The backpropagation algorithm has experienced remarkable success in training large-scale artificial neural networks; however, its biological plausibility has been strongly criticized, and it remains an open question whether the brain employs supervised learning mechanisms akin to it. Here, we propose correlative information maximization between layer activations as an alternative normative approach to describe the signal propagation in biological neural networks in both forward and backward directions. This new framework addresses many concerns about the biological-plausibility of conventional artificial neural networks and the backpropagation algorithm. The coordinate descent-based optimization of the corresponding objective, combined with the mean square error loss function for fitting labeled supervision data, gives rise to a neural network structure that emulates a more biologically realistic network of multi-compartment pyramidal neurons with dendritic processing and lateral inhibitory neurons. Furthermore, our approach provides a natural resolution to the weight symmetry problem between forward and backward signal propagation paths, a significant critique against the plausibility of the conventional backpropagation algorithm. This is achieved by leveraging two alternative, yet equivalent forms of the correlative mutual information objective. These alternatives intrinsically lead to forward and backward prediction networks without weight symmetry issues, providing a compelling solution to this long-standing challenge.

Generative models capable of precisely capturing nuanced clinical features in medical images hold great promise for facilitating clinical data sharing, enhancing rare disease datasets, and efficiently synthesizing (annotated) medical images at scale. Despite their potential, assessing the quality of synthetic medical images remains a challenge. While modern generative models can synthesize visually-realistic medical images, the clinical plausibility of these images may be called into question. Domain-agnostic scores, such as FID score, precision, and recall, cannot incorporate clinical knowledge and are, therefore, not suitable for assessing clinical sensibility. Additionally, there are numerous unpredictable ways in which generative models may fail to synthesize clinically plausible images, making it challenging to anticipate potential failures and design automated scores for their detection.

Retrosynthesis is one of the domains transformed by the rise of generative models, and it is one where the problem of nonsensical or erroneous outputs (hallucinations) is particularly insidious: reliable assessment of synthetic plans is time-consuming, with automatic methods lacking. In this work, we present RetroTrim, a retrosynthesis system that successfully avoids nonsensical plans on a set of challenging drug-like targets. Compared to common baselines in the field, our system is not only the sole method that succeeds in filtering out hallucinated reactions, but it also results in the highest number of high-quality paths overall. The key insight behind RetroTrim is the combination of diverse reaction scoring strategies, based on machine learning models and existing chemical databases. We show that our scoring strategies capture different classes of hallucinations by analyzing them on a dataset of labeled retrosynthetic intermediates. This approach formed the basis of our winning solution to the Standard Industries \$1 million Retrosynthesis Challenge. To measure the performance of retrosynthesis systems, we propose a novel evaluation protocol for reactions and synthetic paths based on a structured review by expert chemists. Using this protocol, we compare systems on a set of 32 novel targets, curated to reflect recent trends in drug structures. While the insights behind our methodology are broadly applicable to retrosynthesis, our focus is on targets in the drug-like domain. By releasing our benchmark targets and the details of our evaluation protocol, we hope to inspire further research into reliable retrosynthesis.

Quantitative Systems Pharmacology (QSP) modeling is essential for drug development but it requires significant time investment that limits the throughput of domain experts. We present \textbf{GRASP} -- a multi-agent, graph-reasoning framework with a human-in-the-loop conversational interface -- that encodes QSP models as typed biological knowledge graphs and compiles them to executable MATLAB/SimBiology code while preserving units, mass balance, and physiological constraints. A two-phase workflow -- \textsc{Understanding} (graph reconstruction of legacy code) and \textsc{Action} (constraint-checked, language-driven modification) -- is orchestrated by a state machine with iterative validation. GRASP performs breadth-first parameter-alignment around new entities to surface dependent quantities and propose biologically plausible defaults, and it runs automatic execution/diagnostics until convergence. In head-to-head evaluations using LLM-as-judge, GRASP outperforms SME-guided CoT and ToT baselines across biological plausibility, mathematical correctness, structural fidelity, and code quality (\(\approx\)9--10/10 vs.\ 5--7/10). BFS alignment achieves F1 = 0.95 for dependency discovery, units, and range. These results demonstrate that graph-structured, agentic workflows can make QSP model development both accessible and rigorous, enabling domain experts to specify mechanisms in natural language without sacrificing biomedical fidelity.

Current evaluation of mathematical reasoning in language models relies primarily on answer accuracy, potentially masking fundamental failures in logical computation. We introduce a diagnostic framework that distinguishes genuine mathematical reasoning from superficial pattern matching through four complementary axes: forward-backward consistency, transitivity coverage, counterfactual sensitivity, and perturbation robustness. Through a case study applying this framework to Qwen3-0.6B on the MenatQA dataset, we reveal a striking disconnect between surface performance and reasoning fidelity--while the model achieves reasonable answer accuracy (70%+), it demonstrates poor backward consistency (15%), limited transitivity coverage (32.2%), and brittle sensitivity to perturbations. Our diagnostics expose reasoning failures invisible to traditional accuracy metrics, suggesting that this small model relies heavily on pattern matching rather than genuine logical computation. While our empirical findings are based on a single 600M-parameter model, the diagnostic framework itself is model-agnostic and generalizable. We release our evaluation protocols to enable the research community to assess reasoning fidelity across different model scales and architectures, moving beyond surface-level accuracy toward verifiable mathematical reasoning.

Counterfactual explanations enhance the actionable interpretability of machine learning models by identifying the minimal changes required to achieve a desired outcome of the model. However, existing methods often ignore the complex dependencies in real-world datasets, leading to unrealistic or impractical modifications. Motivated by cybersecurity applications in the email marketing domain, we propose a method for generating Diverse, Actionable, and kNowledge-Constrained Explanations (DANCE), which incorporates feature dependencies and causal constraints to ensure plausibility and real-world feasibility of counterfactuals. Our method learns linear and nonlinear constraints from data or integrates expert-provided dependency graphs, ensuring counterfactuals are plausible and actionable. By maintaining consistency with feature relationships, the method produces explanations that align with real-world constraints. Additionally, it balances plausibility, diversity, and sparsity, effectively addressing key limitations in existing algorithms. The work is developed based on a real-life case study with Freshmail, the largest email marketing company in Poland and supported by a joint R&D project Sendguard. Furthermore, we provide an extensive evaluation using 140 public datasets, which highlights its ability to generate meaningful, domain-relevant counterfactuals that outperform other existing approaches based on widely used metrics. The source code for reproduction of the results can be found in a GitHub repository we provide.

Unplanned extubation (UE)--the unintended removal of an airway tube--remains a critical patient safety concern in intensive care units (ICUs), often leading to severe complications or death. Real-time UE detection has been limited, largely due to the ethical and privacy challenges of obtaining annotated ICU video data. We propose Augmented Unplanned Removal Alert (AURA), a vision-based risk detection system developed and validated entirely on a fully synthetic video dataset. By leveraging text-to-video diffusion, we generated diverse and clinically realistic ICU scenarios capturing a range of patient behaviors and care contexts. The system applies pose estimation to identify two high-risk movement patterns: collision, defined as hand entry into spatial zones near airway tubes, and agitation, quantified by the velocity of tracked anatomical keypoints. Expert assessments confirmed the realism of the synthetic data, and performance evaluations showed high accuracy for collision detection and moderate performance for agitation recognition. This work demonstrates a novel pathway for developing privacy-preserving, reproducible patient safety monitoring systems with potential for deployment in intensive care settings.

Chung et al., 2015; Fraccaro et al., 2017) represent states Fraccaro; or Johnson et al., 2016), but currently only implemented for R2: Encoding functions: indeed, we chose fixed but random γ . Gradient descent would be a natural choice, albeit with debatable biological plausibility. If accepted, we will include these new experimental results. Line 92: Indeed, DDC activities encode a distribution or belief about a random variable - we will amend the text. This could follow "normal" learning rules; with the DDC again ensuring that uncertainty is handled correctly.

Figure 1: We depict five core desiderata for VQA models with associated metrics and objectives.