Synaptic transmission must balance the need for reliable signalling against the metabolic cost of achieving that reliability. How energetic constraints shape synaptic precision and its regulation during plasticity remains unclear. Here we develop an energy--constrained framework in which synapses minimise postsynaptic response variance subject to a fixed mean and an effective energy budget. Combinations of candidate physiological costs are used to estimate an energy cost for synaptic transmission; this cost is then inferred from quantal statistics. Analysing five published pre- and post-plasticity datasets, we find that observed synaptic mean--variance pairs cluster near a minimal-energy boundary, indicating that precision is limited by energetic availability. Model comparison identifies a dominant calcium pump-like cost paired with a smaller vesicle turnover-like cost, yielding a separable precision--energy relationship, $σ^{-2} \propto E^5$. We further show that plasticity systematically updates synaptic energy budgets according to the scale-free magnitude of mean change, enabling accurate prediction of post-plasticity variance from energy allocation alone. These results provide direct experimental support for the hypothesis that synaptic precision is governed by energy budgets, establishing energy allocation as a fundamental principle linking metabolic constraints, synaptic reliability, and plasticity.

Alzheimer's disease (AD) is a progressive neurodegenerative condition necessitating early and precise diagnosis to provide prompt clinical management. Given the paramount importance of early diagnosis, recent studies have increasingly focused on computer-aided diagnostic models to enhance precision and reliability. However, most graph-based approaches still rely on fixed structural designs, which restrict their flexibility and limit generalization across heterogeneous patient data. To overcome these limitations, the Meta-Relational Copula-Based Graph Attention Network (MRC-GAT) is proposed as an efficient multimodal model for AD classification tasks. The proposed architecture, copula-based similarity alignment, relational attention, and node fusion are integrated as the core components of episodic meta-learning, such that the multimodal features, including risk factors (RF), Cognitive test scores, and MRI attributes, are first aligned via a copula-based transformation in a common statistical space and then combined by a multi-relational attention mechanism. According to evaluations performed on the TADPOLE and NACC datasets, the MRC-GAT model achieved accuracies of 96.87% and 92.31%, respectively, demonstrating state-of-the-art performance compared to existing diagnostic models. Finally, the proposed model confirms the robustness and applicability of the proposed method by providing interpretability at various stages of disease diagnosis.

Connecting the dynamics of biomolecular networks to experimentally measurable cell phenotypes remains a central challenge in systems biology. Here we introduce a model-based definition of phenotype as a partial steady state that is committed to a certain dynamical outcome while otherwise being minimally constrained. We focus on Boolean models and define \emph{dynamical phenotypes} as complete trap spaces that maximally specify a chosen set of phenotype-determining nodes that correspond to biomarkers while keeping external inputs unconstrained. We show that dynamical phenotypes can be efficiently identified without full attractor enumeration. Using four published models, including a 70-node Boolean model of T cell differentiation, we show that dynamical phenotypes recover known cell types and activation states, and indicate the environmental conditions ensuring their existence. We also propose a method to identify informative phenotype-determining nodes based on the canalization of the Boolean functions. This method reveals biologically relevant cell state information that is complementary to the phenotypes manually defined by model creators and is validated by two attractor-based approaches. Our results demonstrate that dynamical phenotypes provide a scalable framework for linking model structure, external inputs, and phenotypic outcomes, and offer a principled tool for model-guided biomarker selection.

Evaluating large language models (LLMs) on their ability to generate high-quality, accurate, situationally aware answers to clinical questions requires going beyond conventional benchmarks to assess how these systems behave in complex, high-stakes clinical scenarios. Traditional evaluations are often limited to multiple-choice questions that fail to capture essential competencies such as contextual reasoning, contextual awareness, and uncertainty handling. To address these limitations, we evaluate our agentic RAG-based clinical support assistant, DR. INFO, using HealthBench, a rubric-driven benchmark composed of open-ended, expert-annotated health conversations. On the Hard subset of 1,000 challenging examples, DR. INFO achieves a HealthBench Hard score of 0.68, outperforming leading frontier LLMs including the GPT-5 model family (GPT-5: 0.46, GPT-5.2: 0.42, GPT-5.1: 0.40), Grok 3 (0.23), Gemini 2.5 Pro (0.19), and Claude 3.7 Sonnet (0.02) across all behavioral axes (accuracy, completeness, instruction following, etc.). In a separate 100-sample evaluation against similar agentic RAG assistants (OpenEvidence and Pathway.md, now DoxGPT by Doximity), it maintains a performance lead with a HealthBench Hard score of 0.72. These results highlight the strengths of DR. INFO in communication, instruction following, and accuracy, while also revealing areas for improvement in context awareness and response completeness. Overall, the findings underscore the utility of behavior-level, rubric-based evaluation for building reliable and trustworthy AI-enabled clinical support systems.

Drug discovery is a complex and resource-intensive process, making early prediction of approval outcomes critical for optimizing research investments. While classical machine learning and deep learning methods have shown promise in drug approval prediction, their limited interpretability constraints their impact. Here, we present DrugReasoner, a reasoning-based large language model (LLM) built on the LLaMA architecture and fine-tuned with group relative policy optimization (GRPO) to predict the likelihood of small-molecule approval. DrugReasoner integrates molecular descriptors with comparative reasoning against structurally similar approved and unapproved compounds, generating predictions alongside step-by-step rationales and confidence scores. DrugReasoner achieved robust performance with an AUC of 0.732 and an F1 score of 0.729 on the validation set and 0.725 and 0.718 on the test set, respectively. These results outperformed conventional baselines, including logistic regression, support vector machine, and k-nearest neighbors and had competitive performance relative to XGBoost. On an external independent dataset, DrugReasoner outperformed both baseline and the recently developed ChemAP model, achieving an AUC of 0.728 and an F1-score of 0.774, while maintaining high precision and balanced sensitivity, demonstrating robustness in real-world scenarios. These findings demonstrate that DrugReasoner not only delivers competitive predictive accuracy but also enhances transparency through its reasoning outputs, thereby addressing a key bottleneck in AI-assisted drug discovery. This study highlights the potential of reasoning-augmented LLMs as interpretable and effective tools for pharmaceutical decision-making.

A central challenge in modeling neurodegenerative diseases is connecting cellular-level mechanisms to tissue-level pathology, in particular to determine whether pathology is driven primarily by cell-autonomous triggers or by propagation from cells that are already in a pathological, runaway aggregation state. To bridge this gap, we here develop a bottom-up physical model that explicitly incorporates these two fundamental cell-level drivers of protein aggregation dynamics. We show that our model naturally explains the characteristic long, slow development of pathology followed by a rapid acceleration, a hallmark of many neurodegenerative diseases. Furthermore, the model reveals the existence of a critical switch point at which the system's dynamics transition from being dominated by slow, spontaneous formation of diseased cells to being driven by fast propagation. This framework provides a robust physical foundation for interpreting pathological data and offers a method to predict which class of therapeutic strategies is best matched to the underlying drivers of a specific disease.

Keratin composites enable animals to hike with hooves, fly with feathers, and sense with skin. These distinct functions arise from variations in the underlying properties and microscale arrangement of this natural polymer. One well-studied example is mammalian whiskers, elongated keratin rods attached to tactile skin structures that extend the animal's sensory volume. Here, we investigate the non-actuated whiskers that cover Asian elephant (Elephas maximus) trunks and find they are geometrically and mechanically tailored to facilitate tactile perception by encoding contact location in vibrotactile signal amplitude and frequency. Elephant whiskers emerge from armored trunk skin and shift from a thick, circular, porous, stiff root to a thin, ovular, dense, soft point. This smooth transition enables interaction with widely varying substrates, reduces wear, and increases the vibrotactile signal information generated during contact. The functionally graded geometry, porosity, and stiffness of elephant whiskers tune the neuromechanics of trunk touch, facilitating highly dexterous manipulation.

Competition during range expansions is of great interest from both practical and theoretical view points. Experimentally, range expansions are often studied in homogeneous Petri dishes, which lack spatial anisotropy that might be present in realistic populations. Here, we analyze a model of anisotropic growth, based on coupled Kardar-Parisi-Zhang and Fisher-Kolmogorov-Petrovsky-Piskunov equations that describe surface growth and lateral competition. Compared to a previous study of isotropic growth, anisotropy relaxes a constraint between parameters of the model. We completely characterize spatial patterns and invasion velocities in this generalized model. In particular, we find that strong anisotropy results in a distinct morphology of spatial invasion with a kink in the displaced strain ahead of the boundary between the strains. This morphology of the out-competed strain is similar to a shock wave and serves as a signature of anisotropic growth.

Household size impacts the spread of respiratory infectious diseases: Larger households tend to boost transmission by acquiring external infections more frequently and subsequently transmitting them back into the community. Furthermore, mandatory interventions primarily modulate contagion between households rather than within them. We developed an approach to quantify the role of household size in epidemics by separating within-household from out-household transmission, and found that household size explains 41% of the variability in cumulative COVID-19 incidence across 34 European countries (95% confidence interval: [15%, 46%]). The contribution of households to the overall dynamics can be quantified by a boost factor that increases with the effective household size, implying that countries with larger households require more stringent interventions to achieve the same levels of containment. This suggests that households constitute a structural (dis-)advantage that must be considered when designing and evaluating mitigation strategies.

Adaptive systems must strike a balance between prediction and surprise to thrive in uncertain environments. We propose an information-theoretic balance function, $ f(p) = -(1 - p)\ln(1 - p) + \ln p $, which quantifies the net informational gain from contrasting explained variance $p$ with unexplained novelty $(1 - p)$. This function is strictly concave on $(0,1)$ and reaches its unique maximum at $ p^* \approx 0.882$, revealing a regime where confidence is high but the residual uncertainty carries a disproportionate potential for surprise. Independently of this maximum, imposing a self-similarity condition between known, unknown and total information, $p : (1-p) = 1 : p$, leads to the golden-ratio reciprocal $p = 1/φ\approx 0.618$, where $ φ$ is the golden ratio. We interpret this value not as the maximizer of $f$, but as a structurally privileged \emph{partition} in which known and unknown are proportionally nested across scales. Embedding this dual structure into a Compute-Inference-Model-Action (CIMA) loop yields a dynamic process that maintains the system near a critical regime where prediction and surprise coexist. At this edge, neuronal dynamics exhibit power-law structure and maximal dynamic range, while the system's response to perturbations becomes convex at the level of its payoff function-fulfilling the formal definition of antifragility. We suggest that the golden-ratio partition is not merely a mathematical artifact, but a candidate design principle linking prediction, surprise, criticality, and antifragile adaptation across scales and domains, while the maximum of $f$ identifies the point of greatest informational vulnerability to being wrong.

We investigate the spatial organization of dengue cases in the city of Recife, Brazil, from 2015 to 2024, using tools from statistical physics and topological data analysis. Reported cases are modeled as point clouds in a metric space, and their spatial connectivity is studied through Vietoris-Rips filtrations and zero-dimensional persistent homology, which captures the emergence and collapse of connected components across spatial scales. By parametrizing the filtration using percentiles of the empirical distance distribution, we identify critical percolation thresholds associated with abrupt growth of the largest connected component. These thresholds define distinct geometric regimes, ranging from fragmented spatial patterns to highly concentrated, percolated structures. Remarkably, years with similar incidence levels exhibit qualitatively different percolation behavior, demonstrating that case counts alone do not determine the spatial organization of transmission. Our analysis further reveals pronounced temporal heterogeneity in the percolation properties of dengue spread, including a structural rupture in 2020 characterized by delayed or absent spatial percolation. These findings highlight percolation-based topological observables as physically interpretable and sensitive descriptors of urban epidemic structure, offering a complementary perspective to traditional spatial and epidemiological analyses.

The scarcity of high-quality multimodal biomedical data limits the ability to effectively fine-tune pretrained Large Language Models (LLMs) for specialized biomedical tasks. To address this challenge, we introduce MINT (Multimodal Integrated kNowledge Transfer), a framework that aligns unimodal large decoder models with domain-specific decision patterns from multimodal biomedical data through preference optimization. While MINT supports different optimization techniques, we primarily implement it with the Odds Ratio Preference Optimization (ORPO) framework as its backbone. This strategy enables the aligned LLMs to perform predictive tasks using text-only or image-only inputs while retaining knowledge learnt from multimodal data. MINT leverages an upstream multimodal machine learning (MML) model trained on high-quality multimodal data to transfer domain-specific insights to downstream text-only or image-only LLMs. We demonstrate its effectiveness through two key applications: (1) Rare genetic disease prediction from texts, where MINT uses a multimodal encoder model, trained on facial photos and clinical notes, to generate a preference dataset for aligning a lightweight Llama 3.2-3B-Instruct. Despite relying on text input only, the MINT-derived model outperforms models trained with SFT, RAG, or DPO, and even outperforms Llama 3.1-405B-Instruct. (2) Tissue type classification using cell nucleus images, where MINT uses a vision-language foundation model as the preference generator, containing knowledge learnt from both text and histopathological images to align downstream image-only models. The resulting MINT-derived model significantly improves the performance of Llama 3.2-Vision-11B-Instruct on tissue type classification. In summary, MINT provides an effective strategy to align unimodal LLMs with high-quality multimodal expertise through preference optimization.

In both neuroscience and artificial intelligence, popular functional frameworks and neural network formulations operate by making use of extrinsic error measurements and global learning algorithms. Through a set of conjectures based on evolutionary insights on the origin of cellular adaptive mechanisms, we reinterpret the core meaning of sensory signals to allow the brain to be interpreted as a negative feedback control system, and show how this could lead to local learning algorithms without the need for global error correction metrics. Thereby, a sufficiently good minima in sensory activity can be the complete reward signal of the network, as well as being both necessary and sufficient for biological learning to arise. We show that this method of learning was likely already present in the earliest unicellular life forms on earth. We show evidence that the same principle holds and scales to multicellular organisms where it in addition can lead to division of labour between cells. Available evidence shows that the evolution of the nervous system likely was an adaptation to more effectively communicate intercellular signals to support such division of labour. We therefore propose that the same learning principle that evolved already in the earliest unicellular life forms, i.e. negative feedback control of externally and internally generated sensor signals, has simply been scaled up to become a fundament of the learning we see in biological brains today. We illustrate diverse biological settings, from the earliest unicellular organisms to humans, where this operational principle appears to be a plausible interpretation of the meaning of sensor signals in biology, how this relates to current neuroscientific theories and findings, and how it can be applied to solve body control.