Iñaki Arango

Joaquín Polonuer, Lucas Vittor, Iñaki Arango et al.

Retrieving evidence for language model queries from knowledge graphs requires balancing broad search across the graph with multi-hop traversal to follow relational links. Similarity-based retrievers provide coverage but remain shallow, whereas traversal-based methods rely on selecting seed nodes to start exploration, which can fail when queries span multiple entities and relations. We introduce ARK: Adaptive Retriever of Knowledge, an agentic KG retriever that gives a language model control over this breadth-depth tradeoff using a two-operation toolset: global lexical search over node descriptors and one-hop neighborhood exploration that composes into multi-hop traversal. ARK alternates between breadth-oriented discovery and depth-oriented expansion without depending on a fragile seed selection, a pre-set hop depth, or requiring retrieval training. ARK adapts tool use to queries, using global search for language-heavy queries and neighborhood exploration for relation-heavy queries. On STaRK, ARK reaches 59.1% average Hit@1 and 67.4 average MRR, improving average Hit@1 by up to 31.4% and average MRR by up to 28.0% over retrieval-based and agentic training-free methods. Finally, we distill ARK's tool-use trajectories from a large teacher into an 8B model via label-free imitation, improving Hit@1 by +7.0, +26.6, and +13.5 absolute points over the base 8B model on AMAZON, MAG, and PRIME datasets, respectively, while retaining up to 98.5% of the teacher's Hit@1 rate.

Lucas Vittor, Ayush Noori, Iñaki Arango et al.

Biomedical knowledge graphs (KGs) are widely used in the life sciences, yet many are derived from unstructured documents and therefore lack schema-level constrains, whereas graphs assembled from structured resources are difficult to harmonize into a unified representation. We present OptimusKG, a multimodal biomedical labeled property graph (LPG) built from structured and semi-structured resources to preserve factual, type-specific metadata across molecular, anatomical, clinical, and environmental domains. OptimusKG contains 190,531 nodes across 10 entity types, 21,813,816 edges across 26 relation types, and 67,249,863 property instances encoding 110,276,843 values across 150 distinct property keys, derived from 18 ontologies and controlled vocabularies. The graph enforces a top-level schema for nodes and edges and retains granular, type-specific properties, cross-references, and provenance across molecular, anatomical, clinical, and environmental domains. We assessed the validity of OptimusKG by evaluating whether graph relationships are supported by evidence from the scientific literature using a multimodal agent, PaperQA3. PaperQA3 identified supporting evidence for 70.0% of sampled edges, whereas 83.4% of sampled false edges received no supporting evidence. Edges without literature support were concentrated in associations derived from experimental and functional genomics resources, suggesting that OptimusKG captures biomedical knowledge that may precede synthesis in the scientific literature. OptimusKG is distributed as Apache Parquet files, providing a standardized resource for graph-based machine learning, knowledge-grounded retrieval with large language models, and biomedical discovery use cases such as hypothesis generation.

Ayush Noori, Joaquín Polonuer, Katharina Meyer et al.

Neurological diseases are the leading global cause of disability, yet most lack disease-modifying treatments. We present PROTON, a heterogeneous graph transformer that generates testable hypotheses across molecular, organoid, and clinical systems. To evaluate PROTON, we apply it to Parkinson's disease (PD), bipolar disorder (BD), and Alzheimer's disease (AD). In PD, PROTON linked genetic risk loci to genes essential for dopaminergic neuron survival and predicted pesticides toxic to patient-derived neurons, including the insecticide endosulfan, which ranked within the top 1.29% of predictions. In silico screens performed by PROTON reproduced six genome-wide $α$-synuclein experiments, including a split-ubiquitin yeast two-hybrid system (normalized enrichment score [NES] = 2.30, FDR-adjusted $p < 1 \times 10^{-4}$), an ascorbate peroxidase proximity labeling assay (NES = 2.16, FDR $< 1 \times 10^{-4}$), and a high-depth targeted exome sequencing study in 496 synucleinopathy patients (NES = 2.13, FDR $< 1 \times 10^{-4}$). In BD, PROTON predicted calcitriol as a candidate drug that reversed proteomic alterations observed in cortical organoids derived from BD patients. In AD, we evaluated PROTON predictions in health records from $n = 610,524$ patients at Mass General Brigham, confirming that five PROTON-predicted drugs were associated with reduced seven-year dementia risk (minimum hazard ratio = 0.63, 95% CI: 0.53-0.75, $p < 1 \times 10^{-7}$). PROTON generated neurological hypotheses that were evaluated across molecular, organoid, and clinical systems, defining a path for AI-driven discovery in neurological disease.

Xilin Dang, Kexin Chen, Xiaorui Su et al.

In clinical practice, physicians refrain from making decisions when patient information is insufficient. This behavior, known as abstention, is a critical safety mechanism preventing potentially harmful misdiagnoses. Recent investigations have reported the application of large language models (LLMs) in medical scenarios. However, existing LLMs struggle with the abstentions, frequently providing overconfident responses despite incomplete information. This limitation stems from conventional abstention methods relying solely on model self-assessments, which lack systematic strategies to identify knowledge boundaries with external medical evidences. To address this, we propose \textbf{KnowGuard}, a novel \textit{investigate-before-abstain} paradigm that integrates systematic knowledge graph exploration for clinical decision-making. Our approach consists of two key stages operating on a shared contextualized evidence pool: 1) an evidence discovery stage that systematically explores the medical knowledge space through graph expansion and direct retrieval, and 2) an evidence evaluation stage that ranks evidence using multiple factors to adapt exploration based on patient context and conversation history. This two-stage approach enables systematic knowledge graph exploration, allowing models to trace structured reasoning paths and recognize insufficient medical evidence. We evaluate our abstention approach using open-ended multi-round clinical benchmarks that mimic realistic diagnostic scenarios, assessing abstention quality through accuracy-efficiency trade-offs beyond existing closed-form evaluations. Experimental evidences clearly demonstrate that KnowGuard outperforms state-of-the-art abstention approaches, improving diagnostic accuracy by 3.93\% while reducing unnecessary interaction by 7.27 turns on average.

Ayush Noori, Iñaki Arango, William E. Byrd et al.

The strict selectivity of the blood-brain barrier (BBB) represents one of the most formidable challenges to successful central nervous system (CNS) drug delivery. Computational methods to generate BBB permeable drugs in silico may be valuable tools in the CNS drug design pipeline. However, in real-world applications, BBB penetration alone is insufficient; rather, after transiting the BBB, molecules must bind to a specific target or receptor in the brain and must also be safe and non-toxic. To discover small molecules that concurrently satisfy these constraints, we use multi-objective generative AI to synthesize drug-like BBB-permeable small molecules. Specifically, we computationally synthesize molecules with predicted binding affinity against dopamine receptor D2, the primary target for many clinically effective antipsychotic drugs. After training several graph neural network-based property predictors, we adapt SyntheMol (Swanson et al., 2024), a recently developed Monte Carlo Tree Search-based algorithm for antibiotic design, to perform a multi-objective guided traversal over an easily synthesizable molecular space. We design a library of 26,581 novel and diverse small molecules containing hits with high predicted BBB permeability and favorable predicted safety and toxicity profiles, and that could readily be synthesized for experimental validation in the wet lab. We also validate top scoring molecules with molecular docking simulation against the D2 receptor and demonstrate predicted binding affinity on par with risperidone, a clinically prescribed D2-targeting antipsychotic. In the future, the SyntheMol-based computational approach described here may enable the discovery of novel neurotherapeutics for currently intractable disorders of the CNS.