GPT-4 as a biomedical simulator.

BACKGROUND: Computational simulation of biological processes can be a valuable tool for accelerating biomedical research, but usually requires extensive domain knowledge and manual adaptation. Large language models (LLMs) such as GPT-4 have proven surprisingly successful for a wide range of tasks. This study provides proof-of-concept for the use of GPT-4 as a versatile simulator of biological systems. METHODS: We introduce SimulateGPT, a proof-of-concept for knowledge-driven simulation across levels of biological organization through structured prompting of GPT-4. We benchmarked our approach against direct GPT-4 inference in blinded qualitative evaluations by domain experts in four scenarios and in two quantitative scenarios with experimental ground truth. The qualitative scenarios included mouse experiments with known outcomes and treatment decision support in sepsis. The quantitative scenarios included prediction of gene essentiality in cancer cells and progression-free survival in cancer patients. RESULTS: In qualitative experiments, biomedical scientists rated SimulateGPT's predictions favorably over direct GPT-4 inference. In quantitative experiments, SimulateGPT substantially improved classification accuracy for predicting the essentiality of individual genes and increased correlation coefficients and precision in the regression task of predicting progression-free survival. CONCLUSION: This proof-of-concept study suggests that LLMs may enable a new class of biomedical simulators. Such text-based simulations appear well suited for modeling and understanding complex living systems that are difficult to describe with physics-based first-principles simulations, but for which extensive knowledge is available as written text. Finally, we propose several directions for further development of LLM-based biomedical simulators, including augmentation through web search retrieval, integrated mathematical modeling, and fine-tuning on experimental data.

SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer.

Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies also demonstrate a positive correlation between the expression levels of wild-type SF3B1 and tumor malignancy. Here, we demonstrate that SF3B1 is a hypoxia-inducible factor (HIF)-1 target gene that positively regulates HIF1 pathway activity. By physically interacting with HIF1α, SF3B1 facilitates binding of the HIF1 complex to hypoxia response elements (HREs) to activate target gene expression. To further validate the relevance of this mechanism for tumor progression, we show that a reduction in SF3B1 levels via monoallelic deletion of Sf3b1 impedes tumor formation and progression via impaired HIF signaling in a mouse model for pancreatic cancer. Our work uncovers an essential role of SF3B1 in HIF1 signaling, thereby providing a potential explanation for the link between high SF3B1 expression and aggressiveness of solid tumors.

AGO1 regulates pericentromeric regions in mouse embryonic stem cells.

Argonaute proteins (AGOs), which play an essential role in cytosolic post-transcriptional gene silencing, have been also reported to function in nuclear processes like transcriptional activation or repression, alternative splicing and, chromatin organization. As most of these studies have been conducted in human cancer cell lines, the relevance of AGOs nuclear functions in the context of mouse early embryonic development remains uninvestigated. Here, we examined a possible role of the AGO1 protein on the distribution of constitutive heterochromatin in mouse embryonic stem cells (mESCs). We observed a specific redistribution of the repressive histone mark H3K9me3 and the heterochromatin protein HP1α, away from pericentromeric regions upon Ago1 depletion. Furthermore, we demonstrated that major satellite transcripts are strongly up-regulated in Ago1_KO mESCs and that their levels are partially restored upon AGO1 rescue. We also observed a similar redistribution of H3K9me3 and HP1α in Drosha_KO mESCs, suggesting a role for microRNAs (miRNAs) in the regulation of heterochromatin distribution in mESCs. Finally, we showed that specific miRNAs with complementarity to major satellites can partially regulate the expression of these transcripts.

Lung-brain 'cross-talk': systemic propagation of cytokines in the ARDS via the bloodstream using a blood transfusion model does not influence cerebral inflammatory response in pigs.

Background: Interorgan cross-talk describes the phenomenon in which a primarily injured organ causes secondary damage to a distant organ. This cross-talk is well known between the lung and brain. One theory suggests that the release and systemic distribution of cytokines via the bloodstream from the primarily affected organ sets in motion proinflammatory cascades in distant organs. In this study, we analysed the role of the systemic distribution of cytokines via the bloodstream in a porcine ARDS model for organ cross-talk and possible inflammatory changes in the brain. Methods: After approval of the State and Institutional Animal Care Committee, acute respiratory distress syndrome (ARDS) induction with oleic acid injection was performed in seven animals. Eight hours after ARDS induction, blood (35-40 ml kg-1) was taken from these seven 'ARDS donor' pigs. The collected 'ARDS donor' blood was transfused into seven healthy 'ARDS-recipient' pigs. Three animals served as a control group, and blood from these animals was transfused into three healthy pigs after an appropriate ventilation period. All animals were monitored for 8 h using advanced cardiorespiratory monitoring. Postmortem assessment included cerebral (hippocampal and cortex) mediators of early inflammatory response (IL-6, TNF-alpha, iNOS, sLCN-2), wet-to-dry ratio and lung histology. TNF-alpha serum concentration was measured in all groups. Results: ARDS was successfully induced in the 'ARDS donor' group, and serum TNF-alpha levels were elevated compared with the 'ARDS-recipient' group. In the 'ARDS-recipient' group, neither significant ARDS alterations nor upregulation of inflammatory mediators in the brain tissue were detected after high-volume random allogenic 'ARDS-blood' transfusion. The role of the systemic distribution of inflammatory cytokines from one affected organ to another could not be confirmed in this study.