Towards Understanding Self-Pretraining for Sequence Classification

Amos et al. (2024) showed that the accuracy of Transformer models in sequence classification can be significantly improved by first pretraining with a masked token prediction objective without external data or augmentation, a procedure referred to as self-pretraining (SPT). While the primary objective of Amos et al. (2024) was to showcase that Transformers can achieve strong performance on the Long-Range Arena (LRA), their pipeline raises more fundamental questions: How does SPT drive optimization to better solutions? Why can standard supervised training fail in Transformers? To better understand this, we replicate and systematically ablate the findings of Amos et al. (2024). Our ablations suggest that a central bottleneck in the studied settings is not depth or generalization alone, but the ability of label supervision to learn useful query-key Attention patterns from random initialization. With a minimal setup, we identify learning proximity interactions - turning absolute positional encodings into proximity-biased Attention scores - as a key source of the improvements brought by SPT. Finally, in a simplified theoretical setup, we show that label supervision can be locally blind to certain Attention-score directions that are instead detectable through masked reconstruction.

ELISA: An Interpretable Hybrid Generative AI Agent for Expression-Grounded Discovery in Single-Cell Genomics

Translating single-cell RNA sequencing (scRNA-seq) data into mechanistic biological hypotheses remains a critical bottleneck, as agentic AI systems lack direct access to transcriptomic representations while expression foundation models remain opaque to natural language. Here we introduce ELISA (Embedding-Linked Interactive Single-cell Agent), an interpretable framework that unifies scGPT expression embeddings with BioBERT-based semantic retrieval and LLM-mediated interpretation for interactive single-cell discovery. An automatic query classifier routes inputs to gene marker scoring, semantic matching, or reciprocal rank fusion pipelines depending on whether the query is a gene signature, natural language concept, or mixture of both. Integrated analytical modules perform pathway activity scoringacross 60+ gene sets, ligand--receptor interaction prediction using 280+ curated pairs, condition-aware comparative analysis, and cell-type proportion estimation all operating directly on embedded data without access to the original count matrix. Benchmarked across six diverse scRNA-seq datasets spanning inflammatory lung disease, pediatric and adult cancers, organoid models, healthy tissue, and neurodevelopment, ELISA significantly outperforms CellWhisperer in cell type retrieval (combined permutation test, $p < 0.001$), with particularly large gains on gene-signature queries (Cohen's $d = 5.98$ for MRR). ELISA replicates published biological findings (mean composite score 0.90) with near-perfect pathway alignment and theme coverage (0.98 each), and generates candidate hypotheses through grounded LLM reasoning, bridging the gap between transcriptomic data exploration and biological discovery. Code available at: https://github.com/omaruno/ELISA-An-AI-Agent-for-Expression-Grounded-Discovery-in-Single-Cell-Genomics.git (If you use ELISA in your research, please cite this work).