RESUMEN
Radiation exposure poses a significant threat to human health. Emerging research indicates that even low-dose radiation once believed to be safe, may have harmful effects. This perception has spurred a growing interest in investigating the potential risks associated with low-dose radiation exposure across various scenarios. To comprehensively explore the health consequences of low-dose radiation, our study employs a robust statistical framework that examines whether specific groups of genes, belonging to known pathways, exhibit coordinated expression patterns that align with the radiation levels. Notably, our findings reveal the existence of intricate yet consistent signatures that reflect the molecular response to radiation exposure, distinguishing between low-dose and high-dose radiation. Moreover, we leverage a pathway-constrained variational autoencoder to capture the nonlinear interactions within gene expression data. By comparing these two analytical approaches, our study aims to gain valuable insights into the impact of low-dose radiation on gene expression patterns, identify pathways that are differentially affected, and harness the potential of machine learning to uncover hidden activity within biological networks. This comparative analysis contributes to a deeper understanding of the molecular consequences of low-dose radiation exposure.
RESUMEN
Heterogeneous response to Enzalutamide, a second-generation androgen receptor signaling inhibitor, is a central problem in castration-resistant prostate cancer (CRPC) management. Genome-wide systems investigation of mechanisms that govern Enzalutamide resistance promise to elucidate markers of heterogeneous treatment response and salvage therapies for CRPC patients. Focusing on the de novo role of MYC as a marker of Enzalutamide resistance, here we reconstruct a CRPC-specific mechanism-centric regulatory network, connecting molecular pathways with their upstream transcriptional regulatory programs. Mining this network with signatures of Enzalutamide response identifies NME2 as an upstream regulatory partner of MYC in CRPC and demonstrates that NME2-MYC increased activities can predict patients at risk of resistance to Enzalutamide, independent of co-variates. Furthermore, our experimental investigations demonstrate that targeting MYC and its partner NME2 is beneficial in Enzalutamide-resistant conditions and could provide an effective strategy for patients at risk of Enzalutamide resistance and/or for patients who failed Enzalutamide treatment.
Asunto(s)
Resistencia a Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Antagonistas de Receptores Androgénicos , Benzamidas , Nucleósido Difosfato Quinasas NM23 , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Transducción de SeñalRESUMEN
We develop a generalizable AI-driven workflow that leverages heterogeneous HPC resources to explore the time-dependent dynamics of molecular systems. We use this workflow to investigate the mechanisms of infectivity of the SARS-CoV-2 spike protein, the main viral infection machinery. Our workflow enables more efficient investigation of spike dynamics in a variety of complex environments, including within a complete SARS-CoV-2 viral envelope simulation, which contains 305 million atoms and shows strong scaling on ORNL Summit using NAMD. We present several novel scientific discoveries, including the elucidation of the spike's full glycan shield, the role of spike glycans in modulating the infectivity of the virus, and the characterization of the flexible interactions between the spike and the human ACE2 receptor. We also demonstrate how AI can accelerate conformational sampling across different systems and pave the way for the future application of such methods to additional studies in SARS-CoV-2 and other molecular systems.