute nodes. Communication speed seems limited by the interconnect between the nodes and the software library orchestrating the data transfer. Profiling reveals, however, that the variability of the time required by the compute nodes between communication calls is large. The bottleneck is in fact the waiting time for the slowest node. A statistical model explains total simulation time on the basis of the distribution of computation times between communication calls. A fundamental cure is to avoid communication calls because this requires fewer synchronizations and reduces the variability of computation times across compute nodes. The organization of the mammalian brain into areas lends itself to such an optimization strategy. Connections between neurons within an area have short delays, but the delays of the long-range connections across areas are an order of magnitude longer. This suggests a structure-aware mapping of areas to compute nodes allowing for a partition into more frequent communication between nodes simulating a particular area and less frequent global communication. We demonstrate a substantial performance gain on a real-world example. This work proposes a local-global hybrid communication architecture for large-scale neuronal network simulations as a first step in mapping the structure of the brain to the structure of a supercomputer. It challenges the long-standing belief that the bottleneck of simulation is synchronization inherent in the collective calls of standard communication libraries. We provide guidelines for the energy efficient simulation of neuronal networks on conventional computing systems and raise the bar for neuromorphic systems. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2305.11953 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2305.11953v3 Announce Type: replace Abstract: Representational drift refers to an unstable mapping between neural activity and input sensory or output behavioral variables. While much work has focused on the effect of representational drift on single, simple external variables, we investigate the differences in representational drift across spatiotemporal features in a moving visual stimulus. The neural responses across animals to the same movie reflect both common, encoded stimulus features and idiosyncratic individual variation. To extract the shared neural encoding of stimulus features only, we learn a latent space embedding using weakly supervised contrastive learning. This approach pulls neural activity together in the embedding space if they are responses to the same stimulus segment and push them apart if not. This approach enables us to probe how stimulus features fluctuating as fast as 33 ms (the movie frame rate) are encoded by variable neural codes across animals. It also allows us to investigate how representational drift changes the encoding in individuals across sessions. We observe that our learned embedding is near-optimal for decoding natural features (background scenery, local motion, complex spatio-temporal features, and time) and neural activity from novel animals. This suggests that our embedding retains the encoding of multiple features at higher temporal granularity compared to previous methods. To quantify representational drift, we apply the trained decoder (which achieves near-optimal performance in one session) to a subsequent session recorded 90 minutes later. We then use the decrease in decoding performance as a proxy for the magnitude of drift. We show that the drift changes the encoding of fast-varying local motion features at a rate 5-6 times higher than slower-varying scenery features. Drift also perturbs the local geometry in the embedding. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2510.14382 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2510.14382v3 Announce Type: replace Abstract: The brain anticipates future events using internal models that specify not only what will occur, but also when it will occur and with what probability. We refer to this joint specification of identity, timing, and likelihood as a complete prediction object. Existing computational models typically capture identity and timing separately, omit probability as an explicit representational dimension, or rely on biologically implausible global learning rules. Here we show that a single population of spiking neurons can acquire and flexibly maintain a complete prediction object through biologically grounded learning. We implemented a heterogeneous Izhikevich spiking reservoir with multiplexed readouts trained by an error-modulated, attention-gated three-factor Hebbian rule, and tested it on a task that independently manipulates event identity, latency, and probability. The network develops time-locked anticipatory activity whose amplitude scales with outcome probability and rapidly adapts when timing or probability statistics change. Identity and timing components self-organize into near-orthogonal readout subspaces within a shared neural population, demonstrating that multidimensional predictive structure can emerge without anatomical modularization or global error broadcast. Compared with least-squares-based approaches, local gated plasticity enables stable recalibration under nonstationary conditions. These results suggest that cortical mixed-selective populations, coupled with neuromodulator-gated synaptic plasticity, may be sufficient to jointly encode and update identity, timing, and probability within a single recurrent circuit. Flexible predictive cognition may therefore arise from generic population dynamics shaped by local learning rules rather than from specialized predictive modules. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2506.15190 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2506.15190v3 Announce Type: replace-cross Abstract: Animals flexibly recombine a finite set of core motor motifs to meet diverse task demands, but existing behavior segmentation methods oversimplify this process by imposing discrete syllables under restrictive generative assumptions. To better capture the continuous structure of behavior generation, we introduce motif-based continuous dynamics (MCD) discovery, a framework that (1) uncovers interpretable motif sets as latent basis functions of behavior by leveraging representations of behavioral transition structure, and (2) models behavioral dynamics as continuously evolving mixtures of these motifs. We validate MCD on a multi-task gridworld, a labyrinth navigation task, and freely moving animal behavior. Across settings, it identifies reusable motif components, captures continuous compositional dynamics, and generates realistic trajectories beyond the capabilities of traditional discrete segmentation models. By providing a generative account of how complex animal behaviors emerge from dynamic combinations of fundamental motor motifs, our approach advances the quantitative study of natural behavior. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2602.23268 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.23268v1 Announce Type: new Abstract: The ribosome is responsible for protein synthesis in all cells, and is the largest energy consumer in the cell. We propose that the ribosome originated as a mutualistic symbiont of an RNA-dependent RNA polymerase ribozyme, supplying peptides that enhanced replication. As life transitioned from the RNA to the RNA-protein world, autonomous replicators became irreversibly addicted to the ribosome for producing replication proteins. Subsequent evolution is construed as a ribosomal takeover, whereby the ribosome evolved to consume most of the resources of the cell, while other cellular componentry ensured the propagation of the ribosome. Under this perspective, the ribosome is the ultimate biological selfish element. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2602.22270 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.22270v1 Announce Type: cross Abstract: Spatio-temporal epidemic forecasting is critical for public health management, yet existing methods often struggle with insensitivity to weak epidemic signals, over-simplified spatial relations, and unstable parameter estimation. To address these challenges, we propose the Spatio-Temporal priOr-aware Epidemic Predictor (STOEP), a novel hybrid framework that integrates implicit spatio-temporal priors and explicit expert priors. STOEP consists of three key components: (1) Case-aware Adjacency Learning (CAL), which dynamically adjusts mobility-based regional dependencies using historical infection patterns; (2) Space-informed Parameter Estimating (SPE), which employs learnable spatial priors to amplify weak epidemic signals; and (3) Filter-based Mechanistic Forecasting (FMF), which uses an expert-guided adaptive thresholding strategy to regularize epidemic parameters. Extensive experiments on real-world COVID-19 and influenza datasets demonstrate that STOEP outperforms the best baseline by 11.1% in RMSE. The system has been deployed at one provincial CDC in China to facilitate downstream applications. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2602.22783 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.22783v1 Announce Type: cross Abstract: Branching processes are models used to describe populations that reproduce and die over time. In the classical setting, an individual's reproductive capacity remains constant throughout its lifetime. However, in real-world situations, reproductive capacity typically undergoes ageing - that is, after reaching a peak, it decreases over time. In this work, we study the influence of ageing on the behaviour of the process and how modifying its parameters, along with reproduction rates, affects the destiny of the process. Quantitative_Biology/q-bio.PE_(Populations_and_Evolution) https://arxiv.org/abs/2602.23202 Fri, 27 Feb 2026 00:00:00 -0500 arXiv:2602.23202v1 Announce Type: new Abstract: Dale's Principle has historically guided neuroscience research as a valuable rule of thumb, namely that all synapses on each neuron release the same set of neurotransmitters. Most existing Spiking Neuron Network models share this dichotomous assumption that neurons are either excitatory or inhibitory; however, recent experimental evidence points towards co-release mechanisms that violate this assumption. Here, we introduce a minimal model of "Bilingual" neurons violating Dale's principle that can exert both excitatory and inhibitory effects. We identify parameter regimes in which this architecture exhibits transitions between synchronous and asynchronous dynamics that differ quantitatively from those observed in a matched monolingual control architecture. We report distinct information-processing signatures both at the level of neurons and higher-order interactions between them near the phase transitions. These results suggest that the population of neurons violating Dales principle may provide an alternative mechanism for regulating large-scale oscillatory activity in neural circuits. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2601.09767 Thu, 26 Feb 2026 00:00:00 -0500 arXiv:2601.09767v2 Announce Type: replace Abstract: Malignant tumors exhibit complex pathogenesis, yet classical oncological theories remain fragmented, failing to provide a unifying framework to address this complexity. This gap limits the utility and translational potential of the prevailing "confront-and-eradicate" therapeutic paradigm, constraining transformative therapeutic breakthroughs and driving the emergence of acquired and recurrent drug resistance. Here, we propose the Tumor Existential Crisis-Driven Survival (ECDS) theory, anchored in the core proposition that impairment of Existential Stability drives the compensatory hyperactivation of Survival Capacity. This framework defines three foundational constructs (Existential Stability, Survival Capacity, and Existence Threshold) and three guiding principles, unifying and integrating canonical core theories of tumorigenesis. It delineates the dynamic coupling between declining Existential Stability and escalating Survival Capacity during tumor evolution, reinterprets the hierarchical activation of the well-established 14 cancer hallmarks, elucidates the redundancy of survival signaling pathways that underpins intratumoral and intertumoral heterogeneity, and unravels the "hierarchical leap" in therapeutic resistance. By reframing tumors as "Existential Stability erosion-driven passive survival systems" rather than "intrinsically aggressive cellular aggregates", ECDS challenges prevailing dogma, uncovers tumors' intrinsic vulnerability, and establishes a robust meta-theoretical foundation for both basic cancer research and translational clinical management. Quantitative_Biology/q-bio.TO_(Tissues_and_Organs) https://arxiv.org/abs/2602.21648 Thu, 26 Feb 2026 00:00:00 -0500 arXiv:2602.21648v1 Announce Type: cross Abstract: Clinical risk prediction models often underperform in real-world settings due to poor calibration, limited transportability, and subgroup disparities. These challenges are amplified in high-dimensional multimodal cancer datasets characterized by complex feature interactions and a p >> n structure. We present a fully reproducible multimodal machine learning framework for 5-year overall survival prediction in breast cancer, integrating clinical variables with high-dimensional transcriptomic and copy-number alteration (CNA) features from the METABRIC cohort. After variance- and sparsity-based filtering and dimensionality reduction, models were trained using stratified train/validation/test splits with validation-based hyperparameter tuning. Two survival approaches were compared: an elastic-net regularized Cox model (CoxNet) and a gradient-boosted survival tree model implemented using XGBoost. CoxNet provides embedded feature selection and stable estimation, whereas XGBoost captures nonlinear effects and higher-order interactions. Performance was assessed using time-dependent area under the ROC curve (AUC), average precision (AP), calibration curves, Brier score, and bootstrapped 95 percent confidence intervals. CoxNet achieved validation and test AUCs of 98.3 and 96.6, with AP values of 90.1 and 80.4. XGBoost achieved validation and test AUCs of 98.6 and 92.5, with AP values of 92.5 and 79.9. Fairness diagnostics showed stable discrimination across age groups, estrogen receptor status, molecular subtypes, and menopausal state. This work introduces a governance-oriented multimodal survival framework emphasizing calibration, fairness auditing, robustness, and reproducibility for high-dimensional clinical machine learning. Quantitative_Biology/q-bio.QM_(Quantitative_Methods) https://arxiv.org/abs/2412.02515 Thu, 26 Feb 2026 00:00:00 -0500 arXiv:2412.02515v2 Announce Type: replace-cross Abstract: As numerical simulations grow in complexity, their demands on computing time and energy increase. Accelerators for numerical computation offer significant efficiency gains in many computationally-intensive scientific fields, but their use in simulating spiking neural networks in computational neuroscience is hindered by challenges, mainly in effective parallelism and efficient use of memory in the presence of sparse representations and sparse communication. The BrainScaleS architectures are neuromorphic substrates that can emulate spiking neural networks at accelerated timescales compared to real time, which offers an advantage for studying complex plasticity rules that require extended simulation runtimes. This work presents the implementation of a calcium-based plasticity rule that integrates calcium dynamics based on the synaptic tagging-and-capture hypothesis on the BrainScaleS-2 system. The implementation of the plasticity rule for a single synapse involves incorporating the calcium dynamics and the plasticity rule equations. The calcium dynamics are mapped to the analog circuits of BrainScaleS-2, while the plasticity rule equations are numerically solved on its embedded digital processors. The main hardware constraints include the speed of the processors and the use of integer arithmetic. By adjusting the timestep of the numerical solver and introducing stochastic rounding, we demonstrate that BrainScaleS-2 accurately emulates a single synapse following a calcium-based plasticity rule across four established stimulation protocols and validate our implementation against a software reference model. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2512.17989 Thu, 26 Feb 2026 00:00:00 -0500 arXiv:2512.17989v2 Announce Type: replace Abstract: We examine the conceptual and ethical gaps in current representations of Superintelligence misalignment. We find throughout Superintelligence discourse an absent human subject, and an under-developed theorization of an "AI unconscious" that together are potentiality laying the groundwork for anti-social harm. With the rise of AI Safety that has both thematic potential for establishing pro-social and anti-social potential outcomes, we ask: what place does the human subject occupy in these imaginaries? How is human subjecthood positioned within narratives of catastrophic failure or rapid "takeoff" toward superintelligence? On another register, we ask: what unconscious or repressed dimensions are being inscribed into large-scale AI models? Are we to blame these agents in opting for deceptive strategies when undesirable patterns are inherent within our beings? In tracing these psychic and epistemic absences, our project calls for re-centering the human subject as the unstable ground upon which the ethical, unconscious, and misaligned dimensions of both human and machinic intelligence are co-constituted. Emergent misalignment cannot be understood solely through technical diagnostics typical of contemporary machine-learning safety research. Instead, it represents a multi-layered crisis. The human subject disappears not only through computational abstraction but through sociotechnical imaginaries that prioritize scalability, acceleration, and efficiency over vulnerability, finitude, and relationality. Likewise, the AI unconscious emerges not as a metaphor but as a structural reality of modern deep learning systems: vast latent spaces, opaque pattern formation, recursive symbolic play, and evaluation-sensitive behavior that surpasses explicit programming. These dynamics necessitate a reframing of misalignment as a relational instability embedded within human-machine ecologies. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition) https://arxiv.org/abs/2410.18933 Thu, 26 Feb 2026 00:00:00 -0500 arXiv:2410.18933v3 Announce Type: replace Abstract: Confidence estimates are often "detection-like" - driven by positive evidence in favour of a decision. This empirical observation has been interpreted as showing human metacognition is limited by biases or heuristics. Here we show that Bayesian confidence estimates also exhibit heightened sensitivity to decision-congruent evidence in higher-dimensional signal detection theoretic spaces, leading to detection-like confidence criteria. This effect is due to a nonlinearity induced by normalisation of confidence by a large number of unchosen alternatives. Our analysis suggests that detection-like confidence is rational when computing confidence in a higher-dimensional evidence space than that assumed by the experimenter. Quantitative_Biology/q-bio.NC_(Neurons_and_Cognition)