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Abstract Analysis of single-cell datasets generated from diverse organisms offers unprecedented opportunities to unravel fundamental evolutionary processes of conservation and diversification of cell types. However, interspecies genomic differences limit the joint analysis of cross-species datasets to homologous genes. Here we present SATURN, a deep learning method for learning universal cell embeddings that encodes genes’ biological properties using protein language models. By coupling protein embeddings from language models with RNA expression, SATURN integrates datasets profiled from different species regardless of their genomic similarity. SATURN can detect functionally related genes coexpressed across species, redefining differential expression for cross-species analysis. Applying SATURN to three species whole-organism atlases and frog and zebrafish embryogenesis datasets, we show that SATURN can effectively transfer annotations across species, even when they are evolutionarily remote. We also demonstrate that SATURN can be used to find potentially divergent gene functions between glaucoma-associated genes in humans and four other species. 

Abstract Understanding cellular responses to genetic perturbation is central to numerous biomedical applications, from identifying genetic interactions involved in cancer to developing methods for regenerative medicine. However, the combinatorial explosion in the number of possible multigene perturbations severely limits experimental interrogation. Here, we present graph-enhanced gene activation and repression simulator (GEARS), a method that integrates deep learning with a knowledge graph of gene–gene relationships to predict transcriptional responses to both single and multigene perturbations using single-cell RNA-sequencing data from perturbational screens. GEARS is able to predict outcomes of perturbing combinations consisting of genes that were never experimentally perturbed. GEARS exhibited 40% higher precision than existing approaches in predicting four distinct genetic interaction subtypes in a combinatorial perturbation screen and identified the strongest interactions twice as well as prior approaches. Overall, GEARS can predict phenotypically distinct effects of multigene perturbations and thus guide the design of perturbational experiments. 

Abstract A long-standing expectation is that large, dense and cosmopolitan areas support socioeconomic mixing and exposure among diverse individuals^1–6. Assessing this hypothesis has been difficult because previous measures of socioeconomic mixing have relied on static residential housing data rather than real-life exposures among people at work, in places of leisure and in home neighbourhoods^7,8. Here we develop a measure of exposure segregation that captures the socioeconomic diversity of these everyday encounters. Using mobile phone mobility data to represent 1.6 billion real-world exposures among 9.6 million people in the United States, we measure exposure segregation across 382 metropolitan statistical areas (MSAs) and 2,829 counties. We find that exposure segregation is 67% higher in the ten largest MSAs than in small MSAs with fewer than 100,000 residents. This means that, contrary to expectations, residents of large cosmopolitan areas have less exposure to a socioeconomically diverse range of individuals. Second, we find that the increased socioeconomic segregation in large cities arises because they offer a greater choice of differentiated spaces targeted to specific socioeconomic groups. Third, we find that this segregation-increasing effect is countered when a city’s hubs (such as shopping centres) are positioned to bridge diverse neighbourhoods and therefore attract people of all socioeconomic statuses. Our findings challenge a long-standing conjecture in human geography and highlight how urban design can both prevent and facilitate encounters among diverse individuals. 

Predictive tasks on relational databases are critical in real-world applications spanning e-commerce, healthcare, and social media. To address these tasks effectively, Relational Deep Learning (RDL) encodes relational data as graphs, enabling Graph Neural Networks (GNNs) to exploit relational structures for improved predictions. However, existing RDL methods often overlook the intrinsic structural properties of the graphs built from relational databases, leading to modeling inefficiencies, particularly in handling many-tomany relationships. Here we introduce RELGNN, a novel GNN framework specifically designed to leverage the unique structural characteristics of the graphs built from relational databases. At the core of our approach is the introduction of atomic routes, which are simple paths that enable direct single-hop interactions between the source and destination nodes. Building upon these atomic routes, RELGNN designs new composite message passing and graph attention mechanisms that reduce redundancy, highlight key signals, and enhance predictive accuracy. RELGNN is evaluated on 30 diverse real-world tasks from RELBENCH (Fey et al., 2024), and achieves state-of-the-art performance on the vast majority of tasks, with improvements of up to 25%. 

Large Language Models are typically trained with next-turn rewards, limiting their ability to optimize for long-term interaction. As a result, they often respond passively to ambiguous or open-ended user requests, failing to help users reach their ultimate intents and leading to inefficient conversations. To address these limitations, we introduce COLLABLLM, a novel and general training framework that enhances multiturn human-LLM collaboration. Its key innovation is a collaborative simulation that estimates the long-term contribution of responses using Multiturn-aware Rewards. By reinforcement fine-tuning these rewards, COLLABLLM goes beyond responding to user requests, and actively uncovers user intent and offers insightful suggestions—a key step towards more humancentered AI. We also devise a multiturn interaction benchmark with three challenging tasks such as document creation. COLLABLLM significantly outperforms our baselines with averages of 18.5% higher task performance and 46.3% improved interactivity by LLM judges. Finally, we conduct a large user study with 201 judges, where COLLABLLM increases user satisfaction by 17.6% and reduces user spent time by 10.4%. 

Generating social networks is essential for many applications, such as epidemic modeling and social simulations. The emergence of generative AI, especially large language models (LLMs), offers new possibilities for social network generation: LLMs can generate networks without additional training or need to define network parameters, and users can flexibly define individuals in the network using natural language. However, this potential raises two critical questions: 1) are the social networks generated by LLMs realistic, and 2) what are risks of bias, given the importance of demographics in forming social ties? To answer these questions, we develop three prompting methods for network generation and compare the generated networks to a suite of real social networks. We find that more realistic networks are generated with “local” methods, where the LLM constructs relations for one persona at a time, compared to “global” methods that construct the entire network at once. We also find that the generated networks match real networks on many characteristics, including density, clustering, connectivity, and degree distribution. However, we find that LLMs emphasize political homophily over all other types of homophily and significantly overestimate political homophily compared to real social networks.