Biology subjects

Adduri, A.

Publications and source records attributed to Adduri, A..

6 recordsLinked to original sources

bioRxiv2026

PIE: Generalizing perturbation effects across unseen perturbations, contexts and datasets

Predicting cellular response to perturbations is key to understanding biological mechanisms and selecting therapeutic targets. However, generalizing across cellular contexts, perturbations, and experimental datasets remains challenging due to incomplete representations of the system being perturbed and the difficulty of measuring true perturbation effects within that system. We introduce PIE, a model that addresses these limitations by reformulating the learning task around population level perturbation effects and incorporating auxiliary inputs that better characterize the biological system. PIE directly predicts differentially expressed genes and changes in gene expression for each (context, perturbation) pair, using external biological knowledge, baseline gene expression, and observed perturbation responses. Its architecture accommodates input sources with variable feature sets and predicts effects on genes seen and unseen during training. On the Replogle Nadig dataset, PIE achieves state of the art performance on most metrics across all tested generalization settings, including the most challenging setting where both the context and perturbation are unseen during training. For predicting differentially expressed genes, PIE achieves 1.2 to 3.2 times the AUPRC of the strongest baseline in each setting: across unseen contexts, perturbations, experimental datasets, and jointly unseen contexts and perturbations. Overall, PIE provides a framework for generalizing perturbation effects across diverse experimental conditions.

bioinformatics↗

bioRxiv2026

BioReason-Pro: Advancing Protein Function Prediction with Multimodal Biological Reasoning

Protein function annotation is fundamental to understanding biological mechanisms, designing therapeutics, and advancing biomedical research. Current computational methods either rely on shallow sequence similarity or treat function prediction as isolated classification tasks, failing to capture the integrative reasoning across sequence, structure, domains, and interactions that expert biologists perform to infer function. We introduce BioReason-Pro, the first multimodal reasoning large language model (LLM) for protein function prediction that integrates protein embeddings with biological context to generate structured reasoning traces. A key input into BioReason-Pro is the set of GO term predictions made by GO-GPT, our autoregressive transformer that captures hierarchical and cross-aspect dependencies of GO terms. BioReason-Pro is trained via supervised fine-tuning on synthetic reasoning traces generated by GPT-5 for over 130K proteins and further optimized through reinforcement learning. It achieves 73.6% Fmax on GO term prediction and an LLM judge score of 8/10 on functional summaries, substantially outperforming previous methods. Evaluations with human protein experts show that BioReason-Pro annotations are preferred over ground truth UniProt annotations in 79% of cases. Remarkably, BioReason-Pro predicted a novel interaction partner for the renal cancer biomarker RCDG1, which we confirmed in the lab by co-immunoprecipitation. In other binding-partner predictions, its per-residue attention localized to the exact contact residues resolved in cryo-EM structures. Together, GO-GPT and BioReason-Pro establish a framework for protein function prediction that combines precise ontology modeling with interpretable biological reasoning.

molecular biology↗

bioRxiv2026

Stack: In-Context Learning of Single-Cell Biology

Foundation models trained on single-cell transcriptomic data offer the promise of identifying and predicting the diversity of cellular phenotypes across species, diseases, and other biological conditions. However, the current models are limited to their supervised training conditions and tasks, which limits their utility for biological discovery. Here, we present SO_SCPLOWTACKC_SCPLOW, a foundation model trained on 149 million uniformly preprocessed human single cells that leverages tabular attention to generate representations for each cell informed by the cells in its context. SO_SCPLOWTACKC_SCPLOW offers substantial improvements for downstream tasks in the zero-shot setting compared to baselines, whether they are zero-shot, fine-tuned, or trained from scratch on the target dataset. SO_SCPLOWTACKC_SCPLOW can perform in-context learning from unlabeled cells representing arbitrary conditions, such as a chemical perturbation or a different donor, and predict the effect of those conditions on a target cell population without requiring data-specific fine-tuning. We apply SO_SCPLOWTACKC_SCPLOW to generate Perturb Sapiens, the first human whole-organism atlas of perturbed cells, spanning 28 tissues, 40 cell types, and 892 drug, cytokine, and genetic perturbations. We validated subsets of Perturb Sapiens using in vitro stimulation profiles. SO_SCPLOWTACKC_SCPLOW uniquely empowers prioritization of donor-specific perturbation effects, a capability we validated in our newly collected DiseasePert-3M data, comprising T cells from 40 donors across 14 diseases, stimulated with 11 cytokines. Overall, SO_SCPLOWTACKC_SCPLOW presents a new modeling framework where cells themselves act as guiding examples at inference time, unlocking general-purpose in-context learning capabilities for single-cell biology.

bioinformatics↗

bioRxiv2025

Predicting cellular responses to perturbation across diverse contexts with STATE

Cellular responses to perturbations are a cornerstone for understanding biological mechanisms and selecting drug targets. While machine learning models offer tremendous potential for predicting perturbation effects, they currently struggle to generalize to unobserved cellular contexts. Here, we introduce SO_SCPLOWTATEC_SCPLOW, a transformer model that predicts perturbation effects while accounting for cellular heterogeneity within and across experiments. SO_SCPLOWTATEC_SCPLOW predicts perturbation effects across sets of cells and is trained using gene expression data from over 100 million perturbed cells. SO_SCPLOWTATEC_SCPLOW improved discrimination of effects on large datasets by more than 30% and identified differentially expressed genes across genetic, signaling and chemical perturbations with significantly improved accuracy. Using its cell embedding trained on observational data from 167 million cells, SO_SCPLOWTATEC_SCPLOW identified strong perturbations in novel cellular contexts where no perturbations were observed during training. We further introduce Cell-Eval, a comprehensive evaluation framework that highlights SO_SCPLOWTATEC_SCPLOWs ability to detect cell type-specific perturbation responses, such as cell survival. Overall, the performance and flexibility of SO_SCPLOWTATEC_SCPLOW sets the stage for scaling the development of virtual cell models.

systems biology↗

bioRxiv2025

Interpretable adenylation domain specificity prediction using protein language models

Natural products have long been a rich source of diverse and clinically effective drug candidates. Non-ribosomal peptides (NRPs), polyketides (PKs), and NRP-PK hybrids are three classes of natural products that display a broad range of bioactivities, including antibiotic, antifungal, anticancer, and immunosuppressant activities. However, discovering these compounds through traditional bioactivity-guided techniques is costly and time-consuming, often resulting in the rediscovery of known molecules. Consequently, genome mining has emerged as a high-throughput strategy to screen hundreds of thousands of microbial genomes to identify their potential to produce novel natural products. Adenylation domains play a key role in the biosynthesis of NRPs and NRP-PKs by recruiting substrates to incrementally build the final structure. We propose MASPR, a machine learning method that leverages protein language models for accurate and interpretable predictions of A-domain substrate specificities. MASPR demonstrates superior accuracy and generalization over existing methods and is capable of predicting substrates not present in its training data, or zero-shot classification. We use MASPR to develop Seq2Hybrid, an efficient algorithm to predict the structure of hybrid NRP-PK natural products from microbial genomes. Using Seq2Hybrid, we propose putative biosynthetic gene clusters for the orphan natural products Octaminomycin A, Dityromycin, SW-163B, and JBIR-39.

bioinformatics↗

bioRxiv2023

Ornaments for Accurate and Efficient Allele-Specific Expression Estimation with Bias Correction

Allele-specific expression has been used to elucidate various biological mechanisms, such as genomic imprinting and gene expression variation caused by genetic changes in cis-regulatory elements. However, existing methods for obtaining allele-specific expression from RNA-seq reads do not adequately and efficiently remove various biases, such as reference bias, where reads containing the alternative allele do not map to the reference transcriptome, or ambiguous mapping bias, where reads containing the reference allele map differently from reads containing the alternative allele. We present Ornaments, a computational tool for rapid and accurate estimation of allele-specific expression at unphased heterozygous loci from RNA-seq reads while correcting for allele-specific read mapping bias. Ornaments removes reference bias by accounting for personalized transcriptome, and ambiguous mapping bias by probabilistically assigning reads to multiple transcripts and variant loci they map to. Ornaments is a lightweight extension of kallisto, a popular tool for fast RNA-seq quantification, that improves the efficiency and accuracy of WASP, a popular tool for bias correction in allele-specific read mapping. Our experiments on simulated and human lymphoblastoid cell-line RNA-seq reads with the genomes of the 1000 Genomes Project show that Ornaments is as efficient as kallisto, an order of magnitude faster than WASP, and more accurate than WASP and kallisto. In addition, Ornaments detected genes that are imprinted at transcript level with higher sensitivity, compared to WASP that detected the imprinted signals only at gene level.

genetics↗