Joseph Loscalzo

Harto Saarinen, Mark Goldsmith, Rui-Sheng Wang et al.

Disease gene prioritization assigns scores to genes or proteins according to their likely relevance for a given disease based on a provided set of seed genes. Here, we describe a new algorithm for disease gene prioritization based on continuous-time quantum walks using the adjacency matrix of a protein-protein interaction (PPI) network. Our algorithm can be seen as a quantum version of a previous method known as the diffusion kernel, but, importantly, has higher performance in predicting disease genes, and also permits the encoding of seed node self-loops into the underlying Hamiltonian, which offers yet another boost in performance. We demonstrate the success of our proposed method by comparing it to several well-known gene prioritization methods on three disease sets, across seven different PPI networks. In order to compare these methods, we use cross-validation and examine the mean reciprocal ranks and recall values. We further validate our method by performing an enrichment analysis of the predicted genes for coronary artery disease. We also investigate the impact of adding self-loops to the seeds, and argue that they allow the quantum walker to remain more local to low-degree seed nodes.

Zhaohan Meng, Zhen Bai, Ke Yuan et al.

Protein-ligand modeling underpins computational drug discovery and molecular design. Existing protein-ligand benchmarks typically evaluate whether a protein and ligand interact and how strongly they bind, through tasks such as binary binding prediction and affinity regression. However, these evaluations provide limited evidence of whether models can localize binding sites or identify the non-covalent interactions underlying molecular recognition. To address this gap, we introduce InteractBind, a large-scale protein-ligand dataset comprising approximately 100k protein-ligand pairs, together with a benchmark for fine-grained evaluation. The core fine-grained task is that of binding-site localization, which uses protein-residue and ligand-atom interaction maps spanning six major types of non-covalent interactions to assess whether model-derived interaction maps localize binding sites. InteractBind further includes binding affinity and protein similarity-controlled splits to support realistic generalization assessment. Using InteractBind, we evaluate eight existing sequence-based and interaction-aware models, assessing binary binding prediction and binding-site localization. Results reveal limited binding-site localization despite strong binary binding prediction, with marked variation across non-covalent interaction types. Overall, InteractBind establishes a benchmark paradigm that encourages the development of more interpretable and physically grounded protein-ligand models.

Michelle M. Li, Ben Y. Reis, Adam Rodman et al.

Medical AI, including clinical language models, vision-language models, and multimodal health record models, already summarizes notes, answers questions, and supports decisions. Their adaptation to new populations, specialties, or care settings often relies on fine-tuning, prompting, or retrieval from external knowledge bases. These strategies can scale poorly and risk contextual errors: outputs that appear plausible but miss critical patient or situational information. We envision context switching as a solution. Context switching adjusts model reasoning at inference without retraining. Generative models can tailor outputs to patient biology, care setting, or disease. Multimodal models can reason on notes, laboratory results, imaging, and genomics, even when some data are missing or delayed. Agent models can coordinate tools and roles based on tasks and users. In each case, context switching enables medical AI to adapt across specialties, populations, and geographies. It requires advances in data design, model architectures, and evaluation frameworks, and establishes a foundation for medical AI that scales to infinitely many contexts while remaining reliable and suited to real-world care.

Deisy Morselli Gysi, Ítalo Do Valle, Marinka Zitnik et al.

The current pandemic has highlighted the need for methodologies that can quickly and reliably prioritize clinically approved compounds for their potential effectiveness for SARS-CoV-2 infections. In the past decade, network medicine has developed and validated multiple predictive algorithms for drug repurposing, exploiting the sub-cellular network-based relationship between a drug's targets and disease genes. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity, tasking each of them to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. To test the predictions, we used as ground truth 918 drugs that had been experimentally screened in VeroE6 cells, and the list of drugs under clinical trial, that capture the medical community's assessment of drugs with potential COVID-19 efficacy. We find that while most algorithms offer predictive power for these ground truth data, no single method offers consistently reliable outcomes across all datasets and metrics. This prompted us to develop a multimodal approach that fuses the predictions of all algorithms, showing that a consensus among the different predictive methods consistently exceeds the performance of the best individual pipelines. We find that 76 of the 77 drugs that successfully reduced viral infection do not bind the proteins targeted by SARS-CoV-2, indicating that these drugs rely on network-based actions that cannot be identified using docking-based strategies. These advances offer a methodological pathway to identify repurposable drugs for future pathogens and neglected diseases underserved by the costs and extended timeline of de novo drug development.